National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA.
Morgridge Institute for Research, 330 N. Orchard Street, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
Cell Rep. 2018 May 22;23(8):2467-2481. doi: 10.1016/j.celrep.2018.04.092.
Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4. Blood cells generated from arterial HE were more than 100-fold enriched in T cell precursor frequency and possessed the capacity to produce B lymphocytes and red blood cells expressing high levels of BCL11a and β-globin. Together, these findings provide an innovative strategy to aid in the generation of definitive lymphomyeloid progenitors and lymphoid cells from hPSCs for immunotherapy through enhancing arterial programming of HE.
理解指导具有淋巴样潜能的定型造血发生的途径对于推进人类多能干细胞（hPSC）技术用于治疗血液疾病和免疫疗法至关重要。在胚胎中，淋巴祖细胞和造血干细胞（HSCs）来源于动脉内皮（HE），而不是静脉内皮。在这里，我们表明，通过过表达 ETS1 或在发育的中胚层阶段调节 MAPK/ERK 信号通路来激活动脉程序，可显著增强表达 DLL4 和 CXCR4 的动脉型 HE 的形成。源自动脉 HE 的血细胞在 T 细胞前体频率中富集超过 100 倍，并且具有产生表达高水平 BCL11a 和β-球蛋白的 B 淋巴细胞和红细胞的能力。总之，这些发现提供了一种创新策略，通过增强 HE 的动脉编程，有助于从 hPSC 中产生定型淋巴骨髓祖细胞和淋巴细胞，用于免疫治疗。
