Array ( [0] => {{short description|Miniaturized and simplified version of an organ}} [1] => {{For|Organoids appearing in an anime series|Zoids#Organoids}} [2] => [[File:Intestinal organoid.PNG|thumb|Intestinal organoid grown from Lgr5+ stem cells]] [3] => [4] => An '''organoid''' is a miniaturised and simplified version of an [[Organ (anatomy)|organ]] produced [[in vitro]] in three dimensions that mimics the key functional, structural, and biological complexity of that organ.Zhao Z, Chen X, Dowbaj AM, Sljukic A, Bratlie K, Lin L, Fong ELS, Balachander GM, Chen Z, Soragni A, Huch M, Zeng YA, Wang Q, Yu H. Organoids. Nature Reviews Methods Primers 2, 94 (2022). https://doi.org/10.1038/s43586-022-00174-y It is derived from one or a few [[Cell (biology)|cells]] from a [[Tissue (biology)|tissue]], [[embryonic stem cell]]s, or [[induced pluripotent stem cell]]s, which can [[Self-organization|self-organize]] in three-dimensional culture owing to their [[Stem cell|self-renewal]] and [[Cellular differentiation|differentiation]] capacities. The technique for growing organoids has rapidly improved since the early 2010s, and ''[[The Scientist (magazine)|The Scientist]]'' named it one of the biggest scientific advancements of 2013.{{cite web |last=Grens |first=Kerry | name-list-style = vanc |title=2013's Big Advances in Science |url=http://www.the-scientist.com/?articles.view/articleNo/38747/title/2013-s-Big-Advances-in-Science/ |website=[[The Scientist (magazine)|The Scientist]] |access-date=26 December 2013 |date=December 24, 2013}} Scientists and engineers use organoids to study development and disease in the [[laboratory]], for drug discovery, development in industry,Hans Clevers, Asher Mullard. Mini-organs attract big pharma. Nature Reviews Drug Discovery (16 February 2023). https://doi.org/10.1038/d41573-023-00030-y personalized diagnostics and medicine, gene and cell therapies, tissue engineering, and regenerative medicine. [5] => [6] => == History == [7] => Attempts to create [[organ (biology)|organ]]s ''[[in vitro]]'' started with one of the first dissociation-reaggregation experiments{{cite journal | vauthors = Lancaster MA, Knoblich JA | title = Organogenesis in a dish: modeling development and disease using organoid technologies | journal = Science | volume = 345 | issue = 6194 | pages = 1247125 | date = July 2014 | pmid = 25035496 | doi = 10.1126/science.1247125 | s2cid = 16105729 }} where [[Henry Van Peters Wilson]] demonstrated that mechanically dissociated sponge cells can reaggregate and self-organize to generate a whole organism.{{cite journal | vauthors = Wilson HV | title = A new method by which sponges may be artificially reared | journal = Science | volume = 25 | issue = 649 | pages = 912–5 | date = June 1907 | pmid = 17842577 | doi = 10.1126/science.25.649.912 | bibcode = 1907Sci....25..912W | url = https://zenodo.org/record/1447988 }} In the subsequent decades, multiple labs were able to generate different types of organs ''in vitro'' through the dissociation and reaggregation of organ tissues obtained from amphibians{{cite journal | vauthors = Holtfreter J | title = Experimental studies on the development of the pronephros. | journal = Rev. Can. Biol. | volume = 3 | pages = 220–250 | date = 1944 }} and embryonic chicks.{{cite journal | vauthors = Weiss P, Taylor AC | title = Reconstitution of complete organs from single-cell suspensions of chick embryos in advanced stages of differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 46 | issue = 9 | pages = 1177–85 | date = September 1960 | pmid = 16590731 | pmc = 223021 | doi = 10.1073/pnas.46.9.1177 | bibcode = 1960PNAS...46.1177W | doi-access = free }} The formation of first tissue-like colonies ''in vitro'' was observed for the first time by co-culturing [[Keratinocyte|keratinocytes]] and 3T3 fibroblasts.{{Cite journal |last1=Rheinwald |first1=James G. |last2=Green |first2=Howard |date=November 1975 |title=Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma |url=|journal=Cell |volume=6 |issue=3 |pages=317–330 |doi=10.1016/0092-8674(75)90183-x |pmid=1052770 |s2cid=28185779 |issn=0092-8674}} The phenomena of mechanically dissociated cells aggregating and reorganizing to reform the tissue they were obtained from subsequently led to the development of the [[differential adhesion hypothesis]] by [[Malcolm Steinberg]]. With the advent of the field of [[stem cell]] biology, the potential of stem cells to form organs ''in vitro'' was realized early on with the observation that when stem cells form [[teratoma]]s or [[embryoid body|embryoid bodies]], the [[Cellular differentiation|differentiated cells]] can organize into different structures resembling those found in multiple [[Tissue (biology)|tissue]] types. The advent of the field of organoids, started with a shift from culturing and differentiating stem cells in two dimensional (2D) media, to three dimensional (3D) media to allow for the development of the complex 3-dimensional structures of organs. Utilization of 3D media culture media methods for the structural organization was made possible with the development of [[Extracellular matrix|extracellular matrices]] (ECM).{{Cite journal |last1=Yi |first1=Sang Ah |last2=Zhang |first2=Yixiao |last3=Rathnam |first3=Christopher |last4=Pongkulapa |first4=Thanapat |last5=Lee |first5=Ki-Bum |date=November 2021 |title=Bioengineering Approaches for the Advanced Organoid Research |journal=Advanced Materials |language=en |volume=33 |issue=45 |pages=e2007949 |doi=10.1002/adma.202007949 |pmid=34561899 |pmc=8682947 |bibcode=2021AdM....3307949Y |issn=0935-9648}} In the late 1980s, [[Mina Bissell|Bissell]] and colleagues showed that a laminin rich gel can be used as a basement membrane for differentiation and morphogenesis in cell cultures of mammary epithelial cells.{{Cite journal |last1=Li |first1=M L |last2=Aggeler |first2=J |last3=Farson |first3=D A |last4=Hatier |first4=C |last5=Hassell |first5=J |last6=Bissell |first6=M J |date=January 1987 |title=Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells. |journal=Proceedings of the National Academy of Sciences |volume=84 |issue=1 |pages=136–140 |doi=10.1073/pnas.84.1.136 |doi-access=free |pmid=3467345 |bibcode=1987PNAS...84..136L |issn=0027-8424|pmc=304157 }}{{Cite journal |last1=Barcellos-Hoff |first1=M. H. |last2=Aggeler |first2=J. |last3=Ram |first3=T. G. |last4=Bissell |first4=M. J. |date=1989-02-01 |title=Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane |url=|journal=Development |volume=105 |issue=2 |pages=223–235 |doi=10.1242/dev.105.2.223 |pmid=2806122 |pmc=2948482 |issn=0950-1991}} Since 1987, researchers have devised different methods for 3D culturing, and were able to utilize different types of stem cells to generate organoids resembling a multitude of organs. In the 1990s, in addition to their role in physical support, the role of ECM components in gene expression by their interaction with integrin-based focal adhesion pathways was reported.{{Cite journal |last1=Streuli |first1=C H |last2=Schmidhauser |first2=C |last3=Bailey |first3=N |last4=Yurchenco |first4=P |last5=Skubitz |first5=A P |last6=Roskelley |first6=C |last7=Bissell |first7=M J |date=1995-05-01 |title=Laminin mediates tissue-specific gene expression in mammary epithelia. |url=|journal=The Journal of Cell Biology |volume=129 |issue=3 |pages=591–603 |doi=10.1083/jcb.129.3.591 |pmid=7730398 |pmc=2120432 |issn=0021-9525}} In 2006, [[Yaakov Nahmias]] and David Odde showed the self-assembly of vascular [[liver]] organoid maintained for over 50 days ''in vitro''.{{cite journal | vauthors = Nahmias Y, Schwartz RE, Hu WS, Verfaillie CM, Odde DJ | title = Endothelium-mediated hepatocyte recruitment in the establishment of liver-like tissue in vitro | journal = Tissue Engineering | volume = 12 | issue = 6 | pages = 1627–38 | date = June 2006 | pmid = 16846358 | doi = 10.1089/ten.2006.12.1627 }} In 2008, [[Yoshiki Sasai]] and his team at [[RIKEN]] institute demonstrated that [[stem cells]] can be coaxed into balls of [[Neuron|neural]] cells that self-organize into distinctive layers.{{cite web |last=Yong |first=Ed | name-list-style = vanc |author-link=Ed Yong |title=Lab-Grown Model Brains |url=http://www.the-scientist.com/?articles.view/articleNo/37262/title/Lab-Grown-Model-Brains/ |website=[[The Scientist (magazine)|The Scientist]] |access-date=26 December 2013 |date=August 28, 2013}} In 2009 the Laboratory of [[Hans Clevers]] at [[Hubrecht Institute]] and [[UMC Utrecht|University Medical Center Utrecht]], Netherlands, showed that single [[LGR5]]-expressing intestinal stem cells self-organize to crypt-villus structures ''in vitro'' without necessity of a [[mesenchymal]] niche, making them the first organoids.{{cite journal | vauthors = Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H | display-authors = 6 | title = Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche | journal = Nature | volume = 459 | issue = 7244 | pages = 262–5 | date = May 2009 | pmid = 19329995 | doi = 10.1038/nature07935 | bibcode = 2009Natur.459..262S | s2cid = 4373784 | author-link10 = Peter J. Peters }} In 2010, Mathieu Unbekandt & [[Jamie A. Davies]] demonstrated the production of renal organoids from murine fetus-derived renogenic stem cells.{{cite journal | vauthors = Unbekandt M, Davies JA | title = Dissociation of embryonic kidneys followed by reaggregation allows the formation of renal tissues | journal = Kidney International | volume = 77 | issue = 5 | pages = 407–16 | date = March 2010 | pmid = 20016472 | doi = 10.1038/ki.2009.482 | doi-access = free }} In 2014, Qun Wang and co-workers engineered collagen-I and laminin based gels and synthetic foam biomaterials for the culture and delivery of intestinal organoidsPeng H, Poovaiah N, Forrester M, Cochran E, Wang Q. Ex Vivo Culture of Primary Intestinal Stem Cells in Collagen Gels and Foams. ACS Biomaterials Science & Engineering. 2014 Dec 2;1(1):37–42. https://doi.org/10.1021/ab500041d. PMID: 33435081. and encapsulated DNA-functionalized gold nanoparticles into intestinal organoids to form an intestinal Trojan horse for drug delivery and gene therapy.Peng H, Wang C, Xu X, Yu C, Wang Q. An intestinal Trojan horse for gene delivery. Nanoscale. 2015 Jan 6;7(10):4354–4360. https://doi.org/10.1039/C4NR06377E. PMID: 25619169. Subsequent reports showed significant physiological function of these organoids ''in vitro''{{cite journal | vauthors = Lawrence ML, Chang CH, Davies JA | title = Transport of organic anions and cations in murine embryonic kidney development and in serially-reaggregated engineered kidneys | journal = Scientific Reports | volume = 5 | pages = 9092 | date = March 2015 | pmid = 25766625 | pmc = 4357899 | doi = 10.1038/srep09092 | bibcode = 2015NatSR...5E9092L }} and ''[[in vivo]]''.{{cite journal | vauthors = Xinaris C, Benedetti V, Rizzo P, Abbate M, Corna D, Azzollini N, Conti S, Unbekandt M, Davies JA, Morigi M, Benigni A, Remuzzi G | display-authors = 6 | title = In vivo maturation of functional renal organoids formed from embryonic cell suspensions | journal = Journal of the American Society of Nephrology | volume = 23 | issue = 11 | pages = 1857–68 | date = November 2012 | pmid = 23085631 | pmc = 3482737 | doi = 10.1681/ASN.2012050505 }}Yui, S., Nakamura, T., Sato, T. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nature Medicine 18, 618–623 (2012). https://doi.org/10.1038/nm.2695 [8] => [9] => Other significant early advancements included in 2013, [[Madeline Lancaster]] at the [[Institute of Molecular Biotechnology]] of the [[Austrian Academy of Sciences]] established a protocol starting from pluripotent stem cells to generate [[cerebral organoid]]s that mimic the developing human brain's cellular organization.{{cite journal | vauthors = Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA | display-authors = 6 | title = Cerebral organoids model human brain development and microcephaly | journal = Nature | volume = 501 | issue = 7467 | pages = 373–9 | date = September 2013 | pmid = 23995685 | pmc = 3817409 | doi = 10.1038/nature12517 | bibcode = 2013Natur.501..373L }} [[Meritxell Huch]] and Craig Dorrell at [[Hubrecht Institute]] and [[UMC Utrecht|University Medical Center Utrecht]] demonstrated that single Lgr5+ cells from damaged mouse liver can be clonally expanded as liver organoids in Rspo1-based culture medium over several months.Huch, M., Dorrell, C., Boj, S. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013). https://doi.org/10.1038/nature11826 In 2014, Artem Shkumatov et al. at the University of Illinois at Urbana-Champaign demonstrated that cardiovascular organoids can be formed from [[Embryonic stem cell|ES cells]] through modulation of the substrate stiffness, to which they adhere. Physiological stiffness promoted three-dimensionality of EBs and cardiomyogenic differentiation.{{cite journal | vauthors = Shkumatov A, Baek K, Kong H | title = Matrix rigidity-modulated cardiovascular organoid formation from embryoid bodies | journal = PLOS ONE | volume = 9 | issue = 4 | pages = e94764 | year = 2014 | pmid = 24732893 | pmc = 3986240 | doi = 10.1371/journal.pone.0094764 | bibcode = 2014PLoSO...994764S | doi-access = free }} In 2015, Takebe et al. demonstrated a generalized method for organ bud formation from diverse tissues by combining pluripotent stem cell-derived tissue-specific progenitors or relevant tissue samples with endothelial cells and mesenchymal stem cells. They suggested that the less mature tissues, or organ buds, generated through the self-organized condensation principle might be the most efficient approach toward the reconstitution of mature organ functions after transplantation, rather than condensates generated from cells of a more advanced stage.{{cite journal | vauthors = Takebe T, Enomura M, Yoshizawa E, Kimura M, Koike H, Ueno Y, Matsuzaki T, Yamazaki T, Toyohara T, Osafune K, Nakauchi H, Yoshikawa HY, Taniguchi H | display-authors = 6 | title = Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation | journal = Cell Stem Cell | volume = 16 | issue = 5 | pages = 556–65 | date = May 2015 | pmid = 25891906 | doi = 10.1016/j.stem.2015.03.004 | doi-access = free }} [10] => [11] => == Properties == [12] => Lancaster and Knoblich define an organoid as a collection of organ-specific cell types that develops from stem cells or organ progenitors, self-organizes through cell sorting and spatially restricted lineage commitment in a manner similar to ''in vivo'', and exhibits the following properties: [13] => * it has multiple organ-specific cell types; [14] => * it is capable of recapitulating some specific function of the organ (e.g. [[muscle contraction|contraction]], [[neural]] activity, [[endocrine]] secretion, filtration, [[excretion]]); [15] => * its cells are grouped together and spatially organized, similar to an organ. [16] => [17] => ==Process== [18] => Organoid formation generally requires culturing the [[stem cells]] or [[progenitor cells]] in a 3D medium. Stem cells have the ability to self-renew and differentiate into various cell subtypes, and they enable understanding the processes of development and disease progression.{{Cite journal |last1=Murry |first1=Charles E. |last2=Keller |first2=Gordon |date=February 2008 |title=Differentiation of Embryonic Stem Cells to Clinically Relevant Populations: Lessons from Embryonic Development |journal=Cell |volume=132 |issue=4 |pages=661–680 |doi=10.1016/j.cell.2008.02.008 |pmid=18295582 |issn=0092-8674|doi-access=free }} Therefore organoids derived from stem cells enable studying biology and physiology at the organ level.{{Cite journal |last1=Choudhury |first1=Deepak |last2=Ashok |first2=Aswathi |last3=Naing |first3=May Win |date=March 2020 |title=Commercialization of Organoids |url=|journal=Trends in Molecular Medicine |volume=26 |issue=3 |pages=245–249 |doi=10.1016/j.molmed.2019.12.002 |pmid=31982341 |s2cid=210922708 |issn=1471-4914}} The 3D medium can be made using an extracellular matrix [[hydrogel]] such as [[Matrigel]] or Cultrex BME, which is a [[laminin]]-rich extracellular matrix that is secreted by the Engelbreth-Holm-Swarm tumor line.{{cite journal | vauthors = Li ML, Aggeler J, Farson DA, Hatier C, Hassell J, Bissell MJ | title = Influence of a reconstituted basement membrane and its components on casein gene expression and secretion in mouse mammary epithelial cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 1 | pages = 136–40 | date = January 1987 | pmid = 3467345 | pmc = 304157 | doi = 10.1073/pnas.84.1.136 | bibcode = 1987PNAS...84..136L | doi-access = free }} Organoid bodies can then be made through embedding stem cells in the 3D medium. When [[pluripotent]] stem cells are used for the creation of the organoid, the cells are usually, but not all the time, allowed to form [[embryoid body|embryoid bodies]]. Those embryoid bodies are then pharmacologically treated with patterning factors to drive the formation of the desired organoid identity. Organoids have also been created using adult stem cells extracted from the target organ, and cultured in 3D media.{{cite journal | vauthors = Pastuła A, Middelhoff M, Brandtner A, Tobiasch M, Höhl B, Nuber AH, Demir IE, Neupert S, Kollmann P, Mazzuoli-Weber G, Quante M | display-authors = 6 | title = Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche | journal = Stem Cells International | volume = 2016 | pages = 3710836 | year = 2016 | pmid = 26697073 | pmc = 4677245 | doi = 10.1155/2016/3710836 | doi-access = free }} [19] => [20] => Biochemical cues have been incorporated in 3D organoid cultures and with exposure of morphogenes, morphogen inhibitors, or growth factors, organoid models can be developed using embryonic stem cells (ESCs) or adult stem cells (ASCs). Vascularization techniques can be utilized to embody microenvironments that are close to their counterparts, physiologically. Vasculature systems that can facilitate oxygen or nutrients to the inner mass of organoids can be achieved through microfluidic systems, vascular endothelial growth factor delivery systems, and endothelial cell-coated modules. With patient-derived [[Induced pluripotent stem cell|induced pluripotent stem cells]] (iPSCs){{Cite journal |last1=Takahashi |first1=Kazutoshi |last2=Yamanaka |first2=Shinya |date=August 2006 |title=Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors |url=|journal=Cell |volume=126 |issue=4 |pages=663–676 |doi=10.1016/j.cell.2006.07.024 |pmid=16904174 |issn=0092-8674|hdl=2433/159777 |hdl-access=free }} and [[CRISPR|CRISPR/Cas]]-based genome editing{{Cite journal |last1=Ran |first1=F Ann |last2=Hsu |first2=Patrick D |last3=Wright |first3=Jason |last4=Agarwala |first4=Vineeta |last5=Scott |first5=David A |last6=Zhang |first6=Feng |date=2013-10-24 |title=Genome engineering using the CRISPR-Cas9 system |url=|journal=Nature Protocols |volume=8 |issue=11 |pages=2281–2308 |doi=10.1038/nprot.2013.143 |pmid=24157548 |pmc=3969860 |issn=1754-2189}} technologies, genome-edited or mutated pluripotent stem cells (PSCs) with altered signaling cues can be generated to control intrinsic cues within organoids. [21] => [22] => == Types == [23] => [24] => A multitude of organ structures have been recapitulated using organoids. This section aims to outline the state of the field as of now through providing an abridged list of the organoids that have been successfully created, along with a brief outline based on the most recent literature for each organoid, and examples of how it has been utilized in research. [25] => [26] => === Cerebral organoid === [27] => A [[cerebral organoid]] describes artificially grown, ''[[in vitro]]'', miniature organs resembling the [[brain]]. Cerebral organoids are created by culturing human [[stem cell|pluripotent stem cells]] in a three-dimensional structure using rotational [[bioreactor]] and develop over the course of months.