Ricolinostat promotes the generation of megakaryocyte progenitors from human hematopoietic stem and progenitor cells

• Published in: Stem cell research & therapy Vol. 13; no. 1; p. 54
• Main Authors: Jiang, Jianan, Qin, Jinhua, Li, Jisheng, Lin, Xiaosong, Zhang, Bowen, Fan, Zeng, He, Lijuan, Zeng, Quan, Yue, Wen, Zheng, Min, Pei, Xuetao, Li, Yanhua
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.02.2022; BioMed Central; BMC
• Subjects: Analysis; Blood platelets; Cell culture; Cell Differentiation; Cell fate; Cell surface; Chemical compounds; Cord blood; CXCR2 protein; Cytokines; Flow cytometry; Gene expression; Hematopoietic stem and progenitor cell; Hematopoietic Stem Cells; High-throughput screening; Humans; Hydroxamic Acids - metabolism; Hydroxamic Acids - pharmacology; Interleukin 8; Manufacturers; Megakaryocyte; Megakaryocyte progenitor; Megakaryocyte Progenitor Cells; Megakaryocytes; Platelet factor 4; Platelets; Progenitor cells; Pyrimidines; Ricolinostat; Software; Stem cells; Surface markers; United States > US; Japan; Germany; Megakaryocyte; Megakaryocyte progenitor; Hematopoietic stem and progenitor cell; Ricolinostat
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-022-02722-5

Ex vivo production of induced megakaryocytes (MKs) and platelets from stem cells is an alternative approach for supplying transfusible platelets. However, it is difficult to generate large numbers of MKs and platelets from hematopoietic stem cells and progenitor cells (HSPCs). To optimize the differentiation efficiency of megakaryocytic cells from HSPCs, we first employed a platelet factor 4 (PF4)-promoter reporter and high-throughput screening strategy to screen for small molecules. We also investigated the effects and possible mechanisms of candidate small molecules on megakaryocytic differentiation of human HSPCs. The small molecule Ricolinostat remarkably promoted the expression of PF4-promoter reporter in the megakaryocytic cell line. Notably, Ricolinostat significantly enhanced the cell fate commitment of MK progenitors (MkPs) from cord blood HSPCs and promoted the proliferation of MkPs based on cell surface marker detection, colony-forming unit-MK assay, and quantitative real-time PCR analyses. MkPs generated from Ricolinostat-induced HSPCs differentiated into mature MKs and platelets. Mechanistically, we found that Ricolinostat enhanced MkP fate mainly by inhibiting the secretion of IL-8 and decreasing the expression of the IL-8 receptor CXCR2. The addition of Ricolinostat to the culture medium promoted MkP differentiation from HSPCs and enhanced the proliferation of MkPs mainly by suppressing the IL-8/CXCR2 pathway. Our results can help the development of manufacturing protocols for the efficient generation of MKs and platelets from stem cells in vitro.