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]
日期:2021-03-12
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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