LGR4, Not LGR5, Enhances hPSC Hematopoiesis by Facilitating Mesoderm Induction via TGF-Beta Signaling Activation.
LGR4, Not LGR5, Enhances hPSC Hematopoiesis by Facilitating Mesoderm Induction via TGF-Beta Signaling Activation.
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DOI：
10.1016/j.celrep.2020.107600
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发表时间：
2020-05
期刊：
影响因子：
8.8
通讯作者：
Yu Wang;Hongtao Wang;Jiaojiao Guo;Jie Gao;Mengge Wang;Meijuan Xia;Yuqi Wen;Pei Su;Ming-Zhu Yang-Mi
中科院分区：
文献类型：
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作者：
Yu Wang;Hongtao Wang;Jiaojiao Guo;Jie Gao;Mengge Wang;Meijuan Xia;Yuqi Wen;Pei Su;Ming-Zhu Yang-Mi
从人多能干细胞（hPSC）产生功能性血细胞的尝试在很大程度上仍然不成功，主要是由于缺乏对人造血的调控网络的理解。在这项研究中，我们确定了富含亮氨酸重复序列的G蛋白偶联受体4（LGR 4）作为hPSC早期造血分化的重要调节因子。LGR 4的缺失严重损害中胚层发育，从而限制体外和体内造血分化。相比之下，LGR 5对于hPSC造血作用是无效的。四种R-spondin蛋白在造血分化中显示出不同的活性和对LGR 4的依赖性。LGR 4的缺失几乎完全消除了由R-spondin 1和R-spondin 3诱导的增强，但不是R-spondin 2。此外，ZNRF 3是R-spondin 1-R-spondin 3反应所必需的。在机制水平，LGR 4调节转化生长因子β（TGF-β）信号传导以控制造血分化。总之，我们的研究结果揭示了LGR 4在造血发育中的重要作用，并揭示了R-spondins的独特功能和潜在机制。
Attempts to generate functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful, mainly due to the lack of understanding of the regulatory network of human hematopoiesis. In this study, we identified leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) as an essential regulator of early hematopoietic differentiation of hPSCs. The deletion of LGR4 severely impairs mesoderm development, thereby limiting hematopoietic differentiation bothin vitroandin vivo. In contrast, LGR5 is dispensable for hPSC hematopoiesis. The four R-spondin proteins show differential activities and dependencies on LGR4 in hematopoietic differentiation. The deletion of LGR4 almost entirely abolishes the enhancement induced by R-spondin1 and R-spondin3, but not R-spondin2. In addition, ZNRF3 is required for the response of R-spondin1–R-spondin3. At the mechanistic level, LGR4 regulates transforming growth factor beta (TGF-beta) signaling to control hematopoietic differentiation. Together, our results reveal vital roles of LGR4 in hematopoietic development and uncover distinct functions and underlying mechanisms for R-spondins.