R-spondin2 promotes hematopoietic differentiation of human pluripotent stem cells by activating TGF beta signaling

Stem Cell Research & Therapy

Wen Zhou¹  Jiaojiao Guo¹  Jie Gao²  Lihong Shi²  Hongtao Wang²  Mengge Wang²  Yuqi Wen²  Pei Su²  Jiaxi Zhou²  Yv Wang² 

[1] 0000 0001 0379 7164, grid.216417.7, School of Basic Medical Science and Cancer Research Institute, Central South University, 410013, Changsha, China;grid.461843.c, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, 300020, Tianjin, China;0000 0001 0662 3178, grid.12527.33, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Department of Stem Cells and Regenerative Medicine, Peking Union Medical College, 300020, Tianjin, China;

关键词: R-spondin2;    Human pluripotent stem cells;    Hematopoietic differentiation;    Mesoderm;    TGF-β signaling;   

DOI  :  10.1186/s13287-019-1242-9

来源: publisher

【 摘 要 】

BackgroundHuman pluripotent stem cells (hPSCs) provide supplies of potential functional blood cells to suffice the clinical needs. However, the underlying mechanism of generating genuine hematopoietic stem cells (HSCs) and functional blood cells from hPSCs remains largely elusive.MethodIn this study, we supplied R-spondin2 exogenously during hematopoietic differentiation of hPSCs under various culture conditions and analyzed the production of hematopoietic progenitor cells (HPCs). We further added R-spondin2 at different temporal window to pin down the stage at which R-spondin2 conferred its effects. RNA-SEQ-based gene profiling was applied to analyze genes with significantly altered expression and altered signaling pathways. Finally, megakaryocytic differentiation and platelet generation were determined using HPCs with R-spondin2 treatment.ResultsWe found that R-spondin2 generated by hematopoiesis-supporting stromal cells significantly enhances hematopoietic differentiation of hPSCs. Supply of R-spondin2 exogenously at the early stage of mesoderm differentiation elevates the generation of APLNR+ cells. Furthermore, early treatment of cells with R-spondin2 enables us to increase the output of hPSC-derived platelet-like particles (PLPs) with intact function. At the mechanistic level, R-spondin2 activates TGF-β signaling to promote the hematopoietic differentiation.ConclusionsOur results demonstrate that a transient supply of R-spondin2 can efficiently promote hematopoietic development by activating both WNT and TGF-β signaling. R-spondin2 can be therefore used as a powerful tool for large-scale generation of functional hematopoietic progenitors and platelets for translational medicine.

【 授权许可】

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