The Lower in Vivo Osteogenicity of Adipose Tissue-Derived Stem Cells Correlates with a Higher Innate Immune Response

Adipose tissue-derived mesenchymal stem cells (ATSCs) have been used as an alternative to bone marrow-derived mesenchymal stem cells (BMSCs) for bone tissue engineering applications. The ability of ATSCs to promote new bone formation remains lower than that of BMSCs. This study aimed to investigate the mechanisms underlying osteogenicity differences between human ATSCs and BMSCs in ceramic constructs, focusing on the effects of inflammation on this process. In contrast to ATSC-containing constructs, which did not induce bone formation in an ectopic mouse model, BMSC constructs consistently did so. Gene expression analysis revealed that human BMSCs, concomitantly with host murine progenitors, differentiated into the osteogenic lineage early post-implantation. In contrast, ATSCs differentiated later, when few implanted viable cells remained post-implantation, while the host murine cells did not differentiate. Comparison of the inflammatory profile in the cell constructs indicated concomitant upregulation of some human and murine inflammatory genes in the ATSC-constructs compared to the BMSC-constructs during the first-week post-implantation. The high level of chemokine production by the ATSCs was confirmed at the gene and protein levels before implantation. The immune cell recruitment within the constructs was then explored post-implantation. Higher numbers of TRAP-/ MRC1 (CD206) + multinucleated giant cells, NOS2 + M1, and ARG1 + M2 macrophages were present in the ATSC constructs than in the BMSC constructs. These results proved that ATSCs are a transient source of inflammatory cytokines promoting a transient immune response post-implantation; this milieu correlates with impaired osteogenic differentiation of both the implanted ATSCs and the host osteoprogenitor cells.