Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models.
Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models.
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DOI：
10.5966/sctm.2016-0224
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发表时间：
2017-03
影响因子：
6
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Guan X;Qin M;Zhang Y;Wang Y;Shen B;Ren Z;Ding X;Dai W;Jiang Y
由于缺乏血小板供应和美国食品和药物管理局批准的血小板生长因子，巨核细胞已成为缓解血小板减少症的有效替代品。在这里，我们报告了一种有效的两阶段培养系统的开发，该系统不含基质，动物成分和遗传操作，用于从造血干细胞生产功能性巨核细胞。在鼠和非人灵长类动物模型中进行了安全性和功能研究。一个人冻存脐带血CD 34+细胞可以离体诱导产生高达1.0 × 104个巨核细胞，其中包括分别为82.4% ± 6.1%和73.3% ± 8.5%（平均值± SD）的CD 41 a+和CD 42 b+细胞，产生的细胞数量比先前报告的高约650倍。诱导的人巨核细胞能够在小鼠异种移植模型中植入并产生功能性血小板。在非人灵长类动物模型中，移植灵长类巨核细胞祖细胞可增加血小板计数最低值并增强止血功能，且无不良反应。此外，灵长类动物血小板在体内与自体或同种异体成熟巨核细胞移植后早在3小时即释放，并持续48小时以上。这些结果有力地表明，大规模诱导功能性巨核细胞适用于临床治疗血小板减少性血液病。干细胞转化医学2017;6：897-909
Because of a lack of platelet supply and a U.S. Food and Drug Administration‐approved platelet growth factor, megakaryocytes have emerged as an effective substitute for alleviating thrombocytopenia. Here, we report the development of an efficient two‐stage culture system that is free of stroma, animal components, and genetic manipulations for the production of functional megakaryocytes from hematopoietic stem cells. Safety and functional studies were performed in murine and nonhuman primate models. One human cryopreserved cord blood CD34+ cell could be induced ex vivo to produce up to 1.0 × 104 megakaryocytes that included CD41a+ and CD42b+ cells at 82.4% ± 6.1% and 73.3% ± 8.5% (mean ± SD), respectively, yielding approximately 650‐fold higher cell numbers than reported previously. Induced human megakaryocytic cells were capable of engrafting and producing functional platelets in the murine xenotransplantation model. In the nonhuman primate model, transplantation of primate megakaryocytic progenitors increased platelet count nadir and enhanced hemostatic function with no adverse effects. In addition, primate platelets were released in vivo as early as 3 hours after transplantation with autologous or allogeneic mature megakaryocytes and lasted for more than 48 hours. These results strongly suggest that large‐scale induction of functional megakaryocytic cells is applicable for treating thrombocytopenic blood diseases in the clinic. Stem Cells Translational Medicine 2017;6:897–909