Integrins ?2?1 and ?11?1 regulate the survival of mesenchymal stem cells on collagen I.

ABSTRACT: Although mesenchymal stem cells (MSCs) are the natural source for bone regeneration, the exact mechanisms governing MSC crosstalk with collagen I have not yet been uncovered. Cell adhesion to collagen I is mostly mediated by three integrin receptors - ?1?1, ?2?1 and ?11?1. Using human MSC (hMSC), we show that ?11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both ?2 and ?11 integrins were significantly upregulated. To elucidate the possible roles of collagen-binding integrins, we applied short hairpin RNA (shRNA)-mediated knockdown in hMSC and found that ?2 or ?11 deficiency, but not ?1, results in a tremendous reduction of hMSC numbers owing to mitochondrial leakage accompanied by Bcl-2-associated X protein upregulation. In order to clarify the signaling conveyed by the collagen-binding integrins in hMSC, we analyzed the activation of focal adhesion kinase, extracellular signal-regulated protein kinase and serine/threonine protein kinase B (PKB/Akt) kinases and detected significantly reduced Akt phosphorylation only in ?2- and ?11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of ?2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of ?2?1- or ?11?1-mediated interactions to collagen I results in the cell death of MSCs and urges for further investigations examining the impact of MSCs in bone conditions with abnormal collagen I.

SUBMITTER: Popov C 

PROVIDER: S-EPMC3199721 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature