Institute of Experimental Hematology, Hannover Medical School, 30625, Hannover, Germany.
REBIRTH, Research Center for Translational Regenerative Medicine, Hannover Medical School, 30625, Hannover, Germany.
Cell Mol Life Sci. 2021 May;78(9):4143-4160. doi: 10.1007/s00018-021-03777-y. Epub 2021 Feb 9.
In vitro generation of hematopoietic cells and especially hematopoietic stem cells (HSCs) from human pluripotent stem cells (PSCs) are subject to intensive research in recent decades, as these cells hold great potential for regenerative medicine and autologous cell replacement therapies. Despite many attempts, in vitro, de novo generation of bona fide HSCs remains challenging, and we are still far away from their clinical use, due to insufficient functionality and quantity of the produced HSCs. The challenges of generating PSC-derived HSCs are already apparent in early stages of hemato-endothelial specification with the limitation of recapitulating complex, dynamic processes of embryonic hematopoietic ontogeny in vitro. Further, these current shortcomings imply the incompleteness of our understanding of human ontogenetic processes from embryonic mesoderm over an intermediate, specialized hemogenic endothelium (HE) to their immediate progeny, the HSCs. In this review, we examine the recent investigations of hemato-endothelial ontogeny and recently reported progress for the conversion of PSCs and other promising somatic cell types towards HSCs with the focus on the crucial and inevitable role of the HE to achieve the long-standing goal-to generate therapeutically applicable PSC-derived HSCs in vitro.
在过去几十年中，从人类多能干细胞（PSCs）体外生成造血细胞，特别是造血干细胞（HSCs），一直是研究的热点，因为这些细胞在再生医学和自体细胞替代疗法中有很大的应用潜力。尽管进行了许多尝试，但由于产生的 HSCs 功能和数量不足，体外重新生成真正的 HSCs 仍然具有挑战性，我们离其临床应用还很远。由于在体外难以重现胚胎造血发生的复杂、动态过程，因此从 PSC 中生成 HSCs 的挑战在造血内皮特化的早期阶段就已经很明显。此外，这些当前的缺点表明，我们对人类从胚胎中胚层到中间特化的造血内皮（HE），再到其直接前体造血干细胞（HSCs）的胚胎发生过程的理解还不完整。在这篇综述中，我们检查了最近对造血内皮发生的研究，并报告了最近在将 PSCs 和其他有前途的体细胞类型转化为 HSCs 方面的进展，重点是 HE 的关键和不可避免的作用，以实现长期目标——在体外生成治疗上适用的 PSC 衍生的 HSCs。
