Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a.
Regeneration of Articular Cartilage by Human ESC-Derived Mesenchymal Progenitors Treated Sequentially with BMP-2 and Wnt5a.
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DOI：
10.5966/sctm.2016-0020
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发表时间：
2017-01
影响因子：
6
通讯作者：
Drissi H
中科院分区：
文献类型：
--
作者：
Gibson JD;O'Sullivan MB;Alaee F;Paglia DN;Yoshida R;Guzzo RM;Drissi H
以细胞为基础的治疗要成功地修复关节软骨，需要有最佳的修复祖细胞来源，并严格控制其分化为永久软骨表型。骨形态发生蛋白2(BMP-2)在体外和体内均能促进间充质细胞向软骨细胞分化。相反，发育研究表明，无翼型MMTV整合位点家族成员5A(Wnt5a)导致软骨细胞成熟减少。因此，我们推测，用BMP-2和Wnt5a处理人胚胎干细胞(HESC)来源的软骨前体细胞可能控制这些细胞向透明样软骨细胞表型的成熟进程。我们在体外检测了hESC来源的间充质样祖细胞持续暴露于重组WNT5a或BMP-2的影响。我们的数据表明，BMP-2促进了强烈的软骨形成反应，导致了终末成熟，而重组WNT5a诱导了轻微的软骨形成反应，而不促进肥大。此外，Wnt5a抑制BMP-2介导的软骨细胞成熟，阻止BMP-2和Wnt5a顺序处理的高密度培养中纤维软骨组织的形成。将经BMP-2和Wnt5a处理的hESC来源的软骨前体细胞无支架颗粒植入大鼠软骨缺损区，在体内诱导出关节样表型。综上所述，这些数据确立了Wnt5a在体外和体内控制从多能性到关节样软骨表型进展的新角色。干细胞转化医学2017；6：40-50
The success of cell‐based therapies to restore joint cartilage requires an optimal source of reparative progenitor cells and tight control of their differentiation into a permanent cartilage phenotype. Bone morphogenetic protein 2 (BMP‐2) has been extensively shown to promote mesenchymal cell differentiation into chondrocytes in vitro and in vivo. Conversely, developmental studies have demonstrated decreased chondrocyte maturation by Wingless‐Type MMTV Integration Site Family, Member 5A (Wnt5a). Thus, we hypothesized that treatment of human embryonic stem cell (hESC)‐derived chondroprogenitors with BMP‐2 followed by Wnt5a may control the maturational progression of these cells into a hyaline‐like chondrocyte phenotype. We examined the effects of sustained exposure of hESC‐derived mesenchymal‐like progenitors to recombinant Wnt5a or BMP‐2 in vitro. Our data indicate that BMP‐2 promoted a strong chondrogenic response leading to terminal maturation, whereas recombinant Wnt5a induced a mild chondrogenic response without promoting hypertrophy. Moreover, Wnt5a suppressed BMP‐2‐mediated chondrocyte maturation, preventing the formation of fibrocartilaginous tissue in high‐density cultures treated sequentially with BMP‐2 and Wnt5a. Implantation of scaffoldless pellets of hESC‐derived chondroprogenitors pretreated with BMP‐2 followed by Wnt5a into rat chondral defects induced an articular‐like phenotype in vivo. Together, the data establish a novel role for Wnt5a in controlling the progression from multipotency into an articular‐like cartilage phenotype in vitro and in vivo. Stem Cells Translational Medicine 2017;6:40–50