Mesenchymal–epithelial transition: Difference between revisions

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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] and cancer metastasis.^[2]

Introduction

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^[3], 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^[3]. MET playes 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^[4].

In development

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^[5] and nephrogenesis^[6] and carcinogenesis during metastasis^[7], but it also occurs in cardiogenesis^[8] or foregut development^[9]. 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

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^[6]. 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.^[10]

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 GTPases – Cdc42 and Rac1 – as well as the transcription factor Paraxis are required for chick somitic MET.^[11]

Cardiogenesis and hepatogenesis

^[12]^[13]

In cancer

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.^[7]

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.

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 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]

References

^ ^a ^b Pei, Duanqing; Shu, Xiaodong; Gassama-Diagne, Ama; Thiery, Jean Paul (January 2019). "Mesenchymal–epithelial transition in development and reprogramming". Nature Cell Biology. 21 (1): 44–53. doi:10.1038/s41556-018-0195-z. ISSN 1465-7392.
^ Pastushenko, Ievgenia; Brisebarre, Audrey; Sifrim, Alejandro; Fioramonti, Marco; Revenco, Tatiana; Boumahdi, Soufiane; Van Keymeulen, Alexandra; Brown, Daniel; Moers, Virginie; Lemaire, Sophie; De Clercq, Sarah (April 2018). "Identification of the tumour transition states occurring during EMT". Nature. 556 (7702): 463–468. doi:10.1038/s41586-018-0040-3. ISSN 0028-0836.
^ ^a ^b Das, Vishal; Bhattacharya, Sourya; Chikkaputtaiah, Channakeshavaiah; Hazra, Saugata; Pal, Mintu (2019-09). "The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective". Journal of Cellular Physiology. 234 (9): 14535–14555. doi:10.1002/jcp.28160. ISSN 0021-9541. {{cite journal}}: Check date values in: |date= (help)
^ Owusu-Akyaw, Amma; Krishnamoorthy, Kavitha; Goldsmith, Laura T; Morelli, Sara S (1 January 2019). "The role of mesenchymal–epithelial transition in endometrial function". Human Reproduction Update. 25 (1): 114–133. doi:10.1093/humupd/dmy035. ISSN 1355-4786.
^ Hamidi, Sofiane; Nakaya, Yukiko; Nagai, Hiroki; Alev, Cantas; Shibata, Tatsuo; Sheng, Guojun (23 April 2019). "Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast". Physical Biology. 16 (4): 041002. doi:10.1088/1478-3975/ab1048. ISSN 1478-3975.
^ ^a ^b Holmquist Mengelbier, Linda; Lindell-Munther, Simon; Yasui, Hiroaki; Jansson, Caroline; Esfandyari, Javanshir; Karlsson, Jenny; Lau, Kimberly; Hui, Chi-chung; Bexell, Daniel; Hopyan, Sevan; Gisselsson, David (2019-01). "The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis: IRX3 and IRX5 in Wilms tumour and mammalian nephrogenesis". The Journal of Pathology. 247 (1): 86–98. doi:10.1002/path.5171. PMC 6588170. PMID 30246301. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ ^a ^b Liao, Tsai-Tsen; Yang, Muh-Hwa (2017-07). "Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness". Molecular Oncology. 11 (7): 792–804. doi:10.1002/1878-0261.12096. PMC 5496497. PMID 28649800. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ Nebigil, Canan G.; Désaubry, Laurent (2019-05). "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. {{cite journal}}: Check date values in: |date= (help)
^ Mu, Tianhao; Xu, Liqin; Zhong, Yu; Liu, Xinyu; Zhao, Zhikun; Huang, Chaoben; Lan, Xiaofeng; Lufei, Chengchen; Zhou, Yi; Su, Yixun; Xu, Luang (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)
^ Horster, Michael F.; Braun, Gerald S.; Huber, Stephan M. (10 January 1999). "Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation". Physiological Reviews. 79 (4): 1157–1191. doi:10.1152/physrev.1999.79.4.1157. ISSN 0031-9333.
^ Nakaya, Yukiko; Kuroda, Shinya; Katagiri, Yuji T.; Kaibuchi, Kozo; Takahashi, Yoshiko (2004-09). "Mesenchymal-Epithelial Transition during Somitic Segmentation Is Regulated by Differential Roles of Cdc42 and Rac1". Developmental Cell. 7 (3): 425–438. doi:10.1016/j.devcel.2004.08.003. {{cite journal}}: Check date values in: |date= (help)
^ Nakajima Y, Yamagishi T, Hokari S, Nakamura H (2000). "Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP)". Anat Rec. 258 (2): 119–27. doi:10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U. PMID 10645959.
^ Li B, Zheng YW, Sano Y, Taniguchi H (2011). Abdelhay E (ed.). "Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation". PLoS ONE. 6 (2): e17092. doi:10.1371/journal.pone.0017092. PMC 3037942. PMID 21347296.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Pattabiraman, D. R.; Bierie, B.; Kober, K. I.; Thiru, P.; Krall, J. A.; Zill, C.; Reinhardt, F.; Tam, W. L.; Weinberg, R. A. (4 March 2016). "Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability". Science. 351 (6277): aad3680–aad3680. doi:10.1126/science.aad3680. ISSN 0036-8075. PMC 5131720. PMID 26941323.{{cite journal}}: CS1 maint: PMC format (link)
^ Takahashi K, Yamanaka S (2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (6): 652–5. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
^ Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL (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.
^ ^a ^b 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 (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.
^ Baum B, Settleman J, Quinlan MP (2008). "Transitions between epithelial and mesenchymal states in development and disease". Semin Cell Dev Biol. 19 (3): 294–308. doi:10.1016/j.semcdb.2008.02.001. PMID 18343170.

