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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 cell]]s 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 junction]]s, 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 transcription factor|Twist]], and [[SNAI1|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>{{Cite journal|last=Pei|first=Duanqing|last2=Shu|first2=Xiaodong|last3=Gassama-Diagne|first3=Ama|last4=Thiery|first4=Jean Paul|date=2019-01|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=2018-04|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>.

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== Introduction ==
Unlike [[epithelial cells]] – which are stationary and characterized by an apical-basal polarity, [[tight junction]]s, and expression of cell-cell adhesion markers such as [[E-cadherin]]<ref>{{Cite journal|last=Rodriguez-Boulan|first=Enrique|last2=Macara|first2=Ian G.|date=2014-04|title=Organization and execution of the epithelial polarity programme|url=http://www.nature.com/articles/nrm3775|journal=Nature Reviews Molecular Cell Biology|language=en|volume=15|issue=4|pages=225–242|doi=10.1038/nrm3775|issn=1471-0072}}</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="pmid18343170">{{cite journal|vauthors=Baum B, Settleman J, Quinlan MP|year=2008|title=Transitions between epithelial and mesenchymal states in development and disease|url=|journal=Semin Cell Dev Biol|volume=19|issue=3|pages=294–308|doi=10.1016/j.semcdb.2008.02.001|issn=|pmid=18343170}}</ref><ref name="pmid12189386">{{cite journal|author=Thiery JP.|year=2002|title=Epithelial-mesenchymal transitions in tumour progression|url=|journal=Nat Rev Cancer|volume=2|issue=6|pages=442–54|doi=10.1038/nrc822|issn=|pmid=12189386}}</ref> MET playes also a critical role in metabolic switching and epigenetic modifications<ref>{{Cite journal|last=Wu|first=Jun|last2=Ocampo|first2=Alejandro|last3=Belmonte|first3=Juan Carlos Izpisua|date=2016-09|title=Cellular Metabolism and Induced Pluripotency|url=http://dx.doi.org/10.1016/j.cell.2016.08.008|journal=Cell|volume=166|issue=6|pages=1371–1385|doi=10.1016/j.cell.2016.08.008|issn=0092-8674}}</ref>.


==In development==
==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 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 Anatomica | 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 | 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 | 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}}
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 [[nephrogenesis]],<ref name="pmid9124036">{{cite journal | author=Davies JA. | title = Mesenchyme to epithelium transition during development of the mammalian kidney tubule | journal=Acta Anatomica | 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> [[Heart development|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 | 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 | 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}}


===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 = | doi = 10.1152/physrev.1999.79.4.1157 }}</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="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 = | doi = 10.1152/physrev.1999.79.4.1157 }}</ref>


Revision as of 15:30, 29 January 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) 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 apical-basal polarity, tight 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.[4][5] MET playes also a critical role in metabolic switching and epigenetic modifications[6].

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 nephrogenesis,[7] but also occurs in somitogenesis,[8] cardiogenesis,[9] and hepatogenesis.[10] 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]

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.[11] 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.[12]

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.[8]

Cardiogenesis and hepatogenesis

[9][10]

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.[13]

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.[4]

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

References

  1. ^ Pei, Duanqing; Shu, Xiaodong; Gassama-Diagne, Ama; Thiery, Jean Paul (2019-01). "Mesenchymal–epithelial transition in development and reprogramming". Nature Cell Biology. 21 (1): 44–53. doi:10.1038/s41556-018-0195-z. ISSN 1465-7392. {{cite journal}}: Check date values in: |date= (help)
  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 (2018-04). "Identification of the tumour transition states occurring during EMT". Nature. 556 (7702): 463–468. doi:10.1038/s41586-018-0040-3. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
  3. ^ Rodriguez-Boulan, Enrique; Macara, Ian G. (2014-04). "Organization and execution of the epithelial polarity programme". Nature Reviews Molecular Cell Biology. 15 (4): 225–242. doi:10.1038/nrm3775. ISSN 1471-0072. {{cite journal}}: Check date values in: |date= (help)
  4. ^ a b 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.
  5. ^ Thiery JP. (2002). "Epithelial-mesenchymal transitions in tumour progression". Nat Rev Cancer. 2 (6): 442–54. doi:10.1038/nrc822. PMID 12189386.
  6. ^ Wu, Jun; Ocampo, Alejandro; Belmonte, Juan Carlos Izpisua (2016-09). "Cellular Metabolism and Induced Pluripotency". Cell. 166 (6): 1371–1385. doi:10.1016/j.cell.2016.08.008. ISSN 0092-8674. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Davies JA. (1996). "Mesenchyme to epithelium transition during development of the mammalian kidney tubule". Acta Anatomica. 156 (3): 187–201. doi:10.1159/000147846. PMID 9124036.
  8. ^ a b Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K, Takahashi Y (2004). "Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1". Dev Cell. 7 (3): 425–38. doi:10.1016/j.devcel.2004.08.003. PMID 15363416.
  9. ^ a b 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.
  10. ^ a b 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)
  11. ^ Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993). "WT-1 is required for early kidney development". Cell. 74 (4): 679–91. doi:10.1016/0092-8674(93)90515-R. PMID 8395349.
  12. ^ Horster MF, Braun GS, Huber SM (1999). "Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation". Physiol Rev. 79 (4): 1157–91. doi:10.1152/physrev.1999.79.4.1157. PMID 10508232.
  13. ^ Yang J, Weinberg RA (2008). "Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis". Dev Cell. 14 (6): 818–26. doi:10.1016/j.devcel.2008.05.009. PMID 18539112.
  14. ^ Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. March 2016. doi=10.1126/science.aad3680
  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.
  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.
  17. ^ 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.
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