Priming integrin α5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis

Zahia Hamidouche, Olivia Fromigué, Jochen Ringe, Thomas Häupl, Pascal Vaudin, Jean Christophe Pagès, Samer Srouji, Erella Livne, Pierre J. Marie

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

Adult human mesenchymal stromal cells (hMSCs) have the potential to differentiate into chondrogenic, adipogenic, or osteogenic lineages, providing a potential source for tissue regeneration. An important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptome analysis, we found that integrin α5 (ITGA5) expression is up-regulated during dexamethasone- induced osteoblast differentiation of hMSCs. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers and in vitro osteogenesis of hMSCs. Down-regulation of endogenous ITGA5 using specific shRNAs blunted osteoblast marker gene expression and osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by ITGA5 was mediated by activation of focal adhesion kinase/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of endogenous ITGA5 using agonists such as a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. Importantly, we demonstrated that hMSCs engineered to overexpress ITGA5 exhibited a marked increase in their osteogenic potential in vivo. Taken together, these findings not only reveal that ITGA5 is required for osteoblast differentiation of adult hMSCs but also provide a targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs. This may be used for tissue regeneration in bone disorders where the recruitment or capacity of hMSCs is compromised.

Original languageEnglish
Pages (from-to)18587-18591
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
StatePublished - 3 Nov 2009
Externally publishedYes

Keywords

  • Agonist
  • Bone formation
  • Mesenchymal stem cells

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