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Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal

Understanding the mechanisms that direct mesenchymal stem cell (MSC) self-renewal fate decisions is a key to most tissue regenerative approaches. The aim of this study here was to investigate the mechanisms of action of platelet-derived growth factor receptor β (PDGFRβ) signalling on MSC proliferati...

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Autores principales: Gharibi, Borzo, Ghuman, Mandeep S, Hughes, Francis J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118247/
https://www.ncbi.nlm.nih.gov/pubmed/22805337
http://dx.doi.org/10.1111/j.1582-4934.2012.01602.x
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author Gharibi, Borzo
Ghuman, Mandeep S
Hughes, Francis J
author_facet Gharibi, Borzo
Ghuman, Mandeep S
Hughes, Francis J
author_sort Gharibi, Borzo
collection PubMed
description Understanding the mechanisms that direct mesenchymal stem cell (MSC) self-renewal fate decisions is a key to most tissue regenerative approaches. The aim of this study here was to investigate the mechanisms of action of platelet-derived growth factor receptor β (PDGFRβ) signalling on MSC proliferation and differentiation. MSC were cultured and stimulated with PDGF-BB together with inhibitors of second messenger pathways. Cell proliferation was assessed using ethynyl-2′-deoxyuridine and phosphorylation status of signalling molecules assessed by Western Blots. To assess differentiation potentials, cells were transferred to adipogenic or osteogenic media, and differentiation assessed by expression of differentiation association genes by qRT-PCR, and by long-term culture assays. Our results showed that distinct pathways with opposing actions were activated by PDGF. PI3K/Akt signalling was the main contributor to MSC proliferation in response to activation of PDGFRβ. We also demonstrate a negative feedback mechanism between PI3K/Akt and PDGFR-β expression. In addition, PI3K/Akt downstream signal cascades, mTOR and its associated proteins p70S6K and 4E-BP1 were involved. These pathways induced the expression of cyclin D1, cyclin D3 and CDK6 to promote cell cycle progression and MSC proliferation. In contrast, activation of Erk by PDGFRβ signalling potently inhibited the adipocytic differentiation of MSCs by blocking PPARγ and CEBPα expression. The data suggest that PDGFRβ-induced Akt and Erk pathways regulate opposing fate decisions of proliferation and differentiation to promote MSC self-renewal. Thus, activation of multiple intracellular cascades is required for successful and sustainable MSC self-renewal strategies.
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spelling pubmed-41182472015-03-25 Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal Gharibi, Borzo Ghuman, Mandeep S Hughes, Francis J J Cell Mol Med Original Articles Understanding the mechanisms that direct mesenchymal stem cell (MSC) self-renewal fate decisions is a key to most tissue regenerative approaches. The aim of this study here was to investigate the mechanisms of action of platelet-derived growth factor receptor β (PDGFRβ) signalling on MSC proliferation and differentiation. MSC were cultured and stimulated with PDGF-BB together with inhibitors of second messenger pathways. Cell proliferation was assessed using ethynyl-2′-deoxyuridine and phosphorylation status of signalling molecules assessed by Western Blots. To assess differentiation potentials, cells were transferred to adipogenic or osteogenic media, and differentiation assessed by expression of differentiation association genes by qRT-PCR, and by long-term culture assays. Our results showed that distinct pathways with opposing actions were activated by PDGF. PI3K/Akt signalling was the main contributor to MSC proliferation in response to activation of PDGFRβ. We also demonstrate a negative feedback mechanism between PI3K/Akt and PDGFR-β expression. In addition, PI3K/Akt downstream signal cascades, mTOR and its associated proteins p70S6K and 4E-BP1 were involved. These pathways induced the expression of cyclin D1, cyclin D3 and CDK6 to promote cell cycle progression and MSC proliferation. In contrast, activation of Erk by PDGFRβ signalling potently inhibited the adipocytic differentiation of MSCs by blocking PPARγ and CEBPα expression. The data suggest that PDGFRβ-induced Akt and Erk pathways regulate opposing fate decisions of proliferation and differentiation to promote MSC self-renewal. Thus, activation of multiple intracellular cascades is required for successful and sustainable MSC self-renewal strategies. BlackWell Publishing Ltd 2012-11 2012-10-29 /pmc/articles/PMC4118247/ /pubmed/22805337 http://dx.doi.org/10.1111/j.1582-4934.2012.01602.x Text en © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
spellingShingle Original Articles
Gharibi, Borzo
Ghuman, Mandeep S
Hughes, Francis J
Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title_full Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title_fullStr Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title_full_unstemmed Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title_short Akt- and Erk-mediated regulation of proliferation and differentiation during PDGFRβ-induced MSC self-renewal
title_sort akt- and erk-mediated regulation of proliferation and differentiation during pdgfrβ-induced msc self-renewal
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118247/
https://www.ncbi.nlm.nih.gov/pubmed/22805337
http://dx.doi.org/10.1111/j.1582-4934.2012.01602.x
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