{{cite journal | vauthors = Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA | display-authors = 6 | title = Cerebral organoids model human brain development and microcephaly | journal = Nature | volume = 501 | issue = 7467 | pages = 373–9 | date = September 2013 | pmid = 23995685 | pmc = 3817409 | doi = 10.1038/nature12517 | bibcode = 2013Natur.501..373L }} The procedure has potential applications in the study of brain development, physiology and function. Cerebral organoids may experience "simple sensations" in response to external stimulation and neuroscientists are among those expressing concern that such organs could develop [[sentience]]. They propose that further evolution of the technique needs to be subject to a rigorous oversight procedure.{{cite journal | vauthors = Lavazza A, Massimini M | title = Cerebral organoids: ethical issues and consciousness assessment | journal = Journal of Medical Ethics | volume = 44 | issue = 9 | pages = 606–610 | date = September 2018 | pmid = 29491041 | doi = 10.1136/medethics-2017-104555 | doi-access = free }}{{cite news |last1=Prosser Scully |first1=Ruby |title=Miniature brains grown in the lab have human-like neural activity |url=https://www.newscientist.com/article/2207911-miniature-brains-grown-in-the-lab-have-human-like-neural-activity/ |work=[[New Scientist]] |issue=3237 |date=6 July 2019}}{{cite news |last1=Sample |first1=Ian |title=Scientists 'may have crossed ethical line' in growing human brains |url=https://www.theguardian.com/science/2019/oct/21/scientists-may-have-crossed-ethical-line-in-growing-human-brains |work=[[The Guardian]] |date=21 October 2019 |page=15}} In 2023, researchers have built a hybrid biocomputer that combines a laboratory-grown human brain organoids with conventional circuits, and can complete tasks such as voice recognition.Cai, H., Ao, Z., Tian, C. et al. Brain organoid reservoir computing for artificial intelligence. Nat Electron (2023). https://doi.org/10.1038/s41928-023-01069-w. Cerebral Organoids are currently being used to research and develop [[Organoid Intelligence|Organoid Intelligence (OI)]] technologies.Smirnova L, Caffo BS, Gracias DH, Huang Q, Morales Pantoja IE, Tang B, Zack DJ, Berlinicke CA, Boyd JL, Harris TD, Johnson EC, Kagan BJ, Kahn J, Muotri AR, Paulhamus BL, Schwamborn JC, Plotkin J, Szalay AS, Vogelstein JT, Worley PF and Hartung T. Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish. Front Sci (2023) 1:1017235. https://doi.org/10.3389/fsci.2023.1017235. [28] => [29] => === Gastrointestinal organoid === [30] => Gastrointestinal organoids refer to organoids that recapitulate structures of the [[gastrointestinal tract]]. The gastrointestinal tract arises from the [[endoderm]], which during development forms a tube that can be divided in three distinct regions, which give rise to, along with other organs, the following sections of the gastrointestinal tract: [31] => :# The [[foregut]] gives rise to the oral cavity and the stomach [32] => :# The [[midgut]] gives rise to the small intestines and the ascending colon [33] => :# The [[hindgut]] gives rise to the rectum and the rest of the colon [34] => [35] => Organoids have been created for the following structures of the gastrointestinal tract: [36] => [37] => ==== Intestinal organoid ==== [38] => Intestinal organoids have thus far been among the gut organoids generated directly from intestinal tissues or pluripotent stem cells. One way human pluripotent stem cells can be driven to form intestinal organoids is through first the application of [[activin]] A to drive the cells into a mesoendodermal identity, followed by the pharmacological upregulation of [[WNT3A|Wnt3a]] and [[FGF4|Fgf4]] signaling pathways as they have been demonstrated to promote posterior gut fate. Intestinal organoids have also been generated from intestinal stem cells, extracted from adult tissue and cultured in 3D media. These adult stem cell-derived organoids are often referred to as enteroids or colonoids, depending on their segment of origin, and have been established from both the human and murine intestine.{{Cite journal|last1=Sato|first1=Toshiro|last2=Stange|first2=Daniel E.|last3=Ferrante|first3=Marc|last4=Vries|first4=Robert G.J.|last5=van Es|first5=Johan H.|last6=van den Brink|first6=Stieneke|last7=van Houdt|first7=Winan J.|last8=Pronk|first8=Apollo|last9=van Gorp|first9=Joost|last10=Siersema|first10=Peter D.|last11=Clevers|first11=Hans|date=November 2011|title=Long-term Expansion of Epithelial Organoids From Human Colon, Adenoma, Adenocarcinoma, and Barrett's Epithelium|journal=Gastroenterology|volume=141|issue=5|pages=1762–1772|doi=10.1053/j.gastro.2011.07.050|pmid=21889923|issn=0016-5085|doi-access=free}}{{Cite journal|last1=Jung|first1=Peter|last2=Sato|first2=Toshiro|last3=Merlos-Suárez|first3=Anna|last4=Barriga|first4=Francisco M|last5=Iglesias|first5=Mar|last6=Rossell|first6=David|last7=Auer|first7=Herbert|last8=Gallardo|first8=Mercedes|last9=Blasco|first9=Maria A|last10=Sancho|first10=Elena|last11=Clevers|first11=Hans|date=October 2011|title=Isolation and in vitro expansion of human colonic stem cells|url=http://www.nature.com/articles/nm.2470|journal=Nature Medicine|language=en|volume=17|issue=10|pages=1225–1227|doi=10.1038/nm.2470|pmid=21892181|s2cid=205388154|issn=1078-8956}} Intestinal organoids consist of a single layer of polarized intestinal [[Epithelium|epithelial]] cells surrounding a central lumen. As such, recapitulate the crypt-villus structure of the intestine, by recapitulating its function, physiology and organization, and maintaining all the cell types found normally in the structure including intestinal stem cells. Thus, intestinal organoids are a valuable model to study intestinal nutrient transport,Cai T, Qi Y, Jergens A, Wannemuehler M, Barrett TA, Wang Q. Effects of six common dietary nutrients on murine intestinal organoid growth. PLoS One. 2018 Feb 1;13(2):e0191517. https://doi.org/10.1371/journal.pone.0191517. PMID: 29389993; PMCID: PMC5794098.Qi Y, Lohman J, Bratlie KM, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Yoon KJ, Barrett TA, Wang Q. Vitamin C and B3 as new biomaterials to alter intestinal stem cells. Journal of Biomedical Materials Research Part A. 2019 Sep;107(9):1886–1897. https://doi.org/10.1002/jbm.a.36715. Epub 2019 May 23. PMID: 31071241; PMCID: PMC6626554. drug absorption and delivery,Davoudi Z, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Barrett TA, Narasimhan B, Wang Q. Intestinal organoids containing poly(lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases. Journal of Biomedical Materials Research Part A. 2018 Apr;106(4):876–886. https://doi.org/10.1002/jbm.a.36305. Epub 2017 Dec 21. PMID: 29226615; PMCID: PMC5826879.Davoudi Z, Peroutka-Bigus N, Bellaire B, Jergens A, Wannemuehler M, Wang Q. Gut Organoid as a New Platform to Study Alginate and Chitosan Mediated PLGA Nanoparticles for Drug Delivery. Marine Drugs. 2021 May 20;19(5):282. https://doi.org/10.3390/md19050282. PMID: 34065505; PMCID: PMC8161322. nanomaterials and nanomedicine,Qi Y, Shi E, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Jergens A, Barrett T, Wu Y, Wang Q. Ex Vivo Study of Telluride Nanowires in Minigut. Journal of Biomedical Nanotechnology. 2018 May 1;14(5):978–986. https://doi.org/10.1166/jbn.2018.2578. PMID: 29883567Reding B, Carter P, Qi Y, Li Z, Wu Y, Wannemuehler M, Bratlie KM, Wang Q. Manipulate intestinal organoids with niobium carbide nanosheets. Journal of Biomedical Materials Research Part A. 2021 Apr;109(4):479–487. https://doi.org/10.1002/jbm.a.37032. Epub 2020 Jun 17. PMID: 32506610. incretin hormone secretion,{{Cite journal| vauthors = Zietek T, Giesbertz P, Ewers M, Reichart F, Weinmüller M, Demir IE, Haller D, Ceyhan GO, Kessler H, Rath E | display-authors = 6 |date=2020|title=Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism – Update to the Human Model and Expansion of Applications |journal=Frontiers in Bioengineering and Biotechnology |volume=8 | page = 577656 |doi=10.3389/fbioe.2020.577656 | pmid = 33015026 | pmc = 7516017 |doi-access=free }}{{cite journal | vauthors = Zietek T, Rath E, Haller D, Daniel H | title = Intestinal organoids for assessing nutrient transport, sensing and incretin secretion | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 16831 | date = November 2015 | pmid = 26582215 | doi = 10.1038/srep16831 | pmc = 4652176 | bibcode = 2015NatSR...516831Z | doi-access = free }} and infection by various enteropathogens.