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{{Short description|Reversible biological process}}
{{Use dmy dates|date=May 2012}}
{{Use dmy dates|date=October 2020}}
A '''mesenchymal–epithelial transition''' (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of [[epithelial–mesenchymal transition]] (EMT). Unlike epithelial cells – which are stationary and characterized by an apical-basal polarity, tight junctions, and expression of cell-cell adhesion markers such as E-cadherin, mesenchymal cells do not make mature cell-cell contacts, can invade through the [[extracellular matrix]], and express markers such as vimentin, fibronectin, N-cadherin, Twist, and Snail.<ref name="pmid18343170 ">{{cite journal |vauthors=Baum B, Settleman J, Quinlan MP | title = Transitions between epithelial and mesenchymal states in development and disease | journal=Semin Cell Dev Biol | volume = 19 | issue = 3 | pages = 294–308 | year = 2008 | pmid = 18343170 | url = | issn = | doi=10.1016/j.semcdb.2008.02.001}}</ref><ref name="pmid12189386">{{cite journal | author=Thiery JP. | title = Epithelial-mesenchymal transitions in tumour progression | journal=Nat Rev Cancer | volume = 2 | issue = 6 | pages = 442–54 | year = 2002 | pmid = 12189386 | url = | issn = | doi=10.1038/nrc822}}</ref> METs occur in normal development, cancer metastasis, and induced pluripotent stem cell reprogramming.
A '''mesenchymal–epithelial transition''' ('''MET''') is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped [[mesenchymal cell]]s to planar arrays of polarized cells called [[epithelia]]. MET is the reverse process of [[epithelial–mesenchymal transition]] (EMT) and it has been shown to occur in normal development, induced [[pluripotent stem cell]] reprogramming,<ref name=":0">{{cite journal | vauthors = Pei D, Shu X, Gassama-Diagne A, Thiery JP | title = Mesenchymal-epithelial transition in development and reprogramming | journal = Nature Cell Biology | volume = 21 | issue = 1 | pages = 44–53 | date = January 2019 | pmid = 30602762 | doi = 10.1038/s41556-018-0195-z | s2cid = 57373557 }}</ref> cancer [[metastasis]]<ref>{{cite journal | vauthors = Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Revenco T, Boumahdi S, Van Keymeulen A, Brown D, Moers V, Lemaire S, De Clercq S, Minguijón E, Balsat C, Sokolow Y, Dubois C, De Cock F, Scozzaro S, Sopena F, Lanas A, D'Haene N, Salmon I, Marine JC, Voet T, Sotiropoulou PA, Blanpain C | display-authors = 6 | title = Identification of the tumour transition states occurring during EMT | journal = Nature | volume = 556 | issue = 7702 | pages = 463–468 | date = April 2018 | pmid = 29670281 | doi = 10.1038/s41586-018-0040-3 | bibcode = 2018Natur.556..463P | s2cid = 4933657 }}</ref> and wound healing.<ref>{{cite journal | vauthors = Kalluri R | title = EMT: when epithelial cells decide to become mesenchymal-like cells | journal = The Journal of Clinical Investigation | volume = 119 | issue = 6 | pages = 1417–9 | date = June 2009 | pmid = 19487817 | pmc = 2689122 | doi = 10.1172/JCI39675 }}</ref>

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== Introduction ==
⚫
==MET in development==
Unlike [[epithelial cells]] – which are stationary and characterized by an apico-basal polarity with binding by a [[basal lamina]], [[tight junction]]s, [[gap junction]]s, [[Adherens junction|adherent junctions]] and expression of cell-cell adhesion markers such as [[E-cadherin]],<ref name=":1">{{cite journal | vauthors = Das V, Bhattacharya S, Chikkaputtaiah C, Hazra S, Pal M | title = The basics of epithelial-mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective | journal = Journal of Cellular Physiology | volume = 234 | issue = 9 | pages = 14535–14555 | date = February 2019 | pmid = 30723913 | doi = 10.1002/jcp.28160 | s2cid = 73448308 }}</ref> mesenchymal cells do not make mature cell-cell contacts, can invade through the [[extracellular matrix]], and express markers such as [[vimentin]], [[fibronectin]], [[N-cadherin]], [[Twist transcription factor|Twist]], and [[SNAI1|Snail]].<ref name=":1" /> MET plays also a critical role in metabolic switching and [[epigenetic modifications]]. In general epithelium-associated genes are upregulated and [[mesenchyme]]-associated genes are downregulated in the process of MET.<ref>{{cite journal | vauthors = Owusu-Akyaw A, Krishnamoorthy K, Goldsmith LT, Morelli SS | title = The role of mesenchymal-epithelial transition in endometrial function | journal = Human Reproduction Update | volume = 25 | issue = 1 | pages = 114–133 | date = January 2019 | pmid = 30407544 | doi = 10.1093/humupd/dmy035 | doi-access = free }}</ref>
During [[embryogenesis]] and early development, cells switch back and forth between different cellular phenotypes via MET and its reverse process, [[epithelial–mesenchymal transition]] (EMT). Developmental METs have been studied most extensively in embryogenesis during [[nephrogenesis]],<ref name="pmid9124036">{{cite journal | author=Davies JA. | title = Mesenchyme to epithelium transition during development of the mammalian kidney tubule | journal=Acta Anat | volume = 156 | issue = 3 | pages = 187–201| year = 1996 | pmid = 9124036 | url = | issn = | doi = 10.1159/000147846 }}</ref> but also occurs in somitogenesis,<ref name="pmid15363416">{{cite journal |vauthors=Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K, Takahashi Y | title = Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1 | journal=Dev Cell | volume = 7 | issue = 3 | pages = 425–38 | year = 2004 | pmid = 15363416 | url = | issn = | doi=10.1016/j.devcel.2004.08.003}}</ref> cardiogenesis,<ref name="pmid10645959">{{cite journal |vauthors=Nakajima Y, Yamagishi T, Hokari S, Nakamura H | title = Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) | journal=Anat Rec | volume = 258 | issue = 2 | pages = 119–27 | year = 2000 | pmid = 10645959 | url = | issn = | doi = 10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U }}</ref> and hepatogenesis.<ref name="pmid21347296">{{cite journal | author=Li B, Zheng YW, Sano Y, Taniguchi H. | title = Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation | journal=PLoS ONE | volume = 6 | issue = 2 | pages = e17092 | year = 2011 | pmid =21347296 | url = | issn = | doi=10.1371/journal.pone.0017092 | pmc=3037942 | editor1-last = Abdelhay | editor1-first = Eliana}}</ref> While the mechanism in which MET occurs during each organ morphogenesis is similar in that epithelium-associated genes are upregulated and mesenchyme-associated genes are downregulated, each process has a unique signaling pathway to induce MET and these changes in gene expression profiles.{{citation needed|date=March 2016}}

