Mesenchymal–epithelial transition in development and reprogramming

Pei, Duanqing; Shu, Xiaodong; Gassama‐Diagne, Ama; Thiery, Jean Paul

doi:10.1038/s41556-018-0195-z

Cited by 235 publications

(198 citation statements)

References 148 publications

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“…Phenotypic characterization of MC injury response. Recent evidence indicates that mesenchymal-toepithelial transition (MET) is crucial during early cell reprogramming and blocking MET can impair stem cell reprogramming [16]. Transcriptome analysis was used to investigate MET during early MC activation (Day 1), MC proliferation (Day 3), and MC regeneration/chronic reactive gliosis (Day 7) in both zebra sh and mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

Conedera

Pousa

Mercader

et al. 2020

Preprint

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Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals. There, MCs undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis. Methods Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the related MC response to human donors with early retinal degeneration. Results Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response. Conclusion This study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases.

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Section: Resultsmentioning

confidence: 99%

The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

Conedera

Pousa

Mercader

et al. 2020

Preprint

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“…Epithelial-mesenchymal transition (EMT, widely considered to be associated with tumor metastasis [36]) and its reverse process MET are basic mechanisms for cell fate conversion [52]. MET involves the progressive increase of epithelial cell polarity and upregulation of junctional complexes to form tight junctions at the apex of the lateral domain and the organization of cytoskeletal structures and organelles [53], accompanied by downregulated mesenchymal genes (E-cadherin, ZEB1, etc.) and upregulated epithelial genes (E-cadherin, P63, et c) [54].…”

Section: Discussionmentioning

confidence: 99%

“…MET is fundamental evolutionarily conserved mechanisms for cell fate conversion [52,53], accompanied by downregulated mesenchymal genes (E-cadherin, ZEB1, etc.) and upregulated epithelial genes (E-cadherin, P63, etc.)…”

Section: Gene Expression Analysismentioning

confidence: 99%

Epithelial differentiation of human adipose-derived stem cells (hASCs) undergoing three-dimensional (3D) cultivation with collagen sponge scaffold (CSS) via an indirect co-culture strategy

Gao

et al. 2020

Stem Cell Res Ther

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Background: Three-dimensional (3D) cultivation with biomaterials was proposed to facilitate stem cell epithelial differentiation for wound healing. However, whether human adipose-derived stem cells (hASCs) on collagen sponge scaffold (CSS) better differentiate to keratinocytes remains unclear. Methods: 3D cultivation with CSS on hASC epidermal differentiation co-cultured with HaCaT cells at air-liquid interface (ALI) was compared with two-dimensional (2D) form and cultivation without "co-culture" or "ALI." Cellular morphology, cell adhesion, and growth condition were evaluated, followed by the protein and gene expression of keratin 14 (K14, keratinocyte specific marker). Results: Typical cobblestone morphology of keratinocytes was remarkably observed in co-cultured hASCs at ALI, but those seeded on the CSS exhibited more keratinocyte-like cells under an invert microscope and scanning electron microscope. Desired cell adhesion and proliferation were confirmed in 3D differentiation groups by rhodamine-labeled phalloidin staining, consistent with H&E staining. Compared with those cultured in 2D culture system or without "ALI," immunofluorescence staining and gene expression analysis revealed hASCs co-cultured over CSS expressed K14 at higher levels at day 15. Conclusions: CSS is positive to promote epithelial differentiation of hASCs, which will foster a deeper understanding of artificial dermis in skin wound healing and regeneration.

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“…These findings have opened an entire field of research, which associates EMT's role in both, the physiological and pathological processes. Based on the biological/physiological context, it can be classified into three subtypes: 1) embryogenesis, organogenesis, 2) tissue homeostasis, repairing and fibrosis or 3) cancer progression and metastasis (Pei et al, 2019;Prieto-García et al, 2017;Stone et al, 2016). The transition of epithelial cells into mesenchymal cells follows a common and conserved program with several hallmarks.…”

Section: Regulation Of Emt By Protein Signaling Pathwaysmentioning

confidence: 99%

Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis

et al. 2019

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Epithelial to mesenchymal transition (EMT) is a process during which cancer cells lose epithelial features, cytoskeletal architecture is re-organized, cell shape changes and cells activate genes that help to define mesenchymal phenotype, what leads to an increased cell motility and dissemination of tumor to distant metastatic sites. This review describes different signaling networks between microRNAs and proteins that regulate EMT in tumor growth. Activation of EMT is mediated via series of paracrine signaling molecules. WNT, TGF-b, NOTCH and Shh signaling pathways play crucial roles in activation of EMT-related transcription factors, such as SNAIL, SLUG, ZEB1/2 or TWIST. Recent data provide evidence that crosstalk between microRNAs, long non-coding RNAs and EMT-transcription factors is crucial event in EMT regulation. MicroRNAs affect also level of proteins responsible for cellular contact, adhesion and cytoskeletal proteins, what induces changes of epithelial to mesenchymal phenotype. Understanding of those signaling networks may help to identify novel biomarkers or develop new treatment strategies based on microRNA therapeutics in future.

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Mesenchymal–epithelial transition in development and reprogramming

Cited by 235 publications

References 148 publications

The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

Epithelial differentiation of human adipose-derived stem cells (hASCs) undergoing three-dimensional (3D) cultivation with collagen sponge scaffold (CSS) via an indirect co-culture strategy

Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis

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