{{Cite journal|date=2019-02-01|title=Intestinal organoids: A new paradigm for engineering intestinal epithelium in vitro|url=|journal=Biomaterials|language=en|volume=194|pages=195–214|doi=10.1016/j.biomaterials.2018.12.006|issn=0142-9612|last1=Rahmani|first1=Sara|last2=Breyner|first2=Natalia M.|last3=Su|first3=Hsuan-Ming|last4=Verdu|first4=Elena F.|last5=Didar|first5=Tohid F.|pmid=30612006|s2cid=58603850}}Sun L, Rollins D, Qi Y, Fredericks J, Mansell TJ, Jergens A, Phillips GJ, Wannemuehler M, Wang Q. TNFα regulates intestinal organoids from mice with both defined and conventional microbiota. International Journal of Biological Macromolecules. 2020 Dec 1;164:548–556. https://doi.org/10.1016/j.ijbiomac.2020.07.176. Epub 2020 Jul 18. PMID: 32693143; PMCID: PMC7657954. For example, Qun Wang's team rationally designed artificial virus nanoparticles as oral drug delivery vehicles (ODDVs) with gut organoid-derived mucosal modelsTong T, Qi Y, Rollins D, Bussiere LD, Dhar D, Miller CL, Yu C, Wang Q. Rational design of oral drugs targeting mucosa delivery with gut organoid platforms. Bioactive Materials. 2023; 30: 116–128. https://doi.org/10.1016/j.bioactmat.2023.07.014. PMID: 37560199. and demonstrated a new concept of using newly established colon organoids as tools for high-throughput drug screening, toxicity testing, and oral drug development.Davoudi Z, Atherly T, Borcherding DC, Jergens AE, Wannemuehler M, Barrett TA, Wang Q. Study Transportation of Drugs within Newly Established Murine Colon Organoid Systems. Advanced Biology. 2023; e2300103. https://doi.org/10.1002/adbi.202300103. PMID: 37607116. Intestinal organoids also recapitulate the [[Intestinal gland|crypt-Villus]] structure to such a high degree of fidelity that they have been successfully transplanted to mouse intestines, and are hence highly regarded as a valuable model for research. One of the fields of research that intestinal organoids have been utilized is that of stem cell niche. Intestinal organoids were used to study the nature of the [[Stem cell niche#Intestinal stem cell niche|intestinal stem cell niche]], and research done with them demonstrated the positive role [[Interleukin 22|IL-22]] has in maintaining in intestinal stem cells,{{cite journal | vauthors = Lindemans C, Mertelsmann A, Dudakov JA, Velardi E, Hua G, O'Connor M, Kolesnick R, van den Brink MR, Hanash AM | display-authors = 6 | year = 2014 | title = IL-22 Administration Protects Intestinal Stem Cells from Gvhd | journal = Biology of Blood and Marrow Transplantation | volume = 20 | issue = 2 | doi = 10.1016/j.bbmt.2013.12.056 | pages=S53–S54| doi-access = free }} along with demonstrating the roles of other cell types like neurons and fibroblasts in maintenance of intestinal stem cells. In the field of infection biology, different intestinal organoid-based model systems have been explored. On one hand, organoids can be infected in bulk by simply mixing them with the [[enteropathogen]] of interest.{{Cite journal|last1=Zhang|first1=Yong-Guo|last2=Wu|first2=Shaoping|last3=Xia|first3=Yinglin|last4=Sun|first4=Jun|date=September 2014|title=Salmonella -infected crypt-derived intestinal organoid culture system for host-bacterial interactions|journal=Physiological Reports|language=en|volume=2|issue=9|pages=e12147|doi=10.14814/phy2.12147|pmc=4270227|pmid=25214524}} However, to model infection via a more natural route starting from the intestinal lumen, microinjection of the [[pathogen]] is required.{{Cite journal|last1=Geiser|first1=Petra|last2=Di Martino|first2=Maria Letizia|last3=Samperio Ventayol|first3=Pilar|last4=Eriksson|first4=Jens|last5=Sima|first5=Eduardo|last6=Al-Saffar|first6=Anas Kh.|last7=Ahl|first7=David|last8=Phillipson|first8=Mia|last9=Webb|first9=Dominic-Luc|last10=Sundbom|first10=Magnus|last11=Hellström|first11=Per M.|date=2021-02-23|editor-last=Sperandio|editor-first=Vanessa|title=Salmonella enterica Serovar Typhimurium Exploits Cycling through Epithelial Cells To Colonize Human and Murine Enteroids|journal=mBio|language=en|volume=12|issue=1|doi=10.1128/mBio.02684-20|issn=2161-2129|pmc=7844539|pmid=33436434}}{{Cite journal|last1=Dutta|first1=Devanjali|last2=Heo|first2=Inha|last3=O'Connor|first3=Roberta|date=2019-09-14|title=Studying Cryptosporidium Infection in 3D Tissue-derived Human Organoid Culture Systems by Microinjection|url=https://www.jove.com/video/59610/studying-cryptosporidium-infection-3d-tissue-derived-human-organoid|journal=Journal of Visualized Experiments|language=en|issue=151|pages=59610|doi=10.3791/59610|pmid=31566619|s2cid=203377662|issn=1940-087X}} In addition, the polarity of intestinal organoids can be inverted,{{Cite journal|last1=Co|first1=Julia Y.|last2=Margalef-Català|first2=Mar|last3=Li|first3=Xingnan|last4=Mah|first4=Amanda T.|last5=Kuo|first5=Calvin J.|last6=Monack|first6=Denise M.|last7=Amieva|first7=Manuel R.|date=February 2019|title=Controlling Epithelial Polarity: A Human Enteroid Model for Host-Pathogen Interactions|journal=Cell Reports|language=en|volume=26|issue=9|pages=2509–2520.e4|doi=10.1016/j.celrep.2019.01.108|pmc=6391775|pmid=30811997}} and they can even be dissociated into single [[Cell (biology)|cells]] and cultured as 2D monolayersTong T , Qi Y , Bussiere LD , Wannemuehler M , Miller CL , Wang Q , Yu C . Transport of artificial virus-like nanocarriers through intestinal monolayers via microfold cells. Nanoscale. 2020 Aug 14;12(30):16339-16347. https://doi.org/10.1039/D0NR03680C. Epub 2020 Jul 29. PMID: 32725029.{{Cite journal|last1=Noel|first1=Gaelle|last2=Baetz|first2=Nicholas W.|last3=Staab|first3=Janet F.|last4=Donowitz|first4=Mark|last5=Kovbasnjuk|first5=Olga|last6=Pasetti|first6=Marcela F.|last7=Zachos|first7=Nicholas C.|date=2017-05-31|title=A primary human macrophage-enteroid co-culture model to investigate mucosal gut physiology and host-pathogen interactions|journal=Scientific Reports|language=en|volume=7|issue=1|pages=45270|doi=10.1038/srep45270|issn=2045-2322|pmc=5366908|pmid=28345602|bibcode=2017NatSR...745270N}} in order to make both the apical and basolateral sides of the epithelium more easily accessible. Intestinal organoids have also demonstrated therapeutic potential.{{cite journal | vauthors = Bouchi R, Foo KS, Hua H, Tsuchiya K, Ohmura Y, Sandoval PR, Ratner LE, Egli D, Leibel RL, Accili D | title = FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures | journal = Nature Communications | volume = 5 | pages = 4242 | date = June 2014 | pmid = 24979718 | pmc = 4083475 | doi = 10.1038/ncomms5242 | bibcode = 2014NatCo...5.4242B }} [39] => [[File:Intestinal Organoid.gif|thumb|An intestinal organoid (Minigut) grows up in 7 days. The scale bars are 200 μm.]] [40] => [41] => In order to more accurately recapitulate the intestine [[in vivo]], co-cultures of intestinal organoids and [[immune cells]] have been developed. Furthermore, [[organ-on-a-chip]] models combine intestinal organoids with other cell types such as [[Endothelium|endothelial]] or [[immune cells]] as well as [[Peristalsis|peristaltic]] flow.{{Cite journal|last1=Sontheimer-Phelps|first1=Alexandra|last2=Chou|first2=David B.|last3=Tovaglieri|first3=Alessio|last4=Ferrante|first4=Thomas C.|last5=Duckworth|first5=Taylor|last6=Fadel|first6=Cicely|last7=Frismantas|first7=Viktoras|last8=Sutherland|first8=Arlene D.|last9=Jalili-Firoozinezhad|first9=Sasan|last10=Kasendra|first10=Magdalena|last11=Stas|first11=Eric|date=2020|title=Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology|journal=Cellular and Molecular Gastroenterology and Hepatology|language=en|volume=9|issue=3|pages=507–526|doi=10.1016/j.jcmgh.2019.11.008|pmc=7036549|pmid=31778828}}{{Cite journal|last1=Grassart|first1=Alexandre|last2=Malardé|first2=Valérie|last3=Gobaa|first3=Samy|last4=Sartori-Rupp|first4=Anna|last5=Kerns|first5=Jordan|last6=Karalis|first6=Katia|last7=Marteyn|first7=Benoit|last8=Sansonetti|first8=Philippe|last9=Sauvonnet|first9=Nathalie|date=September 2019|title=Bioengineered Human Organ-on-Chip Reveals Intestinal Microenvironment and Mechanical Forces Impacting Shigella Infection|journal=Cell Host & Microbe|language=en|volume=26|issue=3|pages=435–444.e4|doi=10.1016/j.chom.2019.08.007|pmid=31492657|s2cid=201868491|doi-access=free}} [42] => [43] => ==== Gastric organoid ==== [44] => Gastric organoids recapitulate at least partly the physiology of the [[stomach]]. Gastric organoids have been generated directly from pluripotent stem cells through the temporal manipulation of the [[Fibroblast growth factor|FGF]], [[Wnt signaling pathway|WNT]], [[Bone morphogenetic protein|BMP]], [[retinoic acid]] and [[Epidermal growth factor|EGF]] signalling pathways in three-dimensional culture conditions.{{cite journal | vauthors = McCracken KW, Catá EM, Crawford CM, Sinagoga KL, Schumacher M, Rockich BE, Tsai YH, Mayhew CN, Spence JR, Zavros Y, Wells JM | display-authors = 6 | title = Modelling human development and disease in pluripotent stem-cell-derived gastric organoids | journal = Nature | volume = 516 | issue = 7531 | pages = 400–4 | date = December 2014 | pmid = 25363776 | pmc = 4270898 | doi = 10.1038/nature13863 | bibcode = 2014Natur.516..400M }} Gastric organoids have also been generated using [[LGR5]] expressing stomach [[adult stem cell]]s.{{cite journal | vauthors = Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H | display-authors = 6 | title = Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro | journal = Cell Stem Cell | volume = 6 | issue = 1 | pages = 25–36 | date = January 2010 | pmid = 20085740 | doi = 10.1016/j.stem.2009.11.013 | doi-access = free }} Gastric organoids have been used as model for the study of [[cancer]]{{cite journal | vauthors = Li X, Nadauld L, Ootani A, Corney DC, Pai RK, Gevaert O, Cantrell MA, Rack PG, Neal JT, Chan CW, Yeung T, Gong X, Yuan J, Wilhelmy J, Robine S, Attardi LD, Plevritis SK, Hung KE, Chen CZ, Ji HP, Kuo CJ | display-authors = 6 | title = Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture | journal = Nature Medicine | volume = 20 | issue = 7 | pages = 769–77 | date = July 2014 | pmid = 24859528 | pmc = 4087144 | doi = 10.1038/nm.3585 }}{{cite journal | vauthors = Nadauld LD, Garcia S, Natsoulis G, Bell JM, Miotke L, Hopmans ES, Xu H, Pai RK, Palm C, Regan JF, Chen H, Flaherty P, Ootani A, Zhang NR, Ford JM, Kuo CJ, Ji HP | display-authors = 6 | title = Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer | journal = Genome Biology | volume = 15 | issue = 8 | pages = 428 | date = August 2014 | pmid = 25315765 | pmc = 4145231 | doi = 10.1186/s13059-014-0428-9 | doi-access = free }} along with human disease and development. For example, one study investigated the underlying genetic alterations behind a patient's [[metastasis|metastatic tumor population]], and identified that unlike the patient's primary tumor, the metastasis had both alleles of the [[TGFBR2]] gene mutated. To further assess the role of TGFBR2 in the metastasis, the investigators created organoids where TGFBR2 expression is knocked down, through which they were able to demonstrate that reduced TGFBR2 activity leads to invasion and metastasis of cancerous tumors both ''in vitro'' and ''in vivo''. [45] => [46] => === Lingual organoid === [47] => Lingual organoids are organoids that recapitulate, at least partly, aspects of the tongue physiology. Epithelial lingual organoids have been generated using [[BMI1]] expressing epithelial stem cells in three-dimensional culture conditions through the manipulation of [[Epidermal growth factor|EGF]], [[Wnt signaling pathway|WNT]], and [[TGF-β]].{{cite journal | vauthors = Hisha H, Tanaka T, Kanno S, Tokuyama Y, Komai Y, Ohe S, Yanai H, Omachi T, Ueno H | display-authors = 6 | title = Establishment of a novel lingual organoid culture system: generation of organoids having mature keratinized epithelium from adult epithelial stem cells | journal = Scientific Reports | volume = 3 | pages = 3224 | date = November 2013 | pmid = 24232854 | pmc = 3828633 | doi = 10.1038/srep03224 | bibcode = 2013NatSR...3E3224H }} This organoid culture, however, lacks [[taste receptor]]s, as these cells do not arise from Bmi1 expressing epithelial stem cells. Lingual taste bud organoids containing taste cells, however, have been created using the [[LGR5]]+ or [[CD44]]+ stem/progenitor cells of circumvallate (CV) papilla tissue.{{cite journal | vauthors = Aihara E, Mahe MM, Schumacher MA, Matthis AL, Feng R, Ren W, Noah TK, Matsu-ura T, Moore SR, Hong CI, Zavros Y, Herness S, Shroyer NF, Iwatsuki K, Jiang P, Helmrath MA, Montrose MH | display-authors = 6 | title = Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid | journal = Scientific Reports | volume = 5 | pages = 17185 | date = November 2015 | pmid = 26597788 | pmc = 4665766 | doi = 10.1038/srep17185 | bibcode = 2015NatSR...517185A }} These taste bud organoids have been successfully created both directly from isolated Lgr5- or [[LGR6]]-expressing taste stem/progenitor cells.{{cite journal | vauthors = Ren W, Lewandowski BC, Watson J, Aihara E, Iwatsuki K, Bachmanov AA, Margolskee RF, Jiang P | title = Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 46 | pages = 16401–6 | date = November 2014 | pmid = 25368147 | pmc = 4246268 | doi = 10.1073/pnas.1409064111 | bibcode = 2014PNAS..11116401R | doi-access = free }} and indirectly, through the isolation, digestion, and subsequent culturing of CV tissue containing Lgr5+ or CD44+ stem/progenitor cells. [48] => [49] => === Other === [50] => [51] => * Tooth organoid (TO){{cite journal |last1=Hermans |first1=F |last2=Hasevoets |first2=S |last3=Vankelecom |first3=H |last4=Bronckaers |first4=A |last5=Lambrichts |first5=I |title=From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration. |journal=Stem Cell Reviews and Reports |date=18 March 2024 |doi=10.1007/s12015-024-10702-w |pmid=38498295|doi-access=free }} (see also [[tooth regeneration]]) [52] => * Thyroid organoid{{cite journal | vauthors = Martin A, Barbesino G, Davies TF | title = T-cell receptors and autoimmune thyroid disease—signposts for T-cell-antigen driven diseases | journal = International Reviews of Immunology | volume = 18 | issue = 1–2 | pages = 111–40 | year = 1999 | pmid = 10614741 | doi = 10.3109/08830189909043021 }} [53] => * Thymic organoid{{cite journal | vauthors = Bredenkamp N, Ulyanchenko S, O'Neill KE, Manley NR, Vaidya HJ, Blackburn CC | title = An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts | journal = Nature Cell Biology | volume = 16 | issue = 9 | pages = 902–8 | date = September 2014 | pmid = 25150981 | pmc = 4153409 | doi = 10.1038/ncb3023 }} [54] => ::Thymic organoids recapitulate at least partly the architecture and [[stem-cell niche]] functionality of the [[thymus]],{{cite book | vauthors = Vianello F, Poznansky MC | title = Immunological Tolerance | chapter = Generation of a tissue-engineered thymic organoid | series = Methods in Molecular Biology | volume = 380 | pages = 163–70 | year = 2007 | pmid = 17876092 | doi = 10.1007/978-1-59745-395-0_9 | isbn = 978-1-59745-395-0 }} which is a lymphoid organ where T cells mature. Thymic organoids have been generated through the seeding of thymic stromal cells in 3-dimensional culture. Thymic organoids seem to successfully recapitulate the thymus' function, as co-culturing human [[hematopoietic stem cell|hematopoietic or bone marrow stem cells]] with mouse thymic organoids resulted in the production of [[T-cell]]s. [55] => * Testicular organoid{{cite journal |last1=Sakib |first1=Sadman |title=Formation of organotypic testicular organoids in microwell culture |journal=Biology of Reproduction |volume=100 |issue=6 |pages=1648–1660 |date=1 June 2019 |doi=10.1093/biolre/ioz053|pmid=30927418 |display-authors=etal|pmc=7302515 }} [56] => *Prostate organoid{{Cite journal|last1=Drost|first1=Jarno|last2=Karthaus|first2=Wouter R.|last3=Gao|first3=Dong|last4=Driehuis|first4=Else|last5=Sawyers|first5=Charles L.|last6=Chen|first6=Yu|last7=Clevers|first7=Hans|date=21 January 2016|title=Organoid culture systems for prostate epithelial and cancer tissue|journal=Nature Protocols|language=en|volume=11|issue=2|pages=347–358|doi=10.1038/nprot.2016.006|pmid=26797458|issn=1750-2799|pmc=4793718}} [57] => * Hepatic organoid.{{cite journal | vauthors = Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H | display-authors = 6 | title = Long-term culture of genome-stable bipotent stem cells from adult human liver | journal = Cell | volume = 160 | issue = 1–2 | pages = 299–312 | date = January 2015 | pmid = 25533785 | pmc = 4313365 | doi = 10.1016/j.cell.2014.11.050 }} A recent study showed the usefulness of the technology for identifying novel medication for the treatment of [[hepatitis E]] as it allows to allows to recapitulate the entire viral life cycle.{{cite journal |author=Li P, Li Y, Wang Y, Liu J, Lavrijsen M, Li Y, Zhang R, Verstegen MMA, Wang Y, Li TC, Ma Z, Kainov DE, Bruno MJ, de Man RA, van der Laan LJW, Peppelenbosch MP, Pan Q|title=Recapitulating hepatitis E virus-host interactions and facilitating antiviral drug discovery in human liver-derived organoids |journal=Science Advances |volume=8|issue=3 |pages=103–111|date=2022 |pmid= 5044825| doi=10.1126/sciadv.abj5908 |bibcode=2022SciA....8.5908L |s2cid=246069868 |url=https://pure.eur.nl/en/publications/2a130980-ce88-4339-934b-df2aef36716c |hdl=11250/3047921 |hdl-access=free }} [58] => * Pancreatic organoid{{cite journal | vauthors = Huch M, Bonfanti P, Boj SF, Sato T, Loomans CJ, van de Wetering M, Sojoodi M, Li VS, Schuijers J, Gracanin A, Ringnalda F, Begthel H, Hamer K, Mulder J, van Es JH, de Koning E, Vries RG, Heimberg H, Clevers H | display-authors = 6 | title = Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis | journal = The EMBO Journal | volume = 32 | issue = 20 | pages = 2708–21 | date = October 2013 | pmid = 24045232 | pmc = 3801438 | doi = 10.1038/emboj.2013.204 }}{{cite journal| author=Hou S, Tiriac H, Sridharan BP, Scampavia L, Madoux F, Seldin J | display-authors=etal| title=Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening. | journal=SLAS Discov | year= 2018 | volume= 23 | issue= 6 | pages= 574–584 | pmid=29673279 | doi=10.1177/2472555218766842 | pmc=6013403 }}{{cite journal| author=Wolff RA, Wang-Gillam A, Alvarez H, Tiriac H, Engle D, Hou S | display-authors=etal| title=Dynamic changes during the treatment of pancreatic cancer. | journal=Oncotarget | year= 2018 | volume= 9 | issue= 19 | pages= 14764–14790 | pmid=29599906 | doi=10.18632/oncotarget.24483 | pmc=5871077 }}{{Cite journal|last1=Below|first1=Christopher R.|last2=Kelly|first2=Joanna|last3=Brown|first3=Alexander|last4=Humphries|first4=Jonathan D.|last5=Hutton|first5=Colin|last6=Xu|first6=Jingshu|last7=Lee|first7=Brian Y.|last8=Cintas|first8=Celia|last9=Zhang|first9=Xiaohong|last10=Hernandez-Gordillo|first10=Victor|last11=Stockdale|first11=Linda|date=2021-09-13|title=A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids|journal=Nature Materials|volume=21|issue=1|language=en|pages=110–119|doi=10.1038/s41563-021-01085-1|pmid=34518665|pmc=7612137|issn=1476-4660}} [59] => ::Recent advances in cell repellent microtiter plates has allowed rapid, cost-effective screening of large small molecule drug like libraries against 3D models of pancreas cancer. These models are consistent in phenotype and expression profiles with those found in the lab of Dr. [[David Tuveson]]. [60] => * Epithelial organoid{{cite journal | vauthors = Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H | display-authors = 6 | title = Identification of stem cells in small intestine and colon by marker gene Lgr5 | journal = Nature | volume = 449 | issue = 7165 | pages = 1003–7 | date = October 2007 | pmid = 17934449 | doi = 10.1038/nature06196 | bibcode = 2007Natur.449.1003B | s2cid = 4349637 | author-link10 = Peter J. Peters }} [61] => * Lung organoid{{cite journal | vauthors = Lee JH, Bhang DH, Beede A, Huang TL, Stripp BR, Bloch KD, Wagers AJ, Tseng YH, Ryeom S, Kim CF | display-authors = 6 | title = Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis | journal = Cell | volume = 156 | issue = 3 | pages = 440–55 | date = January 2014 | pmid = 24485453 | pmc = 3951122 | doi = 10.1016/j.cell.2013.12.039 }} [62] => * Kidney organoid{{cite journal | vauthors = Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, Parton RG, Wolvetang EJ, Roost MS, Chuva de Sousa Lopes SM, Little MH | display-authors = 6 | title = Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis | journal = Nature | volume = 526 | issue = 7574 | pages = 564–8 | date = October 2015 | pmid = 26444236 | doi = 10.1038/nature15695 | bibcode = 2015Natur.526..564T | s2cid = 4443766 }}{{cite journal | vauthors = Morizane R, Lam AQ, Freedman BS, Kishi S, Valerius MT, Bonventre JV | title = Nephron organoids derived from human pluripotent stem cells model kidney development and injury | journal = Nature Biotechnology | volume = 33 | issue = 11 | pages = 1193–200 | date = November 2015 | pmid = 26458176 | pmc = 4747858 | doi = 10.1038/nbt.3392 }} [63] => * [[Gastruloid]] (embryonic organoid){{cite journal | vauthors = van den Brink SC, Baillie-Johnson P, Balayo T, Hadjantonakis AK, Nowotschin S, Turner DA, Martinez Arias A | display-authors = 6 | title = Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells | journal = Development | volume = 141 | issue = 22 | pages = 4231–42 | date = November 2014 | pmid = 25371360 | pmc = 4302915 | doi = 10.1242/dev.113001 }}{{cite journal | vauthors = Turner DA, Baillie-Johnson P, Martinez Arias A | title = Organoids and the genetically encoded self-assembly of embryonic stem cells | journal = BioEssays | volume = 38 | issue = 2 | pages = 181–91 | date = February 2016 | pmid = 26666846 | pmc = 4737349 | doi = 10.1002/bies.201500111 }}{{cite journal | vauthors = Turner DA, Girgin M, Alonso-Crisostomo L, Trivedi V, Baillie-Johnson P, Glodowski CR, Hayward PC, Collignon J, Gustavsen C, Serup P, Steventon B, P Lutolf M, Arias AM | display-authors = 6 | title = Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids | journal = Development | volume = 144 | issue = 21 | pages = 3894–3906 | date = November 2017 | pmid = 28951435 | pmc = 5702072 | doi = 10.1242/dev.150391 }}{{cite journal | vauthors = Beccari L, Moris N, Girgin M, Turner DA, Baillie-Johnson P, Cossy AC, Lutolf MP, Duboule D, Arias AM| display-authors = 6 | title = Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids | language = En | journal = Nature | volume = 562 | issue = 7726 | pages = 272–276 | date = October 2018 | pmid = 30283134 | doi = 10.1038/s41586-018-0578-0 | bibcode = 2018Natur.562..272B | s2cid = 52915553 | url = https://www.repository.cam.ac.uk/handle/1810/285960 }} – Generates all embryonic axes and fully implements the collinear ''Hox'' gene expression patterns along the anteroposterior axis. [64] => * [[Blastoid (Organoid)|Blastoid]] (blastocyst-like organoid){{Cite web | url=https://thenode.biologists.com/blastoid-the-backstory-of-the-formation-of-blastocyst-like-structure-solely-from-stem-cells/highlights/ |title = Blastoid: The backstory of the formation of blastocyst-like structure solely from stem cells|date = 2018-06-27}}{{Cite web | url=https://www.nicolasrivron.org/theblastoid |title = Nicolas Rivron Lab | Blastoid | Netherlands}}{{cite journal | vauthors = Rivron NC, Frias-Aldeguer J, Vrij EJ, Boisset JC, Korving J, Vivié J, Truckenmüller RK, van Oudenaarden A, van Blitterswijk CA, Geijsen N | display-authors = 6 | title = Blastocyst-like structures generated solely from stem cells | journal = Nature | volume = 557 | issue = 7703 | pages = 106–111 | date = May 2018 | pmid = 29720634 | doi = 10.1038/s41586-018-0051-0 | bibcode = 2018Natur.557..106R | s2cid = 13749109 | url = https://cris.maastrichtuniversity.nl/ws/files/60703351/Blitterswijk_2018_Blastocyst_like_structures_generated_solely.pdf }} [65] => * Endometrial organoid{{cite journal |vauthors=Rawlings TM, Makwana K, Tryfonos M, Lucas ES |title=Organoids to model the endometrium: implantation and beyond |journal=Reprod Fertil |volume=2 |issue=3 |pages=R85–R101 |date=July 2021 |pmid=35118399 |pmc=8801025 |doi=10.1530/RAF-21-0023 |url=}} [66] => * Cardiac organoid{{cite journal | vauthors = Lee EJ, Kim DE, Azeloglu EU, Costa KD | title = Engineered cardiac organoid chambers: toward a functional biological model ventricle | journal = Tissue Engineering. Part A | volume = 14 | issue = 2 | pages = 215–25 | date = February 2008 | pmid = 18333774 | doi = 10.1089/tea.2007.0351 }} – In 2018 hollow cardiac organoids were made to beat, and to respond to stimuli to beat faster or slower.{{Cite magazine|url=https://www.wired.com/story/these-beating-mini-hearts-could-save-big-bucksand-maybe-lives/|title=These Beating Mini-Hearts Could Save Big Bucks—And Maybe Lives|last=Molteni |first= Megan | name-list-style = vanc |date=2018-06-27|magazine=WIRED|access-date=2018-06-30 }} [67] => * Retinal organoid{{cite journal | vauthors = Wiley LA, Burnight ER, DeLuca AP, Anfinson KR, Cranston CM, Kaalberg EE, Penticoff JA, Affatigato LM, Mullins RF, Stone EM, Tucker BA | display-authors = 6 | title = cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness | journal = Scientific Reports | volume = 6 | pages = 30742 | date = July 2016 | pmid = 27471043 | pmc = 4965859 | doi = 10.1038/srep30742 | bibcode = 2016NatSR...630742W }}{{Cite journal|last1=Zilova|first1=Lucie|last2=Weinhardt|first2=Venera|last3=Tavhelidse|first3=Tinatini|last4=Schlagheck|first4=Christina|last5=Thumberger|first5=Thomas|last6=Wittbrodt|first6=Joachim|date=2021-07-12|editor-last=Martínez Arias|editor-first=Alfonso|editor2-last=Stainier|editor2-first=Didier YR|editor3-last=Martínez Arias|editor3-first=Alfonso|title=Fish primary embryonic pluripotent cells assemble into retinal tissue mirroring in vivo early eye development|journal=eLife|volume=10|pages=e66998| pmid=34252023 | doi=10.7554/eLife.66998|issn=2050-084X|pmc=8275126 |doi-access=free }} [68] => * [[Breast cancer]] organoid{{Cite journal |last1=Sachs |first1=Norman |last2=de Ligt |first2=Joep |last3=Kopper |first3=Oded |last4=Gogola |first4=Ewa |last5=Bounova |first5=Gergana |last6=Weeber |first6=Fleur |last7=Balgobind |first7=Anjali Vanita |last8=Wind |first8=Karin |last9=Gracanin |first9=Ana |last10=Begthel |first10=Harry |last11=Korving |first11=Jeroen |last12=van Boxtel |first12=Ruben |last13=Duarte |first13=Alexandra Alves |last14=Lelieveld |first14=Daphne |last15=van Hoeck |first15=Arne |display-authors=14 |date=2018 |title=A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity |journal=Cell |volume=172 |issue=1–2 |pages=373–386.e10 |doi=10.1016/j.cell.2017.11.010 |issn=0092-8674|doi-access=free |pmid=29224780 }} [69] => * [[Colorectal cancer]] organoid{{Cite journal |last1=van de Wetering |first1=Marc |last2=Francies |first2=Hayley |last3=Francis |first3=Joshua |last4=Bounova |first4=Gergana |last5=Iorio |first5=Francesco |last6=Pronk |first6=Apollo |last7=van Houdt |first7=Winan |last8=van Gorp |first8=Joost |last9=Taylor-Weiner |first9=Amaro |last10=Kester |first10=Lennart |last11=McLaren-Douglas |first11=Anne |last12=Blokker |first12=Joyce |last13=Jaksani |first13=Sridevi |last14=Bartfeld |first14=Sina |last15=Volckman |first15=Richard |display-authors=14 |date=2015 |title=Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients |url=|journal=Cell |volume=161 |issue=4 |pages=933–945 |doi=10.1016/j.cell.2015.03.053 |issn=0092-8674 |pmc=6428276 |pmid=25957691}} [70] => * [[Glioblastoma]] organoid{{cite journal| author=Quereda V, Hou S, Madoux F, Scampavia L, Spicer TP, Duckett D| title=A Cytotoxic Three-Dimensional-Spheroid, High-Throughput Assay Using Patient-Derived Glioma Stem Cells. | journal=SLAS Discov | year= 2018 | volume= 23 | issue= 8 | pages= 842–849 | pmid=29750582 | doi=10.1177/2472555218775055 | pmc=6102052 }} [71] =>
3D organoid models of brain cancer derived from either patient derived explants (PDX) or direct from cancer tissue is now easily achievable and affords high-throughput screening of these tumors against the current panel of approved drugs form around the world.
