Department of Pathology and Laboratory Medicine, David Geffen School of Medicine (DGSOM), University of California (UCLA), Los Angeles, CA 90095, USA.
Becton Dickinson, San Diego, CA 92121, USA.
Stem Cell Reports. 2018 Feb 13;10(2):436-446. doi: 10.1016/j.stemcr.2017.12.005. Epub 2018 Jan 4.
Various mesenchymal cell types have been identified as critical components of the hematopoietic stem/progenitor cell (HSPC) niche. Although several groups have described the generation of mesenchyme from human pluripotent stem cells (hPSCs), the capacity of such cells to support hematopoiesis has not been reported. Here, we demonstrate that distinct mesenchymal subpopulations co-emerge from mesoderm during hPSC differentiation. Despite co-expression of common mesenchymal markers (CD73, CD105, CD90, and PDGFRβ), a subset of cells defined as CD146CD73 expressed genes associated with the HSPC niche and supported the maintenance of functional HSPCs ex vivo, while CD146CD73 cells supported differentiation. Stromal support of HSPCs was contact dependent and mediated in part through high JAG1 expression and low WNT signaling. Molecular profiling revealed significant transcriptional similarity between hPSC-derived CD146 and primary human CD146 perivascular cells. The derivation of functionally diverse types of mesenchyme from hPSCs opens potential avenues to model the HSPC niche and develop PSC-based therapies.
多种间充质细胞类型已被鉴定为造血干/祖细胞 (HSPC) 龛的关键组成部分。尽管有几个小组已经描述了从人类多能干细胞 (hPSC) 中生成间充质，但这些细胞支持造血的能力尚未得到报道。在这里，我们证明 hPSC 分化过程中中胚层会同时出现不同的间充质亚群。尽管共同表达常见的间充质标记物（CD73、CD105、CD90 和 PDGFRβ），但一部分被定义为 CD146CD73 的细胞表达与 HSPC 龛相关的基因，并支持功能性 HSPCs 的体外维持，而 CD146CD73 细胞支持分化。HSPCs 的基质支持是接触依赖性的，部分通过高 JAG1 表达和低 WNT 信号传导介导。分子谱分析显示 hPSC 衍生的 CD146 和原代人 CD146 血管周细胞之间存在显著的转录相似性。从 hPSC 中衍生出功能多样的间充质类型为模型化 HSPC 龛和开发基于 PSC 的治疗方法开辟了潜在途径。
