Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals theFGF1-RUNX2association in neural crest-derived osteoprogenitors
Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals theFGF1-RUNX2association in neural crest-derived osteoprogenitors
复制标题
DOI：
10.1002/stem.3206
复制
发表时间：
2020-06-09
期刊：
影响因子：
5.2
通讯作者：
Robey, Pamela G.
中科院分区：
文献类型：
--
作者：
Kidwai, Fahad;Mui, Byron W. H.;Robey, Pamela G.
人多能干细胞(HPSCs)可以为模拟骨器官发生和疾病提供一个平台。为了反映人类骨骼的发育过程，hPSC的分化方法应包括来源于三个不同胚胎谱系的成骨祖细胞(OPs)：近轴中胚层、侧板中胚层和神经脊。尽管OP分化方案已经被开发出来，但是它们的起源以及它们的遗传和分子差异的特征还没有很好的报道。因此，为了从人类胚胎干细胞和人类诱导的多能干细胞中产生具有谱系特异性的OP，我们采用了旁轴中胚层样细胞、侧板中胚层样细胞和神经脊样细胞向其各自的OP亚群逐步分化的方法。通过基因表达和体内试验证实，成功的分化使所有三个细胞群体的转录特征得以鉴定。我们还首次报道了神经脊来源的OP中高水平的FGF1--鉴于成纤维细胞生长因子(FGFs)在成骨和矿物质动态平衡中的关键作用，这是一个值得注意的发现。我们的结果表明，FGF1影响RUNX2的水平，并伴随ERK1/2信号的变化。总体而言，我们的研究进一步验证了hPSCs模拟骨骼发育和疾病的能力，并揭示了影响这些过程的新的、潜在的重要途径。
Human pluripotent stem cells (hPSCs) can provide a platform to model bone organogenesis and disease. To reflect the developmental process of the human skeleton, hPSC differentiation methods should include osteogenic progenitors (OPs) arising from three distinct embryonic lineages: the paraxial mesoderm, lateral plate mesoderm, and neural crest. Although OP differentiation protocols have been developed, the lineage from which they are derived, as well as characterization of their genetic and molecular differences, has not been well reported. Therefore, to generate lineage-specific OPs from human embryonic stem cells and human induced pluripotent stem cells, we employed stepwise differentiation of paraxial mesoderm-like cells, lateral plate mesoderm-like cells, and neural crest-like cells toward their respective OP subpopulation. Successful differentiation, confirmed through gene expression and in vivo assays, permitted the identification of transcriptomic signatures of all three cell populations. We also report, for the first time, high FGF1 levels in neural crest-derived OPs-a notable finding given the critical role of fibroblast growth factors (FGFs) in osteogenesis and mineral homeostasis. Our results indicate that FGF1 influences RUNX2 levels, with concomitant changes in ERK1/2 signaling. Overall, our study further validates hPSCs' power to model bone development and disease and reveals new, potentially important pathways influencing these processes.