[72] => * [[Neuroendocrine tumor]] organoid{{Cite journal |last1=Dayton |first1=Talya L. |last2=Alcala |first2=Nicolas |last3=Moonen |first3=Laura |last4=den Hartigh |first4=Lisanne |last5=Geurts |first5=Veerle |last6=Mangiante |first6=Lise |last7=Lap |first7=Lisa |last8=Dost |first8=Antonella F.M. |last9=Beumer |first9=Joep |last10=Levy |first10=Sonja |last11=van Leeuwaarde |first11=Rachel S. |last12=Hackeng |first12=Wenzel M. |last13=Samsom |first13=Kris |last14=Voegele |first14=Catherine |last15=Sexton-Oates |first15=Alexandra |display-authors=14 |date=2023 |title=Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites |journal=Cancer Cell |volume=41 |issue=12 |pages=2083–2099 |doi=10.1016/j.ccell.2023.11.007 |issn=1535-6108|doi-access=free |pmid=38086335 }} [73] => * [[Myelinoid]] (Myelin organoid) [74] => * Blood-brain barrier (BBB) organoid{{Cite journal |last1=Zidarič |first1=Tanja |last2=Gradišnik |first2=Lidija |last3=Velnar |first3=Tomaž |date=2022-04-01 |title=Astrocytes and human artificial blood-brain barrier models |url=https://www.bjbms.org/ojs/index.php/bjbms/article/view/6943 |journal=Bosnian Journal of Basic Medical Sciences |volume=22 |issue=5 |pages=651–672 |language=en |doi=10.17305/bjbms.2021.6943 |pmid=35366791 |pmc=9519155 |issn=1840-4812}} [75] =>
Self-assembled cell aggregates consisting of BMECs, astrocytes, and pericytes are emerging as a potential alternative to transwell and microfluidic models for certain applications. These organoides can generate many features of the BBB, such as the expression of tight junctions, molecular transporters, and drug efflux pumps, and can therefore be used to model drug transport across the BBB. Also, they can serve as a model for evaluating the interactions between the BBB and adjacent brain tissue and provide a platform for understanding the combined abilities of a new drug to overcome the BBB and its effect on brain tissue. In addition, such models are highly scalable and easier to manufacture and operate than microfluidic devices. However, they have limited ability to reconstruct the morphology and physiology of the BBB and are unable to simulate physiological flow and [[shear stress]].
[76] => [77] => == Basic research == [78] => Organoids enable to study how cells interact together in an organ, their interaction with their environment, how diseases affect them and the effect of drugs. ''In vitro'' culture makes this system easy to manipulate and facilitates their monitoring. While organs are difficult to culture because their size limits the penetration of nutrients, the small size of organoids limits this problem. On the other hand, they do not exhibit all organ features and interactions with other organs are not recapitulated ''in vitro''. While research on [[stem cell]]s and regulation of stemness was the first field of application of intestinal organoids, they are now also used to study e.g. uptake of nutrients, drug transport and secretion of [[incretin]] hormones.{{cite journal | vauthors = Zietek T, Rath E, Haller D, Daniel H | title = Intestinal organoids for assessing nutrient transport, sensing and incretin secretion | journal = Scientific Reports | volume = 5 | pages = 16831 | date = November 2015 | pmid = 26582215 | pmc = 4652176 | doi = 10.1038/srep16831 | bibcode = 2015NatSR...516831Z }} This is of great relevance in the context of [[malabsorption]] diseases as well as metabolic diseases such as [[obesity]], [[insulin resistance]], and [[Diabetes mellitus|diabetes]]. [79] => [80] => == Models of disease == [81] => Organoids provide an opportunity to create cellular models of human disease, which can be studied in the laboratory to better understand the causes of disease and identify possible treatments. The power of organoids in this regard was first shown for a genetic form of [[microcephaly]], where patient cells were used to make [[cerebral organoids]], which were smaller and showed abnormalities in early generation of neurons.{{cite journal | vauthors = Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA | display-authors = 6 | title = Cerebral organoids model human brain development and microcephaly | journal = Nature | volume = 501 | issue = 7467 | pages = 373–9 | date = September 2013 | pmid = 23995685 | pmc = 3817409 | doi = 10.1038/nature12517 | bibcode = 2013Natur.501..373L }} In another example, the genome editing system called CRISPR was applied to human pluripotent stem cells to introduce targeted mutations in genes relevant to two different kidney diseases, [[polycystic kidney disease]] and [[focal segmental glomerulosclerosis]].{{cite journal | vauthors = Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV | display-authors = 6 | title = Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids | journal = Nature Communications | volume = 6 | pages = 8715 | date = October 2015 | pmid = 26493500 | pmc = 4620584 | doi = 10.1038/ncomms9715 | bibcode = 2015NatCo...6.8715F }} These CRISPR-modified pluripotent stem cells were subsequently grown into human kidney organoids, which exhibited disease-specific phenotypes. Kidney organoids from stem cells with polycystic kidney disease mutations formed large, translucent cyst structures from kidney tubules. When cultured in the absence of adherent cues (in suspension), these cysts reached sizes of 1 cm in diameter over several months.{{cite journal | vauthors = Cruz NM, Song X, Czerniecki SM, Gulieva RE, Churchill AJ, Kim YK, Winston K, Tran LM, Diaz MA, Fu H, Finn LS, Pei Y, Himmelfarb J, Freedman BS | display-authors = 6 | title = Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease | journal = Nature Materials | volume = 16 | issue = 11 | pages = 1112–1119 | date = November 2017 | pmid = 28967916 | pmc = 5936694 | doi = 10.1038/nmat4994 | bibcode = 2017NatMa..16.1112C}} Kidney organoids with mutations in a gene linked to focal segmental glomerulosclerosis developed junctional defects between podocytes, the filtering cells affected in that disease.{{cite journal | vauthors = Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE, Hughes MR, Cruz NM, Liu Y, Churchill AJ, Wang Y, Fu H, Pippin JW, Lin LY, Shankland SJ, Vogl AW, McNagny KM, Freedman BS | display-authors = 6 | title = Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development | journal = Stem Cells | volume = 35 | issue = 12 | pages = 2366–2378 | date = December 2017 | pmid = 28905451 | pmc = 5742857 | doi = 10.1002/stem.2707 }} Importantly, these disease phenotypes were absent in control organoids of identical genetic background, but lacking the CRISPR mutations. Comparison of these organoid phenotypes to diseased tissues from mice and humans suggested similarities to defects in early development. [82] => [83] => As first developed by Takahashi and Yamanaka in 2007, [[induced pluripotent stem cell]]s (iPSC) can also be reprogrammed from patient skin fibroblasts.{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | display-authors = 6 | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–72 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 | url = https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf | hdl = 2433/49782 | s2cid = 8531539 | hdl-access = free }} These stem cells carry the exact genetic background of the patient including any genetic mutations which might contribute to the development of human disease. Differentiation of these cells into kidney organoids has been performed from patients with [[Oculocerebrorenal syndrome|Lowe Syndrome]] due to ''ORCL1'' mutations.{{cite journal | vauthors = Hsieh WC, Ramadesikan S, Fekete D, Aguilar RC | title = Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex | journal = PLOS ONE | volume = 13 | issue = 2 | pages = e0192635 | date = 2018-02-14 | pmid = 29444177 | pmc = 5812626 | doi = 10.1371/journal.pone.0192635 | bibcode = 2018PLoSO..1392635H | doi-access = free }} This report compared kidney organoids differentiated from patient iPSC to unrelated control iPSC and demonstrated an inability of patient kidney cells to mobilise transcription factor SIX2 from the [[Golgi apparatus|golgi complex]]. Because ''SIX2'' is a well characterised marker of nephron progenitor cells in the cap [[mesenchyme]], the authors concluded that renal disease frequently seen in Lowe Syndrome (global failure of [[proximal tubule]] reabsorption or renal [[Fanconi syndrome]]) could be related to alteration in nephron patterning arising from nephron progenitor cells lacking this important ''SIX2'' gene expression. [84] => [85] => Other studies have used CRISPR gene editing to correct the patient's mutation in the patient iPSC cells to create an [[Isogonic line|isogenic]] control, which can be performed simultaneously with iPSC reprogramming.{{cite journal | vauthors = Howden SE, Thomson JA, Little MH | title = Simultaneous reprogramming and gene editing of human fibroblasts | journal = Nature Protocols | volume = 13 | issue = 5 | pages = 875–898 | date = May 2018 | pmid = 29622803 | pmc = 5997775 | doi = 10.1038/nprot.2018.007 }}{{cite journal | vauthors = Forbes TA, Howden SE, Lawlor K, Phipson B, Maksimovic J, Hale L, Wilson S, Quinlan C, Ho G, Holman K, Bennetts B, Crawford J, Trnka P, Oshlack A, Patel C, Mallett A, Simons C, Little MH | display-authors = 6 | title = Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms | journal = American Journal of Human Genetics | volume = 102 | issue = 5 | pages = 816–831 | date = May 2018 | pmid = 29706353 | pmc = 5986969 | doi = 10.1016/j.ajhg.2018.03.014 }}{{cite journal | vauthors = Tanigawa S, Islam M, Sharmin S, Naganuma H, Yoshimura Y, Haque F, Era T, Nakazato H, Nakanishi K, Sakuma T, Yamamoto T, Kurihara H, Taguchi A, Nishinakamura R | display-authors = 6 | title = Organoids from Nephrotic Disease-Derived iPSCs Identify Impaired NEPHRIN Localization and Slit Diaphragm Formation in Kidney Podocytes | journal = Stem Cell Reports | volume = 11 | issue = 3 | pages = 727–740 | date = September 2018 | pmid = 30174315 | pmc = 6135868 | doi = 10.1016/j.stemcr.2018.08.003 }} Comparison of a patient iPSC derived organoid against an isogenic control is the current gold standard in the field as it permits isolation of the mutation of interest as the only variable within the experimental model.{{cite journal | vauthors = Engle SJ, Blaha L, Kleiman RJ | title = Best Practices for Translational Disease Modeling Using Human iPSC-Derived Neurons | journal = Neuron | volume = 100 | issue = 4 | pages = 783–797 | date = November 2018 | pmid = 30465765 | doi = 10.1016/j.neuron.2018.10.033 | doi-access = free }} In one such report, kidney organoids derived from iPSC of a patient with [[Saldino-Mainzer disease|Mainzer-Saldino Syndrome]] due to [[compound heterozygous]] mutations in ''[[IFT140]]'' were compared to an isogenic control organoid in which an ''IFT140'' variant giving rise to a non-viable mRNA transcript was corrected by CRISPR. Patient kidney organoids demonstrated abnormal [[Primary cilium|ciliary]] morphology consistent with existing animal models which was rescued to wild type morphology in the gene corrected organoids. Comparative transcriptional profiling of epithelial cells purified from patient and control organoids highlighted pathways involved in [[cell polarity]], [[Cell junction|cell-cell junctions]] and [[Dynein|dynein motor]] assembly, some of which had been implicated for other genotypes within the phenotypic family of renal ciliopathies. Another report utilising an isogenic control demonstrated abnormal [[nephrin]] localisation in the [[Glomerulus (kidney)|glomeruli]] of kidney organoids generated from a patient with [[congenital nephrotic syndrome]]. [86] => [87] => Things such as epithelial metabolism can also be modelled.{{Cite web |title=Metabolites |url=https://www.mdpi.com/journal/metabolites/special_issues/Intestinal_Metabolism |access-date=2022-10-16 |website=www.mdpi.com |language=en}} [88] => [89] => ==Personalised medicine== [90] => Intestinal organoids grown from rectal biopsies using culture protocols established by the Clevers group have been used to model [[cystic fibrosis]],{{cite journal | vauthors = Dekkers JF, Wiegerinck CL, de Jonge HR, Bronsveld I, Janssens HM, de Winter-de Groot KM, Brandsma AM, de Jong NW, Bijvelds MJ, Scholte BJ, Nieuwenhuis EE, van den Brink S, Clevers H, van der Ent CK, Middendorp S, Beekman JM | display-authors = 6 | title = A functional CFTR assay using primary cystic fibrosis intestinal organoids | journal = Nature Medicine | volume = 19 | issue = 7 | pages = 939–45 | date = July 2013 | pmid = 23727931 | doi = 10.1038/nm.3201 | s2cid = 5369669 }} and led to the first application of organoids for personalised treatment.{{cite journal | vauthors = Dekkers JF, Berkers G, Kruisselbrink E, Vonk A, de Jonge HR, Janssens HM, Bronsveld I, van de Graaf EA, Nieuwenhuis EE, Houwen RH, Vleggaar FP, Escher JC, de Rijke YB, Majoor CJ, Heijerman HG, de Winter-de Groot KM, Clevers H, van der Ent CK, Beekman JM | display-authors = 6 | title = Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis | journal = Science Translational Medicine | volume = 8 | issue = 344 | pages = 344ra84 | date = June 2016 | pmid = 27334259 | doi = 10.1126/scitranslmed.aad8278 | s2cid = 19462535 }} Cystic fibrosis is an inherited disease that is caused by gene mutations of the cystic fibrosis transmembrane conductance regulator gene that encodes an epithelial ion channel necessary for healthy epithelial surface fluids. Studies by the laboratory of Jeffrey Beekman (Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands) described in 2013 that stimulation of colorectal organoids with cAMP-raising agonists such as forskolin or cholera toxin induced rapid swelling of organoids in a fully CFTR dependent manner. Whereas organoids from non-cystic fibrosis subjects swell in response to forskolin as a consequence of fluid transport into the organoids' lumens, this is severely reduced or absent in organoids derived from people with cystic fibrosis. Swelling could be restored by therapeutics that repair the CFTR protein (CFTR modulators), indicating that individual responses to CFTR modulating therapy could be quantitated in a preclinical laboratory setting. Schwank et al. also demonstrated that the intestinal cystic fibrosis organoid phenotype could be repaired by CRISPR-Cas9 gene editing in 2013.{{cite journal | vauthors = Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H | display-authors = 6 | title = Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients | journal = Cell Stem Cell | volume = 13 | issue = 6 | pages = 653–8 | date = December 2013 | pmid = 24315439 | doi = 10.1016/j.stem.2013.11.002 | doi-access = free }} [91] => [92] => Follow-up studies by Dekkers et al. in 2016 revealed that quantitative differences in forskolin-induced swelling between intestinal organoids derived from people with cystic fibrosis associate with known diagnostic and prognostic markers such as CFTR gene mutations or in vivo biomarkers of CFTR function. In addition, the authors demonstrated that CFTR modulator responses in intestinal organoids with specific CFTR mutations correlated with published clinical trial data of these treatments. This led to preclinical studies where organoids from patients with extremely rare CFTR mutations for who no treatment was registered were found to respond strongly to a clinically available CFTR modulator. The suggested clinical benefit of treatment for these subjects based on the preclinical organoid test was subsequently confirmed upon clinical introduction of treatment by members of the clinical CF center under supervision of Kors van der Ent (Department of Paediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, The Netherlands). These studies show for the first time that organoids can be used for the individual tailoring of therapy or [[personalised medicine]]. [93] => [94] => == Organoid transplants == [95] => The first successful [[organ transplantation|transplantation]] of an organoid into a human, a patient with [[ulcerative colitis]] whose cells were used for the organoid, was carried out in 2022.{{cite news |title=World's first mini organ transportation to a patient with ulcerative colitis |url=https://medicalxpress.com/news/2022-08-world-mini-patient-ulcerative-colitis.html |access-date=18 September 2022 |work=[[Tokyo Medical and Dental University]] via medicalxpress.com |language=en}}{{cite journal |last1=Watanabe |first1=Satoshi |last2=Kobayashi |first2=Sakurako |last3=Ogasawara |first3=Nobuhiko |last4=Okamoto |first4=Ryuichi |last5=Nakamura |first5=Tetsuya |last6=Watanabe |first6=Mamoru |last7=Jensen |first7=Kim B. |last8=Yui |first8=Shiro |title=Transplantation of intestinal organoids into a mouse model of colitis |journal=Nature Protocols |date=March 2022 |volume=17 |issue=3 |pages=649–671 |doi=10.1038/s41596-021-00658-3 |pmid=35110738 |s2cid=246488596 |url=https://www.nature.com/articles/s41596-021-00658-3 |language=en |issn=1750-2799|url-access=subscription}} [96] => [97] => ==As a model for developmental biology== [98] => [99] => Organoids offer researchers an exceptional model to study [[developmental biology]].{{cite journal | vauthors = Ader M, Tanaka EM | title = Modeling human development in 3D culture | journal = Current Opinion in Cell Biology | volume = 31 | pages = 23–8 | date = December 2014 | pmid = 25033469 | doi = 10.1016/j.ceb.2014.06.013 }} Since the identification of [[Potency (stem cell)#Potency meaning|pluripotent stem cells]], there have been great advancements in [[Cellular differentiation|directing pluripotent stem cells fate]] ''in vitro'' using 2D cultures. These advancements in PSC fate direction, coupled with the advancements in 3D culturing techniques allowed for the creation of organoids that recapitulate the properties of various specific subregions of a multitude of organs. The use of these organoids has thus greatly contributed to expanding our understanding of the processes of [[organogenesis]], and the field of developmental biology. In [[central nervous system]] development, for example, organoids have contributed to our understanding of the physical forces that underlie retinal cup formation.{{cite journal | vauthors = Martinez-Morales JR, Cavodeassi F, Bovolenta P | title = Coordinated Morphogenetic Mechanisms Shape the Vertebrate Eye | journal = Frontiers in Neuroscience | volume = 11 | pages = 721 | date = 2017 | pmid = 29326547 | pmc = 5742352 | doi = 10.3389/fnins.2017.00721 | doi-access = free }} More recent work has extended cortical organoid growth periods extensively and at nearly a year under specific differentiation conditions, the organoids persist and have some features of human fetal development stages.{{Cite journal|last1=Gordon|first1=Aaron|last2=Yoon|first2=Se-Jin|last3=Tran|first3=Stephen S.|last4=Makinson|first4=Christopher D.|last5=Park|first5=Jin Young|last6=Andersen|first6=Jimena|last7=Valencia|first7=Alfredo M.|last8=Horvath|first8=Steve|last9=Xiao|first9=Xinshu|last10=Huguenard|first10=John R.|last11=Pașca|first11=Sergiu P.|date=2021-02-22|title=Long-term maturation of human cortical organoids matches key early postnatal transitions|journal=Nature Neuroscience|volume=24|issue=3|language=en|pages=331–342|doi=10.1038/s41593-021-00802-y|pmid=33619405|issn=1546-1726|pmc=8109149}} [100] => [101] => == See also == [102] => [103] => * [[Artificial organ]] [104] => * [[Organ culture]] [105] => [106] => == References == [107] => {{reflist|30em}} [108] => [109] => == Further reading == [110] => {{refbegin}} [111] => * {{cite journal | vauthors = Willyard C | title = The boom in mini stomachs, brains, breasts, kidneys and more | journal = Nature | volume = 523 | issue = 7562 | pages = 520–2 | date = July 2015 | pmid = 26223610 | doi = 10.1038/523520a | bibcode = 2015Natur.523..520W | doi-access = free }} [112] => * Kelly Rae Chi (2015). [http://www.the-scientist.com/?articles.view/articleNo/43842/title/Orchestrating-Organoids/ Orchestrating Organoids. A guide to crafting tissues in a dish that reprise in vivo organs]. The Scientist. [113] => * {{cite journal | vauthors = Takebe T, Enomura M, Yoshizawa E, Kimura M, Koike H, Ueno Y, Matsuzaki T, Yamazaki T, Toyohara T, Osafune K, Nakauchi H, Yoshikawa HY, Taniguchi H | title = Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation | journal = Cell Stem Cell | volume = 16 | issue = 5 | pages = 556–65 | date = May 2015 | pmid = 25891906 | doi = 10.1016/j.stem.2015.03.004 | doi-access = free }} [114] => * {{cite journal | vauthors = Turner DA, Baillie-Johnson P, Martinez Arias A | title = Organoids and the genetically encoded self-assembly of embryonic stem cells | journal = BioEssays | volume = 38 | issue = 2 | pages = 181–91 | date = February 2016 | pmid = 26666846 | pmc = 4737349 | doi = 10.1002/bies.201500111 }} [115] => {{refend}} [116] => * [https://en.longevitywiki.org/wiki/Organoid-based_regenerative_medicine Organoid-based regenerative medicine] [117] => [118] => [[Category:Stem cells]] [119] => [[Category:Tissue engineering]] [] => )
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Organoid

An organoid is a miniaturised and simplified version of an organ produced in vitro in three dimensions that mimics the key functional, structural, and biological complexity of that organ. It is derived from one or a few cells from a tissue, embryonic stem cells, or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities.

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