Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects
Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects
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DOI：
10.1096/fj.13-247965
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发表时间：
2014-08-01
期刊：
影响因子：
4.8
通讯作者：
Huard, Johnny
中科院分区：
文献类型：
--
作者：
Gao, Xueqin;Usas, Arvydas;Huard, Johnny
小鼠肌源性干细胞(MDSCs)在骨形态发生蛋白(BMP)2或4转导下可在颅骨缺损模型中再生骨，但供体细胞在骨愈合过程中的作用及其与宿主细胞的相互作用尚未完全阐明。为解决这一问题，将C57/BL/6J小鼠分为MDSC/BMP4/GFP组、MDSC/GFP组和支架组。将骨髓间充质干细胞移植到正常小鼠的临界大小的颅骨缺损处后，我们发现，转导BMP4GFP的骨髓间充质干细胞移植的小鼠在4wk内愈合了骨缺损，而对照组(MDSC-GFP和支架)没有骨愈合。新形成的松质骨表现出与天然骨相似的生物力学特性，供体细胞通过BMP4-pSMAD5和COX-2-PGE2信号通路向软骨细胞、成骨细胞和骨细胞分化，直接参与软骨内成骨。与支架组相比，MDSC组最初吸引了更多的炎症细胞，并在宿主小鼠中引起更快的炎症消退，增强了血管生成，并抑制了初始免疫反应。MDSCs通过分泌单核细胞趋化蛋白1吸引巨噬细胞，并通过分泌多种生长因子促进内皮细胞增殖。我们的研究结果表明，转导BMP4GFP的MDSCs不仅通过直接分化再生骨，而且通过旁分泌效应积极影响宿主细胞协调和促进骨组织修复。-Gao，X.，USAS，A.，Proto，J.D.，Lu，A.，Cummins，J.H.，Proctor，A.，Chen，C.-W.，Huard，J.
Murine muscle-derived stem cells (MDSCs) have been shown capable of regenerating bone in a critical size calvarial defect model when transduced with BMP 2 or 4; however, the contribution of the donor cells and their interactions with the host cells during the bone healing process have not been fully elucidated. To address this question, C57/BL/6J mice were divided into MDSC/BMP4/GFP, MDSC/GFP, and scaffold groups. After transplanting MDSCs into the critical-size calvarial defects created in normal mice, we found that mice transplanted with BMP4GFP-transduced MDSCs healed the bone defect in 4 wk, while the control groups (MDSC-GFP and scaffold) demonstrated no bone healing. The newly formed trabecular bone displayed similar biomechanical properties as the native bone, and the donor cells directly participated in endochondral bone formation via their differentiation into chondrocytes, osteoblasts, and osteocytes via the BMP4-pSMAD5 and COX-2-PGE2 signaling pathways. In contrast to the scaffold group, the MDSC groups attracted more inflammatory cells initially and incurred faster inflammation resolution, enhanced angiogenesis, and suppressed initial immune responses in the host mice. MDSCs were shown to attract macrophages via the secretion of monocyte chemotactic protein 1 and promote endothelial cell proliferation by secreting multiple growth factors. Our findings indicated that BMP4GFP-transduced MDSCs not only regenerated bone by direct differentiation, but also positively influenced the host cells to coordinate and promote bone tissue repair through paracrine effects.-Gao, X., Usas, A., Proto, J. D., Lu, A., Cummins, J. H., Proctor, A., Chen, C.-W., Huard, J. Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects.