RNAseq analysis reveals divergent molecular events that direct hBMSCs toward fibrosis or bone regeneration: importance of inflammation regulation

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ICE Krakow

ICE Krakow

ul. Marii Konopnickiej 17 30-302 Kraków


Chevallier, Nathalie (IMRB U955-E10, Inserm, Unité d'Ingénierie et de Thérapie Cellulaire-Etablissement Français du Sang, Université Paris-Est, Créteil, France)


Human bone marrow mesenchymal stromal cells (hBMSC) combined with biomaterials are currently used clinically for bone repair, but their bone formation kinetics are heterogeneous. The development of optimized pro-regenerative therapies requires a rigorous understanding of the molecular progression of regeneration. Here we report the divergent molecular events that drive hBMSCs toward fibrosis or bone regeneration. To understand this heterogeneity, we focused on the behavior of hBMSCs and observed that hBMSCs with high bone potential were associated with higher cell survival and proliferation after in vivo transplantation. In order to determine their mechanism of action and to understand how cell survival is controlled, RNAseq analysis was performed at 8h, 1 and 2 weeks after transplantation. Our results show that cells with reduced bone potential have a higher expression level of pro-inflammatory cytokines at 8 hours post-graft, which is associated with a higher inflammatory response. We then confirm that the long-term survival of hBMSCs depends in part on their ability to regulate neutrophil activation. Furthermore, our RNAseq analysis at 1 and 2 weeks highlights that long-term survival of hBMSCs is associated with increased bone formation only if hBMSCs are able to evolve towards osteoblastic differentiation. Our hypothesis is that bone differentiation allows hBMSCs to synthesize paracrine factors necessary for chemoattraction and osteoblastic and osteoclastic differentiation of neighboring cells. However, the heterogeneity of the cells' potential is partly due to their ability to regulate the inflammatory response. Our results will serve as an omics map of hBMSCs for bone regeneration and may have therapeutic implications for managing the inflammatory response.

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