Integrins alpha 2 beta 1 and alpha 11 beta 1 regulate the survival of mesenchymal stem cells on collagen I

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 - alpha 1 beta 1, alpha 2 beta 1 and alpha 11 beta 1. Using human MSC (hMSC), we show that alpha 11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both alpha 2 and alpha 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 alpha 2 or alpha 11 deficiency, but not alpha 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 alpha 2- and alpha 11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of alpha 2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of alpha 2 beta 1- or alpha 11 beta 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.