Mesenchymal–epithelial transition

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.[1][2] METs occur in normal development, cancer metastasis, and induced pluripotent stem cell reprogramming.

MET in development

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,[3] but also occurs in somitogenesis,[4] cardiogenesis,[5] and hepatogenesis.[6] 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.

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.[8]

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.[4]

MET 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.[9] In recent years, researchers have begun to investigate MET as one of many potential therapeutic targets in the prevention of metastases.

MET 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).[10] 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.[11] Addition of exogenous TGF-β1, which blocks MET, decreased iPS reprogramming efficiency significantly.[12] These findings are all consistent with previous observations that embryonic stem cells resemble epithelial cells and express E-cadherin.[1]

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).[12]

See also

Epithelial–mesenchymal transition

References

  1. 1 2 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.
  2. ↑ Thiery JP. (2002). "Epithelial-mesenchymal transitions in tumour progression". Nat Rev Cancer 2 (6): 442–54. doi:10.1038/nrc822. PMID 12189386.
  3. ↑ Davies JA. (1996). "Mesenchyme to epithelium transition during development of the mammalian kidney tubule". Acta Anat 156 (3): 187–201. doi:10.1159/000147846. PMID 9124036.
  4. 1 2 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.
  5. ↑ 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.
  6. ↑ Li B, Zheng YW, Sano Y, Taniguchi H. (2011). Abdelhay, Eliana, 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.
  7. ↑ 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.
  8. ↑ Horster MF, Braun GS, Huber SM. (1999). "Embryonic Renal Epithelia: Induction, Nephrogenesis, and Cell Differentiation". Physiol Rev 79 (4): 1157–91. PMID 10508232.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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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