Defended by Adrien MOYA on 14-09-2016
Bone marrow stromal derived multipotent stem cells (MSCs) are most suited cells for tissue engineering applications. Nowadays, numerous clinical trials use these MSCs in order to develop new innovative therapies. In the present work, we developed two preconditioning strategies with the aim of improving MSCs functionality for bone tissue engineering. Massive cell death upon implantation drastically reduces the potentials benefits of such MSCs- based therapies. The ischemic hostile environment that cells faces upon implantation is, not the sole, but surely the prime factor responsible for this cell-death. The first strategy aimed at improving hMSCs survival in ischemic conditions. We were able to demonstrate that a quiescence preconditioning induces a modification in the hMSCs metabolic profile thus improving their survival for as long as 14 days in an in vitro ischemic model and 7 days in vivo. This modification is characterized by (i) a shift from an OXPHOS- dependent metabolism towards a glycolytic metabolism, and (ii) activation of pro-survival pathways via mTORC1 inhibition and autophagy activation. The second strategy was to induce a pro-osteogenic phenotype likely favorable for bone formation. To this aim, hMSCs were predifferentiated toward the adipogenic lineage (AD); an hMSCs lineage known to be closely related to the osteogenic one. It appears that predifferentiated hMSCs (AD+) are not only committed towards the adipogenic lineage but also towards the osteogenic one. These hMSCs-AD+ exhibit enhanced direct and paracrine pro-osteogenic potentials, as a result, they are capable of inducing bone tissue formation 5-times more in vivo. These two strategies might enhance the therapeutic outcomes of MSCs-based products for bone tissue engineering applications.
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