Siriraj Center of Excellence for Stem Cell Research, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
Center of Excellence in Stem Cell Research and Innovation, Faculty of Medicine, Thammasat University, Pathumthani, 12120, Thailand.
Stem Cell Res Ther. 2023 Sep 29;14(1):279. doi: 10.1186/s13287-023-03508-z.
In vitro production of hematopoietic stem/progenitor cells (HSPCs) from human-induced pluripotent stem cells (hiPSCs) provides opportunities for fundamental research, disease modeling, and large-scale production of HLA-matched HSPCs for therapeutic applications. However, a comprehensive understanding of the signaling mechanisms that regulate human hematopoiesis is needed to develop a more effective procedure for deriving HSPCs from hiPSCs.
In this study, we investigate the role of YAP during the hematopoietic differentiation of hiPSCs to HSPCs and erythrocytes using the isogenic YAP-overexpressing (YAP-S5A) and YAP-depleting (YAP-KD) hiPSCs to eliminate the effects of a genetic background variation.
Although YAP is dispensable for maintaining the self-renewal and pluripotency of these hiPSCs, it affects the early cell-fate determination and hematopoietic differentiation of hiPSCs. Depleting YAP enhances the derivation efficiency of HSPCs from hiPSCs by inducing the mesodermal lineage commitment, promoting hematopoietic differentiation, and preventing the differentiation toward endothelial lineage. On the contrary, the overexpression of YAP reduced HSPCs yield by inducing the endodermal lineage commitment, suppressing hematopoietic differentiation, and promoting the differentiation toward endothelial lineage.
Expression of YAP is crucial for the differentiation of hiPSC-derived HSPCs toward mature erythrocytes. We believe that by manipulating YAP activity using small molecules, the efficiency of the large-scale in vitro production system for generating hematopoietic stem/progenitor cells for future therapeutic use could be improved.
从人诱导多能干细胞（hiPSCs）体外生产造血干/祖细胞（HSPCs）为基础研究、疾病建模以及为治疗应用大规模生产与 HLA 匹配的 HSPCs 提供了机会。然而，为了从 hiPSCs 中开发出更有效的 HSPC 衍生程序，需要全面了解调节人类造血的信号机制。
在这项研究中，我们使用同基因的 YAP 过表达（YAP-S5A）和 YAP 耗竭（YAP-KD）hiPSCs 来消除遗传背景变化的影响，研究 YAP 在 hiPSCs 向 HSPCs 和红细胞的造血分化过程中的作用。
尽管 YAP 对于维持这些 hiPSCs 的自我更新和多能性是可有可无的，但它会影响 hiPSCs 的早期细胞命运决定和造血分化。耗竭 YAP 通过诱导中胚层谱系决定、促进造血分化和防止向内皮谱系分化，提高了 HSPCs 从 hiPSCs 中的衍生效率。相反，YAP 的过表达通过诱导内胚层谱系决定、抑制造血分化和促进向内皮谱系分化，降低了 HSPCs 的产量。
YAP 的表达对于 hiPSC 衍生的 HSPCs 向成熟红细胞的分化至关重要。我们相信，通过使用小分子操纵 YAP 活性，可以提高未来治疗用途的大规模体外产生造血干细胞/祖细胞系统的效率。
