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人类造血干细胞的衰老与 Cdc42 活性的变化有关。

Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity.

机构信息

Institute of Molecular Medicine, Ulm University, Meyerhofstrasse, 89081 Ulm.

Department of Cardiothoracic and Vascular Surgery, Ulm University Hospital, Ulm.

出版信息

Haematologica. 2022 Feb 1;107(2):393-402. doi: 10.3324/haematol.2020.269670.

DOI:10.3324/haematol.2020.269670
PMID:33440922
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8804569/
Abstract

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSC). We report increased frequencies of HSC, hematopoietic progenitor cells and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSC further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSC upon aging. The frequency of human HSC polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarization of aged human HSC with respect to Cdc42. Elevated activity of Cdc42 in aged HSC thus contributed to age-related changes in HSC. Xenotransplant, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSC. Aged HSC treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSC. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSC, and similar to mice, this presents a likely possibility for attenuation of aging in human HSC.

摘要

在这项研究中，我们描述了人类造血干细胞（HSC）与年龄相关的表型。我们报告称，老年人中 HSC、造血祖细胞和谱系阴性细胞的频率增加，但多淋巴祖细胞的频率降低。尽管老年人 HSC 的体外分裂动力学没有变化，但它们的分裂起始时间延迟。衰老的人类造血细胞中小 RhoGTPase Cdc42 的活性升高，我们发现 Cdc42 活性与衰老过程中 HSC 的频率之间存在正相关。与小鼠类似，人类 HSC 极性蛋白的极性频率随着年龄的增长而降低，而通过 Cdc42 活性的特异性药理学抑制剂 CASIN 抑制 Cdc42 活性，导致衰老的人类 HSC 相对于 Cdc42 重新极化。因此，Cdc42 在衰老 HSC 中的活性升高导致了 HSC 的与年龄相关的变化。使用 NBSGW 小鼠作为受体的异种移植显示，与年轻 HSC 相比，衰老 HSC 的嵌合率更高。体外用 CASIN 处理的衰老 HSC 表现出与年轻 HSC 受体相似的植入特征。总之，我们的工作为 Cdc42 活性升高在驱动人类 HSC 衰老中的作用提供了强有力的证据，并且与小鼠类似，这为人类 HSC 衰老的衰减提供了一种可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/ae36ea7f6825/107393.fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/9cb554bac7dd/107393.fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/4fd560094812/107393.fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/1612df7ef1c1/107393.fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/f817e7dd884d/107393.fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/ae36ea7f6825/107393.fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/9cb554bac7dd/107393.fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/4fd560094812/107393.fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/1612df7ef1c1/107393.fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/f817e7dd884d/107393.fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe48/8804569/ae36ea7f6825/107393.fig5.jpg

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