title: Safety and Efficacy of Megakaryocytes Induced from Hematopoietic Stem Cells in Murine and Nonhuman Primate Models.
abstract: 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 × 104megakaryocytes 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.
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guan
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.|Biopharmagen Corp., Suzhou, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Qin
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Diagnosis, Suzhou Municipal Hospital Affiliated Nanjing Medical University, Suzhou, People's Republic of China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.|Biopharmagen Corp., Suzhou, People's Republic of China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.|College of Nanoscale Science, SUNY Polytechnic Institute, Albany, New York, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.|Department of Environmental Medicine, New York University Langone Medical Center, Tuxedo, New York, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Biopharmaceutical R&D Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, People's Republic of China.|Biopharmagen Corp., Suzhou, People's Republic of China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023421:Models, Animal; D011003:Ploidies; D011323:Primates; D014182:Transplantation, Autologous; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34; D004247:DNA
keywords: Expansion and differentiation; Hematopoietic stem cells; Megakaryocytes; Nonhuman primates; Thrombocytopenia; Transplantation