Dong Liaoliao, Wei Chuijin, Xiong Shumin, Yu Ping, Zhou Ren, Cheng Lin
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Exp Hematol Oncol. 2022 Jun 10;11(1):37. doi: 10.1186/s40164-022-00288-9.
The application of hematopoietic stem cells (HSCs) has been restricted due to limited cell sources and conventional methods for generating these cells by cell expansion and pluripotent stem cell differentiation have not been clinically achieved. Cell reprogramming technique provides a new hope for generating desirable cells. We previously reported that mouse differentiated hematopoietic cell reprogramming could be induced by small molecule compounds to generate hematopoietic stem/progenitor-like cells, whether the human hematopoietic cells could also be reprogrammed into HSCs by chemical compounds remains elusive. Here, we demonstrated for the first time that human committed hematopoietic progenitors could be reprogrammed into multipotent progenitors by spliceosome inhibitor. Combination of single cell RNA-sequencing and genetic lineage tracing including exogenous barcodes and endogenous mitochondrial DNA mutations confirmed the reprogramming procession. Although the small chemical compound inhibiting spliceosome function only induces the differentiated hematopoietic progenitors to acquire plasticity and reprograms them into multipotent progenitors but not stem cells so far, this study still provides a proof-of-concept strategy for generating HSCs based on combining two independent steps together in future, first differentiating rare HSCs into large number of progenitors then reprogramming these progenitors into huge number of HSCs. Further dissecting the mechanism underlying spliceosome inhibitor-induced human hematopoietic cell reprogramming in future will help us comprehensively understanding not only the chemical reprogramming to generate desirable human cells for clinical translation but also hematopoiesis under physiological and pathological conditions.
由于细胞来源有限，造血干细胞（HSCs）的应用受到了限制，通过细胞扩增和多能干细胞分化来产生这些细胞的传统方法尚未在临床上实现。细胞重编程技术为生成所需细胞带来了新希望。我们之前报道过，小分子化合物可诱导小鼠分化的造血细胞重编程，以产生造血干/祖细胞样细胞，但人类造血细胞是否也能通过化合物重编程为造血干细胞仍不清楚。在此，我们首次证明，剪接体抑制剂可将人类定向造血祖细胞重编程为多能祖细胞。单细胞RNA测序与包括外源性条形码和内源性线粒体DNA突变在内的遗传谱系追踪相结合，证实了重编程过程。尽管目前抑制剪接体功能的小分子化合物仅诱导分化的造血祖细胞获得可塑性并将其重编程为多能祖细胞，而非干细胞，但这项研究仍为未来基于将两个独立步骤结合在一起（首先将罕见的造血干细胞分化为大量祖细胞，然后将这些祖细胞重编程为大量造血干细胞）来生成造血干细胞提供了一个概念验证策略。未来进一步剖析剪接体抑制剂诱导人类造血细胞重编程的机制，将有助于我们全面理解不仅是用于临床转化的生成所需人类细胞的化学重编程，还有生理和病理条件下的造血过程。