⚫
==In development==
[[File:3311.fig.1.jpg|thumb|EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition|455x455px]]
During [[embryogenesis]] and early development, cells switch back and forth between different cellular phenotypes via MET and its reverse process, [[epithelial–mesenchymal transition]] (EMT). Developmental METs have been studied most extensively in [[Embryonic development|embryogenesis]] during [[somitogenesis]]<ref>{{cite journal | vauthors = Hamidi S, Nakaya Y, Nagai H, Alev C, Shibata T, Sheng G | title = Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast | journal = Physical Biology | volume = 16 | issue = 4 | pages = 041002 | date = April 2019 | pmid = 30875695 | doi = 10.1088/1478-3975/ab1048 | bibcode = 2019PhBio..16d1002H | s2cid = 80627655 }}</ref> and [[nephrogenesis]]<ref name=":2">{{cite journal | vauthors = Holmquist Mengelbier L, Lindell-Munther S, Yasui H, Jansson C, Esfandyari J, Karlsson J, Lau K, Hui CC, Bexell D, Hopyan S, Gisselsson D | display-authors = 6 | title = The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis | journal = The Journal of Pathology | volume = 247 | issue = 1 | pages = 86–98 | date = January 2019 | pmid = 30246301 | pmc = 6588170 | doi = 10.1002/path.5171 }}</ref> and [[carcinogenesis]] during [[metastasis]],<ref name=":3">{{cite journal | vauthors = Liao TT, Yang MH | title = Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness | journal = Molecular Oncology | volume = 11 | issue = 7 | pages = 792–804 | date = July 2017 | pmid = 28649800 | pmc = 5496497 | doi = 10.1002/1878-0261.12096 }}</ref> but it also occurs in [[Heart development|cardiogenesis]]<ref name=":4">{{cite journal | vauthors = Nebigil CG, Désaubry L | title = The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT) | journal = Trends in Cardiovascular Medicine | volume = 29 | issue = 4 | pages = 200–204 | date = May 2019 | pmid = 30172578 | doi = 10.1016/j.tcm.2018.08.007 | doi-access = free }}</ref> or [[foregut]] development.<ref>{{cite journal| vauthors = Mu T, Xu L, Zhong Y, Liu X, Zhao Z, Huang C, Lan X, Lufei C, Zhou Y, Su Y, Xu L | display-authors = 6 |date=2019-07-30|title=Characterizing the Emergence of Liver and Gallbladder from the Embryonic Endoderm through Single-Cell RNA-Seq|language=en|doi=10.1101/718775|doi-access=free}}</ref> MET is an essential process in embryogenesis to gather mesenchymal-like cells into cohesive structures.<ref name=":0" /> Although the mechanism of MET during various organs morphogenesis is quite similar, each process has a unique signaling pathway to induce changes in gene expression profiles.


===Nephrogenesis===
===Nephrogenesis===
One example of this, the most well described of the developmental METs, is kidney [[ontogenesis]]. The mammalian kidney is primarily formed by two early structures: the ureteric bud and the nephrogenic mesenchyme, which form the collecting duct and nephrons respectively (see [[kidney development]] for more details). During kidney ontogenesis, a reciprocal induction of the ureteric bud epithelium and nephrogenic mesenchyme occurs. As the ureteric bud grows out of the Wolffian duct, the nephrogenic mesenchyme induces the ureteric bud to branch. Concurrently, the ureteric bud induces the nephrogenic mesenchyme to condense around the bud and undergo MET to form the renal epithelium, which ultimately forms the nephron.<ref name="pmid8395349">{{cite journal |vauthors=Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R | title = WT-1 is required for early kidney development | journal=Cell | volume = 74 | issue = 4 | pages = 679–91 | year = 1993 | pmid =8395349 | url = | issn = | doi = 10.1016/0092-8674(93)90515-R }}</ref> Growth factors, integrins, cell adhesion molecules, and protooncogenes, such as ''c-ret'', ''c-ros'', and ''c-met'', mediate the reciprocal induction in metanephrons and consequent MET.<ref name="pmid10508232">{{cite journal |vauthors=Horster MF, Braun GS, Huber SM | title = Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation | journal=Physiol Rev | volume = 79 | issue = 4 | pages = 1157–91| year = 1999 | pmid = 10508232 | url = | issn = }}</ref>
One example of this, the most well described of the developmental METs, is kidney [[ontogenesis]]. The [[mammalian kidney]] is primarily formed by two early structures: the ureteric bud and the nephrogenic mesenchyme, which form the collecting duct and nephrons respectively (see [[kidney development]] for more details). During kidney ontogenesis, a reciprocal induction of the ureteric bud epithelium and nephrogenic mesenchyme occurs. As the ureteric bud grows out of the Wolffian duct, the nephrogenic mesenchyme induces the ureteric bud to branch. Concurrently, the ureteric bud induces the nephrogenic mesenchyme to condense around the bud and undergo MET to form the renal epithelium, which ultimately forms the [[nephron]].<ref name=":2" /> [[Growth factor]]s, [[integrin]]s, cell adhesion molecules, and [[Proto oncogenes|protooncogenes]], such as ''c-ret'', ''c-ros'', and ''c-met'', mediate the reciprocal induction in metanephrons and consequent MET.<ref>{{cite journal | vauthors = Horster MF, Braun GS, Huber SM | title = Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation | journal = Physiological Reviews | volume = 79 | issue = 4 | pages = 1157–91 | date = October 1999 | pmid = 10508232 | doi = 10.1152/physrev.1999.79.4.1157 }}</ref>