[:0-1] Pei, Duanqing; Shu, Xiaodong; Gassama-Diagne, Ama; Thiery, Jean Paul (January 2019). "Mesenchymal–epithelial transition in development and reprogramming". Nature Cell Biology. 21 (1): 44–53. doi:10.1038/s41556-018-0195-z. ISSN 1465-7392.

[2] Pastushenko, Ievgenia; Brisebarre, Audrey; Sifrim, Alejandro; Fioramonti, Marco; Revenco, Tatiana; Boumahdi, Soufiane; Van Keymeulen, Alexandra; Brown, Daniel; Moers, Virginie; Lemaire, Sophie; De Clercq, Sarah (April 2018). "Identification of the tumour transition states occurring during EMT". Nature. 556 (7702): 463–468. doi:10.1038/s41586-018-0040-3. ISSN 0028-0836.

[:1-3] Das, Vishal; Bhattacharya, Sourya; Chikkaputtaiah, Channakeshavaiah; Hazra, Saugata; Pal, Mintu (2019-09). "The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective". Journal of Cellular Physiology. 234 (9): 14535–14555. doi:10.1002/jcp.28160. ISSN 0021-9541. {{cite journal}}: Check date values in: |date= (help)

[4] Owusu-Akyaw, Amma; Krishnamoorthy, Kavitha; Goldsmith, Laura T; Morelli, Sara S (1 January 2019). "The role of mesenchymal–epithelial transition in endometrial function". Human Reproduction Update. 25 (1): 114–133. doi:10.1093/humupd/dmy035. ISSN 1355-4786.

[5] Hamidi, Sofiane; Nakaya, Yukiko; Nagai, Hiroki; Alev, Cantas; Shibata, Tatsuo; Sheng, Guojun (23 April 2019). "Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast". Physical Biology. 16 (4): 041002. doi:10.1088/1478-3975/ab1048. ISSN 1478-3975.

[:2-6] Holmquist Mengelbier, Linda; Lindell-Munther, Simon; Yasui, Hiroaki; Jansson, Caroline; Esfandyari, Javanshir; Karlsson, Jenny; Lau, Kimberly; Hui, Chi-chung; Bexell, Daniel; Hopyan, Sevan; Gisselsson, David (2019-01). "The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis: IRX3 and IRX5 in Wilms tumour and mammalian nephrogenesis". The Journal of Pathology. 247 (1): 86–98. doi:10.1002/path.5171. PMC 6588170. PMID 30246301. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:3-7] Liao, Tsai-Tsen; Yang, Muh-Hwa (2017-07). "Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness". Molecular Oncology. 11 (7): 792–804. doi:10.1002/1878-0261.12096. PMC 5496497. PMID 28649800. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[8] Nebigil, Canan G.; Désaubry, Laurent (2019-05). "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. {{cite journal}}: Check date values in: |date= (help)

[9] Mu, Tianhao; Xu, Liqin; Zhong, Yu; Liu, Xinyu; Zhao, Zhikun; Huang, Chaoben; Lan, Xiaofeng; Lufei, Chengchen; Zhou, Yi; Su, Yixun; Xu, Luang (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)

[10] Horster, Michael F.; Braun, Gerald S.; Huber, Stephan M. (10 January 1999). "Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation". Physiological Reviews. 79 (4): 1157–1191. doi:10.1152/physrev.1999.79.4.1157. ISSN 0031-9333.

[11] Nakaya, Yukiko; Kuroda, Shinya; Katagiri, Yuji T.; Kaibuchi, Kozo; Takahashi, Yoshiko (2004-09). "Mesenchymal-Epithelial Transition during Somitic Segmentation Is Regulated by Differential Roles of Cdc42 and Rac1". Developmental Cell. 7 (3): 425–438. doi:10.1016/j.devcel.2004.08.003. {{cite journal}}: Check date values in: |date= (help)

[pmid10645959-12] Nakajima Y, Yamagishi T, Hokari S, Nakamura H (2000). "Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP)". Anat Rec. 258 (2): 119–27. doi:10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U. PMID 10645959.

[pmid21347296-13] Li B, Zheng YW, Sano Y, Taniguchi H (2011). Abdelhay E (ed.). "Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation". PLoS ONE. 6 (2): e17092. doi:10.1371/journal.pone.0017092. PMC 3037942. PMID 21347296.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[14] Pattabiraman, D. R.; Bierie, B.; Kober, K. I.; Thiru, P.; Krall, J. A.; Zill, C.; Reinhardt, F.; Tam, W. L.; Weinberg, R. A. (4 March 2016). "Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability". Science. 351 (6277): aad3680–aad3680. doi:10.1126/science.aad3680. ISSN 0036-8075. PMC 5131720. PMID 26941323.{{cite journal}}: CS1 maint: PMC format (link)

[pmid16904174-15] Takahashi K, Yamanaka S (2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (6): 652–5. doi:10.1016/j.cell.2006.07.024. PMID 16904174.

[pmid20621051-16] Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA, Datti A, Woltjen K, Nagy A, Wrana JL (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.

[pmid20621050-17] 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 (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.

[pmid18343170-18] Baum B, Settleman J, Quinlan MP (2008). "Transitions between epithelial and mesenchymal states in development and disease". Semin Cell Dev Biol. 19 (3): 294–308. doi:10.1016/j.semcdb.2008.02.001. PMID 18343170.

