The lower in vivo osteogenicity of adipose tissue-derived stem cells correlates with a higher innate immune response

Abstract

Abstract Background: 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. However, the ability of ATSCs to promote new bone formation remains lower than that of BMSCs. The aim of this study was to investigate the mechanisms underlying osteogenicity differences between human ATSCs and BMSCs in tissue-engineered constructs, focusing on the effects of the innate immune response on this process. Methods: In vivo bone formation induced by transplanted human BMSCs and ATSCs combined with ceramic granules was evaluated in an ectopic mouse model. Explants were analyzed by micro-computerized tomographic and histology analyses. Kinetic analyses of both the expressed human and murine genes pertaining to osteogenesis and inflammatory response in tissue constructs explanted at 0, 7, 14, and 28 days post-implantation were performed. The gene expression and secretome profiles of pro-inflammatory cytokines/chemokines in both ATSC and BMSC were analyzed. Results: In contrast to ATSC-containing constructs, which did not induce bone formation, BMSC constructs consistently did so. Implanted 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. Concomitant and transient upregulation of some human and murine inflammatory genes in the ATSC-constructs was also observed early post-implantation. The high level of cytokine production by the ATSCs was confirmed at the gene- and protein-levels before implantation. Analysis of the immune cell recruitment within the constructs post-implantation showed higher numbers of multinuclear giant cells as well as M1 macrophages in the ATSC- constructs than in the BMSC-constructs. Conclusions: 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. These data provide new insight regarding use of ATSCs for bone regeneration applications, while acknowledging the substantial potential of BMSCs for bone repair.