===Somitogenesis===
===Somitogenesis===
Another example of developmental MET occurs during [[somitogenesis]]. Vertebrate somites, the precursors of axial bones and trunk skeletal muscles, are formed by the maturation of the presomitic mesoderm (PSM). The PSM, which is composed of mesenchymal cells, undergoes segmentation by delineating somite boundaries (see [[somitogenesis]] for more details). Each somite is encapsulated by an epithelium, formerly mesenchymal cells that had undergone MET. Two [[Rho family of GTPases|Rho family GTPases]] – [[Cdc42]] and [[Rac1]] – as well as the transcription factor [[Paraxis]] are required for chick somitic MET.<ref name="pmid15363416"/>
Another example of developmental MET occurs during [[somitogenesis]]. Vertebrate somites, the precursors of axial bones and trunk skeletal muscles, are formed by the maturation of the [[presomitic mesoderm]] (PSM). The PSM, which is composed of mesenchymal cells, undergoes segmentation by delineating somite boundaries (see [[somitogenesis]] for more details). Each somite is encapsulated by an epithelium, formerly mesenchymal cells that had undergone MET. Two [[Rho family of GTPases|Rho family GTPases]] – [[Cdc42]] and [[Rac1]] – as well as the transcription factor [[Paraxis]] are required for chick somitic MET.<ref>{{cite journal | vauthors = Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K, Takahashi Y | title = Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1 | journal = Developmental Cell | volume = 7 | issue = 3 | pages = 425–38 | date = September 2004 | pmid = 15363416 | doi = 10.1016/j.devcel.2004.08.003 | doi-access = free }}</ref>

⚫
===Cardiogenesis ===
Development of heart is involved in several rounds of EMT and MET. While development [[splanchnopleure]] undergo EMT and produce [[Endothelium|endothelial]] progenitors, these then form the [[endocardium]] through MET. [[Pericardium]] is formed by [[sinus venosus]] mesenchymal cells that undergo MET.<ref name=":0" /> Quite similar processes occur also while regeneration in the injured heart. Injured pericardium undergoes EMT and is transformed into [[adipocyte]]s or [[myofibroblast]]s which induce [[arrhythmia]] and scars. MET than leads to the formation of vascular and epithelial progenitors that can differentiate into vasculogenic cells which lead to regeneration of heart injury.<ref name=":4" />


===Hepatogenesis===
⚫
===Cardiogenesis and hepatogenesis===
{{empty section|date=March 2016}}<ref name="pmid21347296">{{cite journal | vauthors = Li B, Zheng YW, Sano Y, Taniguchi H | title = Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation | journal = PLOS ONE| volume = 6 | issue = 2 | pages = e17092 | date = February 2011 | pmid = 21347296 | pmc = 3037942 | doi = 10.1371/journal.pone.0017092 | veditors = Abdelhay E | bibcode = 2011PLoSO...617092L | doi-access = free }}</ref>
{{empty section|date=March 2016}} <ref name="pmid10645959"/><ref name="pmid21347296"/>