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 {{Use dmy dates|date=May 2012}}
-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|last=Pei|first=Duanqing|last2=Shu|first2=Xiaodong|last3=Gassama-Diagne|first3=Ama|last4=Thiery|first4=Jean Paul|date=January 2019|title=Mesenchymal–epithelial transition in development and reprogramming|url=http://www.nature.com/articles/s41556-018-0195-z|journal=Nature Cell Biology|language=en|volume=21|issue=1|pages=44–53|doi=10.1038/s41556-018-0195-z|issn=1465-7392}}</ref> and cancer [[metastasis]].<ref>{{Cite journal|last=Pastushenko|first=Ievgenia|last2=Brisebarre|first2=Audrey|last3=Sifrim|first3=Alejandro|last4=Fioramonti|first4=Marco|last5=Revenco|first5=Tatiana|last6=Boumahdi|first6=Soufiane|last7=Van Keymeulen|first7=Alexandra|last8=Brown|first8=Daniel|last9=Moers|first9=Virginie|last10=Lemaire|first10=Sophie|last11=De Clercq|first11=Sarah|date=April 2018|title=Identification of the tumour transition states occurring during EMT|url=http://dx.doi.org/10.1038/s41586-018-0040-3|journal=Nature|volume=556|issue=7702|pages=463–468|doi=10.1038/s41586-018-0040-3|issn=0028-0836}}</ref>
+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|last=Pei|first=Duanqing|last2=Shu|first2=Xiaodong|last3=Gassama-Diagne|first3=Ama|last4=Thiery|first4=Jean Paul|date=January 2019|title=Mesenchymal–epithelial transition in development and reprogramming|url=http://www.nature.com/articles/s41556-018-0195-z|journal=Nature Cell Biology|language=en|volume=21|issue=1|pages=44–53|doi=10.1038/s41556-018-0195-z|issn=1465-7392}}</ref> and cancer [[metastasis]].<ref>{{Cite journal|last=Pastushenko|first=Ievgenia|last2=Brisebarre|first2=Audrey|last3=Sifrim|first3=Alejandro|last4=Fioramonti|first4=Marco|last5=Revenco|first5=Tatiana|last6=Boumahdi|first6=Soufiane|last7=Van Keymeulen|first7=Alexandra|last8=Brown|first8=Daniel|last9=Moers|first9=Virginie|last10=Lemaire|first10=Sophie|last11=De Clercq|first11=Sarah|date=April 2018|title=Identification of the tumour transition states occurring during EMT|url=http://dx.doi.org/10.1038/s41586-018-0040-3|journal=Nature|volume=556|issue=7702|pages=463–468|doi=10.1038/s41586-018-0040-3|issn=0028-0836}}</ref>
 __TOC__
 == Introduction ==
-[[File:3311.fig.1.jpg|thumb|EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition|483x483px]]
 Unlike [[epithelial cells]] – which are stationary and characterized by an apico-basal polarity with binding by a [[basal lamina]], [[Tight junction|tight junctions]], [[Gap junction|gap junctions]], [[Adherens junction|adherent junctions]] and expression of cell-cell adhesion markers such as [[E-cadherin]]<ref name=":1">{{Cite journal|last=Das|first=Vishal|last2=Bhattacharya|first2=Sourya|last3=Chikkaputtaiah|first3=Channakeshavaiah|last4=Hazra|first4=Saugata|last5=Pal|first5=Mintu|date=2019-09|title=The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28160|journal=Journal of Cellular Physiology|language=en|volume=234|issue=9|pages=14535–14555|doi=10.1002/jcp.28160|issn=0021-9541}}</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 playes 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|last=Owusu-Akyaw|first=Amma|last2=Krishnamoorthy|first2=Kavitha|last3=Goldsmith|first3=Laura T|last4=Morelli|first4=Sara S|date=2019-01-01|title=The role of mesenchymal–epithelial transition in endometrial function|url=https://academic.oup.com/humupd/article/25/1/114/5165112|journal=Human Reproduction Update|language=en|volume=25|issue=1|pages=114–133|doi=10.1093/humupd/dmy035|issn=1355-4786}}</ref>.
 ==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|last=Hamidi|first=Sofiane|last2=Nakaya|first2=Yukiko|last3=Nagai|first3=Hiroki|last4=Alev|first4=Cantas|last5=Shibata|first5=Tatsuo|last6=Sheng|first6=Guojun|date=2019-04-23|title=Biomechanical regulation of EMT and epithelial morphogenesis in amniote epiblast|url=https://iopscience.iop.org/article/10.1088/1478-3975/ab1048|journal=Physical Biology|volume=16|issue=4|pages=041002|doi=10.1088/1478-3975/ab1048|issn=1478-3975}}</ref> and [[nephrogenesis]]<ref name=":2">{{Cite journal|last=Holmquist Mengelbier|first=Linda|last2=Lindell-Munther|first2=Simon|last3=Yasui|first3=Hiroaki|last4=Jansson|first4=Caroline|last5=Esfandyari|first5=Javanshir|last6=Karlsson|first6=Jenny|last7=Lau|first7=Kimberly|last8=Hui|first8=Chi-chung|last9=Bexell|first9=Daniel|last10=Hopyan|first10=Sevan|last11=Gisselsson|first11=David|date=2019-01|title=The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis: IRX3 and IRX5 in Wilms tumour and mammalian nephrogenesis|url=http://doi.wiley.com/10.1002/path.5171|journal=The Journal of Pathology|language=en|volume=247|issue=1|pages=86–98|doi=10.1002/path.5171|pmc=PMC6588170|pmid=30246301}}</ref> and [[carcinogenesis]] during [[metastasis]]<ref name=":3">{{Cite journal|last=Liao|first=Tsai-Tsen|last2=Yang|first2=Muh-Hwa|date=2017-07|title=Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness|url=http://doi.wiley.com/10.1002/1878-0261.12096|journal=Molecular Oncology|language=en|volume=11|issue=7|pages=792–804|doi=10.1002/1878-0261.12096|pmc=PMC5496497|pmid=28649800}}</ref>, but it also occurs in [[Heart development|cardiogenesis]]<ref>{{Cite journal|last=Nebigil|first=Canan G.