Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis
Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis
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DOI：
10.1073/pnas.1720658115
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发表时间：
2018-05-01
影响因子：
11.1
通讯作者：
Martin, Ivan
中科院分区：
文献类型：
--
作者：
Occhetta, Paola;Pigeot, Sebastien;Martin, Ivan
成人骨髓间充质干细胞（hMSCs）是公认的成骨细胞。即使当诱导成软骨时，hMSC通常形成经历软骨内骨化的肥大软骨。由于胚胎间充质显然有能力产生表型稳定的软骨，因此质疑发育期间和成年期间充质祖细胞之间是否存在对应关系。在这里，我们测试了是否迫使特定的关节软骨发育的早期事件可以程序hMSC的命运稳定的软骨形成。受最近发现的骨形态发生蛋白（BMP）信号传导的空间限制引导胚胎祖细胞形成关节软骨的启发，我们假设选择性抑制BMP可以驱动hMSC来源的软骨细胞的表型稳定性。在微流控平台中筛选了两种BMP I型受体偏向性激酶抑制剂，用于其对hMSC软骨形成的时间和剂量依赖性作用。测试化合物的不同受体选择性特征允许证明，ALK 2和ALK 3受体的瞬时阻断虽然允许hMSC软骨形成，但对于维持稳定的软骨细胞表型是必要的且足够的。值得注意的是，即使在去除化合物后，hMSC也不再能够在体外经历肥大和在体内经历软骨内骨化，表明组成性变化的开始。我们的研究结果表明，成人间充质干细胞有效地共享胚胎间充质的性质，形成短暂的，但也稳定的软骨。这为关节软骨再生开辟了潜在的药理学策略，并更广泛地表明了发育启发协议的相关性，以控制成人祖细胞系统的命运。
It is generally accepted that adult human bone marrow-derived mesenchymal stromal cells (hMSCs) are default committed toward osteogenesis. Even when induced to chondrogenesis, hMSCs typically form hypertrophic cartilage that undergoes endochondral ossification. Because embryonic mesenchyme is obviously competent to generate phenotypically stable cartilage, it is questioned whether there is a correspondence between mesenchymal progenitor compartments during development and in adulthood. Here we tested whether forcing specific early events of articular cartilage development can program hMSC fate toward stable chondrogenesis. Inspired by recent findings that spatial restriction of bone morphogenetic protein (BMP) signaling guides embryonic progenitors toward articular cartilage formation, we hypothesized that selective inhibition of BMP drives the phenotypic stability of hMSC-derived chondrocytes. Two BMP type I receptor-biased kinase inhibitors were screened in a microfluidic platform for their time-and dose-dependent effect on hMSC chondrogenesis. The different receptor selectivity profile of tested compounds allowed demonstration that transient blockade of both ALK2 and ALK3 receptors, while permissive to hMSC cartilage formation, is necessary and sufficient to maintain a stable chondrocyte phenotype. Remarkably, even upon compound removal, hMSCs were no longer competent to undergo hypertrophy in vitro and endochondral ossification in vivo, indicating the onset of a constitutive change. Our findings demonstrate that adult hMSCs effectively share properties of embryonic mesenchyme in the formation of transient but also of stable cartilage. This opens potential pharmacological strategies to articular cartilage regeneration and more broadly indicates the relevance of developmentally inspired protocols to control the fate of adult progenitor cell systems.