==MET in cancer==
==In cancer==
[[File:EMT and MET while metastasis.jpg|thumb|EMT/MET process while metastasis|384x384px]]
While relatively little is known about the role MET plays in cancer when compared to the extensive studies of EMT in tumor metastasis, MET is believed to participate in the establishment and stabilization of distant metastases by allowing cancerous cells to regain epithelial properties and integrate into distant organs.<ref name="pmid18539112">{{cite journal |vauthors=Yang J, Weinberg RA | title = Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis | journal=Dev Cell | volume = 14 | issue = 6 | pages = 818–26| year = 2008| pmid = 18539112 | url = | issn = | doi=10.1016/j.devcel.2008.05.009}}</ref>
While relatively little is known about the role MET plays in cancer when compared to the extensive studies of EMT in [[tumor]] metastasis, MET is believed to participate in the establishment and stabilization of distant metastases by allowing cancerous cells to regain epithelial properties and integrate into distant organs. Between these two states, cells occur in 'intermediate‐state', or so‐called partial EMT.<ref name=":3" />


In recent years, researchers have begun to investigate MET as one of many potential therapeutic targets in the prevention of metastases.<ref name=Patt2016>[http://science.sciencemag.org/content/351/6277/aad3680 Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. March 2016.] doi=10.1126/science.aad3680</ref> This approach to preventing metastasis is known as differentiation-based therapy or [[differentiation therapy]].
In recent years, researchers have begun to investigate MET as one of many potential therapeutic targets in the prevention of metastases.<ref>{{cite journal | vauthors = Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, Reinhardt F, Tam WL, Weinberg RA | display-authors = 6 | title = Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability | journal = Science | volume = 351 | issue = 6277 | pages = aad3680 | date = March 2016 | pmid = 26941323 | pmc = 5131720 | doi = 10.1126/science.aad3680 }}</ref> This approach to preventing metastasis is known as differentiation-based therapy or [[differentiation therapy]] and it can be used for development of new anti-cancer therapeutic strategies.<ref name=":0" />