|last2=Désaubry|first2=Laurent|date=2019-05|title=The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT)|url=https://linkinghub.elsevier.com/retrieve/pii/S1050173818301701|journal=Trends in Cardiovascular Medicine|language=en|volume=29|issue=4|pages=200–204|doi=10.1016/j.tcm.2018.08.007}}</ref> or [[foregut]] development<ref>{{Cite journal|last=Mu|first=Tianhao|last2=Xu|first2=Liqin|last3=Zhong|first3=Yu|last4=Liu|first4=Xinyu|last5=Zhao|first5=Zhikun|last6=Huang|first6=Chaoben|last7=Lan|first7=Xiaofeng|last8=Lufei|first8=Chengchen|last9=Zhou|first9=Yi|last10=Su|first10=Yixun|last11=Xu|first11=Luang|date=2019-07-30|title=Characterizing the Emergence of Liver and Gallbladder from the Embryonic Endoderm through Single-Cell RNA-Seq|url=http://biorxiv.org/lookup/doi/10.1101/718775|language=en|doi=10.1101/718775}}</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=":2" />. [[Growth factor|Growth factors]], [[Integrin|integrins]], 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|last=Horster|first=Michael F.|last2=Braun|first2=Gerald S.|last3=Huber|first3=Stephan M.|date=1999-01-10|title=Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation|url=https://www.physiology.org/doi/10.1152/physrev.1999.79.4.1157|journal=Physiological Reviews|language=en|volume=79|issue=4|pages=1157–1191|doi=10.1152/physrev.1999.79.4.1157|issn=0031-9333}}</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|Growth factors]], [[Integrin|integrins]], 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|last=Horster|first=Michael F.|last2=Braun|first2=Gerald S.|last3=Huber|first3=Stephan M.|date=1999-01-10|title=Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation|url=https://www.physiology.org/doi/10.1152/physrev.1999.79.4.1157|journal=Physiological Reviews|language=en|volume=79|issue=4|pages=1157–1191|doi=10.1152/physrev.1999.79.4.1157|issn=0031-9333}}</ref>
 ===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>{{Cite journal|last=Nakaya|first=Yukiko|last2=Kuroda|first2=Shinya|last3=Katagiri|first3=Yuji T.|last4=Kaibuchi|first4=Kozo|last5=Takahashi|first5=Yoshiko|date=2004-09|title=Mesenchymal-Epithelial Transition during Somitic Segmentation Is Regulated by Differential Roles of Cdc42 and Rac1|url=https://linkinghub.elsevier.com/retrieve/pii/S1534580704002783|journal=Developmental Cell|language=en|volume=7|issue=3|pages=425–438|doi=10.1016/j.devcel.2004.08.003}}</ref>
+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|last=Nakaya|first=Yukiko|last2=Kuroda|first2=Shinya|last3=Katagiri|first3=Yuji T.|last4=Kaibuchi|first4=Kozo|last5=Takahashi|first5=Yoshiko|date=2004-09|title=Mesenchymal-Epithelial Transition during Somitic Segmentation Is Regulated by Differential Roles of Cdc42 and Rac1|url=https://linkinghub.elsevier.com/retrieve/pii/S1534580704002783|journal=Developmental Cell|language=en|volume=7|issue=3|pages=425–438|doi=10.1016/j.devcel.2004.08.003}}</ref>
+===Cardiogenesis and hepatogenesis===
+{{empty section|date=March 2016}} <ref name="pmid10645959">{{cite journal|vauthors=Nakajima Y, Yamagishi T, Hokari S, Nakamura H|year=2000|title=Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP)|url=|journal=Anat Rec|volume=258|issue=2|pages=119–27|doi=10.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U|issn=|pmid=10645959}}</ref><ref name="pmid21347296">{{cite journal|vauthors=Li B, Zheng YW, Sano Y, Taniguchi H|year=2011|editor1-last=Abdelhay|editor1-first=Eliana|title=Evidence for mesenchymal-epithelial transition associated with mouse hepatic stem cell differentiation|url=|journal=PLoS ONE|volume=6|issue=2|pages=e17092|doi=10.1371/journal.pone.0017092|issn=|pmc=3037942|pmid=21347296}}</ref>
 ==In cancer==
-[[File:EMT and MET while metastasis.jpg|thumb|EMT/MET process while metastasis|493x493px]]
 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=":3" />
 In recent years, researchers have begun to investigate MET as one of many potential therapeutic targets in the prevention of metastases.<ref>{{Cite journal|last=Pattabiraman|first=D. R.|last2=Bierie|first2=B.|last3=Kober|first3=K. I.|last4=Thiru|first4=P.|last5=Krall|first5=J. A.|last6=Zill|first6=C.|last7=Reinhardt|first7=F.|last8=Tam|first8=W. L.|last9=Weinberg|first9=R. A.|date=2016-03-04|title=Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability|url=http://www.sciencemag.org/cgi/doi/10.1126/science.aad3680|journal=Science|language=en|volume=351|issue=6277|pages=aad3680–aad3680|doi=10.1126/science.aad3680|issn=0036-8075|pmc=PMC5131720|pmid=26941323}}</ref> This approach to preventing metastasis is known as differentiation-based therapy or [[differentiation therapy]].
 ==In iPS  cell reprogramming==