Université Paris Cité, CNRS, INSERM, ENVA, Paris, B3OA, F-75010, France.
Laboratoire de Biologie, Bioingénierie et Bioimagerie Ostéo-articulaires, Université Paris Cité, 10 Avenue de Verdun, Paris, F-75010, France.
Stem Cell Rev Rep. 2023 Nov;19(8):2869-2885. doi: 10.1007/s12015-023-10614-1. Epub 2023 Aug 29.
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.
脂肪组织来源的间充质干细胞（ATSCs）已被用作骨组织工程应用中骨髓来源的间充质干细胞（BMSCs）的替代品。ATSCs 促进新骨形成的能力仍然低于 BMSCs。本研究旨在探讨陶瓷构建体中人类 ATSCs 和 BMSCs 成骨能力差异的机制，重点研究炎症对这一过程的影响。与在异位小鼠模型中不会诱导骨形成的 ATSC 构建体不同，BMSC 构建体始终会诱导骨形成。基因表达分析表明，人类 BMSCs 与宿主鼠前体一起，在植入后早期分化为成骨谱系。相比之下，ATSCs 分化较晚，在植入后存活的植入细胞很少时分化，而宿主鼠细胞没有分化。细胞构建体中炎症谱的比较表明，与 BMSC 构建体相比，ATSC 构建体在植入后第一周同时上调了一些人类和鼠类炎症基因。在植入前，ATSCs 的趋化因子产生水平较高，在基因和蛋白水平上得到了证实。然后，在植入后研究了构建体内免疫细胞的募集情况。在 ATSC 构建体中，TRAP-/MRC1（CD206）+多核巨细胞、NOS2+M1 和 ARG1+M2 巨噬细胞的数量高于 BMSC 构建体。这些结果证明，ATSCs 是炎症细胞因子的短暂来源，在植入后会引发短暂的免疫反应；这种微环境与植入的 ATSCs 和宿主成骨前体细胞的成骨分化受损相关。