==MET in iPS cell reprogramming==
==In iPS cell reprogramming==
A number of different cellular processes must take place in order for somatic cells to undergo reprogramming into [[induced pluripotent stem cell]]s (iPS cells). iPS cell reprogramming, also known as somatic cell reprogramming, can be achieved by ectopic expression of Oct4, Klf4, Sox2, and c-Myc (OKSM).<ref name="pmid16904174">{{cite journal |vauthors=Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal=Cell | volume = 126 | issue = 6 | pages = 652–5| year = 2006| pmid = 16904174| url = | issn = | doi=10.1016/j.cell.2006.07.024}}</ref> Upon induction, mouse fibroblasts must undergo MET to successfully begin the initiation phase of reprogramming. Epithelial-associated genes such as E-cadherin/Cdh1, Cldns −3, −4, −7, −11, Occludin (Ocln), Epithelial cell adhesion molecule (Epcam), and Crumbs homolog 3 (Crb3), were all upregulated before [[Homeobox protein NANOG|Nanog]], a key transcription factor in maintaining pluripotency, was turned on. Additionally, mesenchymal-associated genes such as Snail, Slug, Zeb −1, −2, and N-cadherin were downregulated within the first 5 days post-OKSM induction.<ref name="pmid20621051">{{cite journal |vauthors=Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL | title = Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming | journal=Cell Stem Cell | volume = 7 | issue = 1 | pages = 64–77 | year = 2010| pmid = 20621051| url = | issn = | doi=10.1016/j.stem.2010.04.015}}</ref> Addition of exogenous TGF-β1, which blocks MET, decreased iPS reprogramming efficiency significantly.<ref name="pmid20621050">{{cite journal |vauthors=Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q, Qin B, Xu J, Li W, Yang J, Gan Y, Qin D, Feng S, Song H, Yang D, Zhang B, Zeng L, Lai L, Esteban MA, Pei D | title = A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts | journal=Cell Stem Cell | volume = 7 | issue = 1 | pages = 51–63 | year = 2010| pmid = 20621050 | url = | issn = | doi=10.1016/j.stem.2010.04.014}}</ref> These findings are all consistent with previous observations that [[embryonic stem cell]]s resemble epithelial cells and express E-cadherin.<ref name="pmid18343170 "/>
A number of different cellular processes must take place in order for somatic cells to undergo reprogramming into [[induced pluripotent stem cell]]s (iPS cells). iPS cell reprogramming, also known as somatic cell reprogramming, can be achieved by ectopic expression of [[Oct-4|Oct4]], [[KLF4|Klf4]], [[SOX21|Sox2]], and [[Myc|c-Myc]] (OKSM).<ref name="pmid16904174">{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–76 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 | hdl-access = free | hdl = 2433/159777 | s2cid = 1565219 }}</ref> Upon induction, mouse fibroblasts must undergo MET to successfully begin the initiation phase of reprogramming. Epithelial-associated genes such as E-cadherin/[[CDH1 (gene)|Cdh1]], [[CLDN3|Cldns]] −3, −4, −7, −11, [[Occludin]] (Ocln), [[Epithelial cell adhesion molecule]] (Epcam), and [[Crumbs homolog 3]] (Crb3), were all upregulated before [[Homeobox protein NANOG|Nanog]], a key [[transcription factor]] in maintaining [[pluripotency]], was turned on. Additionally, mesenchymal-associated genes such as Snail, Slug, Zeb −1, −2, and [[N-cadherin]] were downregulated within the first 5 days post-OKSM induction.<ref name="pmid20621051">{{cite journal | vauthors = Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL | display-authors = 6 | title = Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming | journal = Cell Stem Cell | volume = 7 | issue = 1 | pages = 64–77 | date = July 2010 | pmid = 20621051 | doi = 10.1016/j.stem.2010.04.015 | doi-access = free }}</ref> Addition of exogenous [[TGF beta 1|TGF-β1]], which blocks MET, decreased iPS reprogramming efficiency significantly.<ref name="pmid20621050">{{cite journal | vauthors = Li R, Liang J, Ni S, Zhou T, Qing X, Li H, He W, Chen J, Li F, Zhuang Q, Qin B, Xu J, Li W, Yang J, Gan Y, Qin D, Feng S, Song H, Yang D, Zhang B, Zeng L, Lai L, Esteban MA, Pei D | display-authors = 6 | title = A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts | journal = Cell Stem Cell | volume = 7 | issue = 1 | pages = 51–63 | date = July 2010 | pmid = 20621050 | doi = 10.1016/j.stem.2010.04.014 | doi-access = free }}</ref> These findings are all consistent with previous observations that [[embryonic stem cell]]s resemble epithelial cells and express E-cadherin.<ref name="pmid18343170">{{cite journal | vauthors = Baum B, Settleman J, Quinlan MP | title = Transitions between epithelial and mesenchymal states in development and disease | journal = Seminars in Cell & Developmental Biology | volume = 19 | issue = 3 | pages = 294–308 | date = June 2008 | pmid = 18343170 | doi = 10.1016/j.semcdb.2008.02.001 }}</ref>


Recent studies have suggested that ectopic expression of Klf4 in iPS cell reprogramming may be specifically responsible for inducing E-cadherin expression by binding to promoter regions and the first intron of ''CDH1'' (the gene encoding for E-cadherin).<ref name="pmid20621050"/>
Recent studies have suggested that ectopic expression of Klf4 in iPS cell reprogramming may be specifically responsible for inducing E-cadherin expression by binding to promoter regions and the first intron of ''CDH1'' (the gene encoding for E-cadherin).<ref name="pmid20621050"/>


==See also==
== See also ==
[[Epithelial–mesenchymal transition]]
* [[Epithelial–mesenchymal transition]]


==References==
== References ==
{{reflist|colwidth=30em}}
{{reflist}}


{{DEFAULTSORT:Mesenchymal-epithelial transition}}
{{DEFAULTSORT:Mesenchymal-epithelial transition}}

Latest revision as of 04:00, 19 August 2023

A mesenchymal–epithelial transition (MET) is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial–mesenchymal transition (EMT) and it has been shown to occur in normal development, induced pluripotent stem cell reprogramming,[1] cancer metastasis[2] and wound healing.[3]

Introduction

[edit]

Unlike epithelial cells – which are stationary and characterized by an apico-basal polarity with binding by a basal lamina, tight junctions, gap junctions, adherent junctions and expression of cell-cell adhesion markers such as E-cadherin,[4] mesenchymal cells do not make mature cell-cell contacts, can invade through the extracellular matrix, and express markers such as vimentin, fibronectin, N-cadherin, Twist, and Snail.[4] MET plays also a critical role in metabolic switching and epigenetic modifications. In general epithelium-associated genes are upregulated and mesenchyme-associated genes are downregulated in the process of MET.[5]

In development

[edit]
EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition

During embryogenesis and early development, cells switch back and forth between different cellular phenotypes via MET and its reverse process, epithelial–mesenchymal transition (EMT). Developmental METs have been studied most extensively in embryogenesis during somitogenesis[6] and nephrogenesis[7] and carcinogenesis during metastasis,[8] but it also occurs in cardiogenesis[9] or foregut development.[10] MET is an essential process in embryogenesis to gather mesenchymal-like cells into cohesive structures.[1] Although the mechanism of MET during various organs morphogenesis is quite similar, each process has a unique signaling pathway to induce changes in gene expression profiles.

Nephrogenesis

[edit]

One example of this, the most well described of the developmental METs, is kidney ontogenesis. The mammalian kidney is primarily formed by two early structures: the ureteric bud and the nephrogenic mesenchyme, which form the collecting duct and nephrons respectively (see kidney development for more details). During kidney ontogenesis, a reciprocal induction of the ureteric bud epithelium and nephrogenic mesenchyme occurs. As the ureteric bud grows out of the Wolffian duct, the nephrogenic mesenchyme induces the ureteric bud to branch. Concurrently, the ureteric bud induces the nephrogenic mesenchyme to condense around the bud and undergo MET to form the renal epithelium, which ultimately forms the nephron.[7] Growth factors, integrins, cell adhesion molecules, and protooncogenes, such as c-ret, c-ros, and c-met, mediate the reciprocal induction in metanephrons and consequent MET.[11]

Somitogenesis

[edit]

Another example of developmental MET occurs during somitogenesis. Vertebrate somites, the precursors of axial bones and trunk skeletal muscles, are formed by the maturation of the presomitic mesoderm (PSM). The PSM, which is composed of mesenchymal cells, undergoes segmentation by delineating somite boundaries (see somitogenesis for more details). Each somite is encapsulated by an epithelium, formerly mesenchymal cells that had undergone MET. Two Rho family GTPases – Cdc42 and Rac1 – as well as the transcription factor Paraxis are required for chick somitic MET.[12]

Cardiogenesis

[edit]

Development of heart is involved in several rounds of EMT and MET. While development splanchnopleure undergo EMT and produce endothelial progenitors, these then form the endocardium through MET. Pericardium is formed by sinus venosus mesenchymal cells that undergo MET.[1] Quite similar processes occur also while regeneration in the injured heart. Injured pericardium undergoes EMT and is transformed into adipocytes or myofibroblasts which induce arrhythmia and scars. MET than leads to the formation of vascular and epithelial progenitors that can differentiate into vasculogenic cells which lead to regeneration of heart injury.[9]

Hepatogenesis

[edit]

[13]

In cancer

[edit]
EMT/MET process while metastasis

While relatively little is known about the role MET plays in cancer when compared to the extensive studies of EMT in tumor metastasis, MET is believed to participate in the establishment and stabilization of distant metastases by allowing cancerous cells to regain epithelial properties and integrate into distant organs. Between these two states, cells occur in 'intermediate‐state', or so‐called partial EMT.[8]

In recent years, researchers have begun to investigate MET as one of many potential therapeutic targets in the prevention of metastases.[14] This approach to preventing metastasis is known as differentiation-based therapy or differentiation therapy and it can be used for development of new anti-cancer therapeutic strategies.[1]

In iPS cell reprogramming

[edit]

A number of different cellular processes must take place in order for somatic cells to undergo reprogramming into induced pluripotent stem cells (iPS cells). iPS cell reprogramming, also known as somatic cell reprogramming, can be achieved by ectopic expression of Oct4, Klf4, Sox2, and c-Myc (OKSM).[15] Upon induction, mouse fibroblasts must undergo MET to successfully begin the initiation phase of reprogramming. Epithelial-associated genes such as E-cadherin/Cdh1, Cldns −3, −4, −7, −11, Occludin (Ocln), Epithelial cell adhesion molecule (Epcam), and Crumbs homolog 3 (Crb3), were all upregulated before Nanog, a key transcription factor in maintaining pluripotency, was turned on. Additionally, mesenchymal-associated genes such as Snail, Slug, Zeb −1, −2, and N-cadherin were downregulated within the first 5 days post-OKSM induction.[16] Addition of exogenous TGF-β1, which blocks MET, decreased iPS reprogramming efficiency significantly.[17] These findings are all consistent with previous observations that embryonic stem cells resemble epithelial cells and express E-cadherin.[18]

Recent studies have suggested that ectopic expression of Klf4 in iPS cell reprogramming may be specifically responsible for inducing E-cadherin expression by binding to promoter regions and the first intron of CDH1 (the gene encoding for E-cadherin).[17]

See also

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References

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  5. ^ Owusu-Akyaw A, Krishnamoorthy K, Goldsmith LT, Morelli SS (January 2019). "The role of mesenchymal-epithelial transition in endometrial function". Human Reproduction Update. 25 (1): 114–133. doi:10.1093/humupd/dmy035. PMID 30407544.
  6. ^ Hamidi S, Nakaya Y, Nagai H, Alev C, Shibata T, Sheng G (April 2019). "Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast". Physical Biology. 16 (4): 041002. Bibcode:2019PhBio..16d1002H. doi:10.1088/1478-3975/ab1048. PMID 30875695. S2CID 80627655.
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  9. ^ a b Nebigil CG, Désaubry L (May 2019). "The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT)". Trends in Cardiovascular Medicine. 29 (4): 200–204. doi:10.1016/j.tcm.2018.08.007. PMID 30172578.
  10. ^ Mu T, Xu L, Zhong Y, Liu X, Zhao Z, Huang C, et al. (30 July 2019). "Characterizing the Emergence of Liver and Gallbladder from the Embryonic Endoderm through Single-Cell RNA-Seq". doi:10.1101/718775. {{cite journal}}: Cite journal requires |journal= (help)
  11. ^ Horster MF, Braun GS, Huber SM (October 1999). "Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation". Physiological Reviews. 79 (4): 1157–91. doi:10.1152/physrev.1999.79.4.1157. PMID 10508232.
  12. ^ Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K, Takahashi Y (September 2004). "Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1". Developmental Cell. 7 (3): 425–38. doi:10.1016/j.devcel.2004.08.003. PMID 15363416.
  13. ^ Li B, Zheng YW, Sano Y, Taniguchi H (February 2011). Abdelhay E (ed.). "Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation". PLOS ONE. 6 (2): e17092. Bibcode:2011PLoSO...617092L. doi:10.1371/journal.pone.0017092. PMC 3037942. PMID 21347296.
  14. ^ Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, et al. (March 2016). "Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability". Science. 351 (6277): aad3680. doi:10.1126/science.aad3680. PMC 5131720. PMID 26941323.
  15. ^ Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. hdl:2433/159777. PMID 16904174. S2CID 1565219.
  16. ^ Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, et al. (July 2010). "Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming". Cell Stem Cell. 7 (1): 64–77. doi:10.1016/j.stem.2010.04.015. PMID 20621051.
  17. ^ a b Li R, Liang J, Ni S, Zhou T, Qing X, Li H, et al. (July 2010). "A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts". Cell Stem Cell. 7 (1): 51–63. doi:10.1016/j.stem.2010.04.014. PMID 20621050.
  18. ^ Baum B, Settleman J, Quinlan MP (June 2008). "Transitions between epithelial and mesenchymal states in development and disease". Seminars in Cell & Developmental Biology. 19 (3): 294–308. doi:10.1016/j.semcdb.2008.02.001. PMID 18343170.
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