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Platelet regeneration from stem cells offers a potential solution to reduce reliance on donor\u2010based transfusions. However, the current differentiation efficiency is suboptimal. A novel approach is presented that significantly enhances platelet yield from hematopoietic stem and progenitor cells (HSPCs) by increasing the production of megakaryocyte progenitors (MkPs) and mature megakaryocytes (MKs). This method employs the overexpression of HES7 combined with the HDAC inhibitor and GABA agonist (collectively termed the VGM cocktail). The VGM cocktail induces MkP production with an efficiency of up to 90%, validated across HSPCs from various donors. These MkPs exhibit extended proliferative capacity, remaining viable for up to 51 days in prolonged culture, and show enhanced maturation into MKs. This differentiation system effectively replicates in vivo thrombocytopoiesis, as evidenced by polyploidization, long protrusions, and proplatelet formation. Transfusion of VGM\u2010induced MkPs into thrombocytopenic mice results in the release of platelets into circulation. Mechanistic investigation identifies the JAK2\/STAT3 signaling pathway as critical in promoting megakaryopoiesis within this system. Therefore, this study demonstrates that the VGM cocktail facilitates enhanced platelet production by promoting MkP generation, offering a promising strategy for in vitro platelet regeneration for clinical applications.<\/jats:p>","DOI":"10.1002\/advs.202500612","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T11:11:23Z","timestamp":1745925083000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Efficient Generation of Megakaryocyte Progenitors and Platelets From HSPCs via JAK2\/STAT3 Signaling"],"prefix":"10.1002","volume":"12","author":[{"given":"Huicong","family":"Liu","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingna","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6434-5988","authenticated-orcid":false,"given":"Fangfang","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.713434"},{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.312129"},{"key":"e_1_2_9_1_3","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201304054"},{"key":"e_1_2_9_1_4","doi-asserted-by":"publisher","DOI":"10.1007\/s44258-023-00009-9"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-607929"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V74.4.1196.bloodjournal7441196"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-741611"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055530"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-022-02722-5"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.01.011"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-04-285981"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-11-709881"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100844"},{"key":"e_1_2_9_10_1","volume":"115","author":"Zhu F.","year":"2018","journal-title":"Proc. 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