Safety and efficacy of ex vivo expanded CD34+ stem cells in murine and primate models
Posted on 2019-06-13 - 05:00
Abstract Background Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation. Methods Enriched human CD34+ cells and mobilized nonhuman primate peripheral blood CD34+ cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model. Results HEM could effectively expand human CD34+ cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38−CD90+CD45RA−CD49f+ in CD34+ cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34+ cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34+ cells survived for over 18 months without any noticeable abnormalities. Conclusions Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.
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Zhang, Yu; Shen, Bin; Guan, Xin; Qin, Meng; Ren, Zhihua; Ma, Yupo; et al. (2019). Safety and efficacy of ex vivo expanded CD34+ stem cells in murine and primate models. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.4542176.v1
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AUTHORS (9)
YZ
Yu Zhang
BS
Bin Shen
XG
Xin Guan
MQ
Meng Qin
ZR
Zhihua Ren
YM
Yupo Ma
WD
Wei Dai
XD
Xinxin Ding
YJ
Yongping Jiang