Human mesenchymal stromal cells (hMSC) have been investigated as a clinical therapy to promote tissue repair. However, the disappearance of grafted cells soon after engraftment suggests that hMSC could principally act as initiators of repair through paracrine mechanisms.
The aim of this study was to evaluate the relative contribution of grafted hMSC and host cells in promoting bone tissue repair. We isolated hMSC from three bone marrow (BM) donors, then directly loaded into scaffolds and subcutaneously implanted in mice in order to induce ectopic bone formation (no. 94612).
This work revealed a cell heterogeneity between hMSC from different BM donors regarding their mechanisms of action and their osteogenic activity. We demonstrated by species-specific qPCR that grafted hMSC were able to survive up to 6 weeks post-implantation but with a different manner depends of the donor. This was not dependent on vascularisation as hMSC induced vascularisation with the same efficacy in less than a week as evaluated by the expression of VE-cad and PECAM. However, it seems to depend on MSC apoptosis as hMSC with a poor cell survival show either an higher and/or prolong entry in apoptosis as mesured by Bax/Bcl2 expression. Then, by species-specific RT-qPCR we highlighted the importance of direct and indirect role of the hMSC for optimal bone tissue regeneration. Whereas in our mouse model, hMSC does not modulate macrophage (MP) polarization, they seem to affect MP differentiation into osteoclasts as bone formation is associated with increased osteoclast activity. However, this was not dependent of the osteoclastic canonical pathway as hMSC express RANKL and OPG with the same ratio level.
In conclusion, we validated that grafted hMSC could survive and we demonstrated that mechanisms of action and bone-forming capacities of BM-derived hMSC were donor dependent, which is of critical importance for MSC studies and clinical applications of tissue regeneration.
17 May 2014 - 20 May 2014