Open AccessAging of human hematopoietic stem cells is linked to changes in Cdc42 activity
Author(s) -
Amanda Amoah,
Anja Keller,
Ramiz Emini,
Markus Hoenicka,
Andreas Liebold,
Angelika Vollmer,
Karina Eiwen,
Karin Soller,
Vadim Sakk,
Yi Zheng,
Maria Carolina Florian,
Hartmut Geiger
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2020.269670
Subject(s) - haematopoiesis , progenitor cell , stem cell , cdc42 , microbiology and biotechnology , biology , ex vivo , hematopoietic stem cell , in vivo , immunology , cell division , cancer research , cell , biochemistry , signal transduction , genetics
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.