Using mitochondrial activity to select for potent human hematopoietic stem cells

CD90型 干细胞 造血 川地34 生物 细胞生物学 人口 CD38 移植 线粒体 癌症研究 造血干细胞 免疫学 癌症干细胞 祖细胞 骨髓 造血干细胞移植 粒线体疾病 诱导多能干细胞 内科学 医学 环境卫生
作者
Jiajing Qiu,Jana Gjini,Tasleem Arif,Kateri Moore,Lin Miao,Saghi Ghaffari
出处
期刊:Blood Advances [American Society of Hematology]
卷期号:5 (6): 1605-1616 被引量:16
标识
DOI:10.1182/bloodadvances.2020003658
摘要

Abstract Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38−CD45RA−CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38−CD45RA−CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.
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