Healing of a Large Long-Bone Defect through Serum-Free In Vitro Priming of Human Periosteum-Derived Cells.
Healing of a Large Long-Bone Defect through Serum-Free In Vitro Priming of Human Periosteum-Derived Cells.
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DOI：
10.1016/j.stemcr.2017.01.005
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发表时间：
2017-03-14
影响因子：
5.9
通讯作者：
Luyten FP
中科院分区：
文献类型：
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作者：
Bolander J;Ji W;Leijten J;Teixeira LM;Bloemen V;Lambrechts D;Chaklader M;Luyten FP
基于细胞的再生医学策略的临床转化需要可预测的体内性能，其中在体外制备期间使用血清固有地限制了功效和再现性。在这里，我们提出了一种生物启发的方法，通过无血清预处理的人骨膜来源的细胞，然后将其组装成微聚集体，同时引发骨形态发生蛋白2（BMP-2）。预处理导致更有效的祖细胞群，而聚集诱导骨软骨分化，进一步增强BMP-2刺激。异位植入显示了一系列事件，这些事件与导致骨小骨形成的自然软骨内过程非常相似。在免疫缺陷小鼠的关键尺寸长骨缺损中的评估表明，在植入细胞的积极贡献下，在4周内成功桥接了缺损。简而言之，所提出的无血清过程代表了一种仿生策略，产生了软骨组织中间体，其在植入后稳健地导致大的长骨缺损的愈合。无血清预处理影响骨膜祖细胞的特性：CD 105+降低，CD 34+升高，并且观察到BMP受体表达上调。通过聚集和BMP刺激诱导软骨内骨形成的引发在临界尺寸骨折模型中的验证证实了软骨内愈合。基于的策略严重限制了该过程的功效和再现性，因为它与细胞反应相冲突。Luyten及其同事提出了一种生物启发的工程过程，包括无血清预处理结合微聚集和骨形态发生蛋白引发，产生一种自我维持的组织中间体，在植入后，成功地愈合了关键的长骨缺损。
Clinical translation of cell-based strategies for regenerative medicine demands predictable in vivo performance where the use of sera during in vitro preparation inherently limits the efficacy and reproducibility. Here, we present a bioinspired approach by serum-free pre-conditioning of human periosteum-derived cells, followed by their assembly into microaggregates simultaneously primed with bone morphogenetic protein 2 (BMP-2). Pre-conditioning resulted in a more potent progenitor cell population, while aggregation induced osteochondrogenic differentiation, further enhanced by BMP-2 stimulation. Ectopic implantation displayed a cascade of events that closely resembled the natural endochondral process resulting in bone ossicle formation. Assessment in a critical size long-bone defect in immunodeficient mice demonstrated successful bridging of the defect within 4 weeks, with active contribution of the implanted cells. In short, the presented serum-free process represents a biomimetic strategy, resulting in a cartilage tissue intermediate that, upon implantation, robustly leads to the healing of a large long-bone defect. Serum-free pre-conditioning affects the identity of periosteal progenitor cells A reduced CD105+, elevated CD34+, and upregulated BMP receptor expression was seen Priming by aggregation and BMP stimulation induced endochondral bone formation Validation in a critical size fracture model confirmed endochondral healing The use of sera in the preparation of cell-based strategies critically limits the efficacy and reproducibility of the process as it conflicts with cellular responses. Luyten and colleagues present a bioinspired engineering process including serum-free pre-conditioning combined with micro-aggregation and bone morphogenetic protein priming resulting in a self-sustained tissue intermediate that, upon implantation, successfully heals critical long-bone defects.