Page 51 - 2022_02-Haematologica-web

Hematopoiesis
Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity
Amanda Amoah,1 Anja Keller,1° Ramiz Emini,2° Markus Hoenicka,2 Andreas Liebold,2 Angelika Vollmer,1 Karina Eiwen,1 Karin Soller,1 Vadim Sakk,1 Yi Zheng,3 Maria Carolina Florian1° and Hartmut Geiger1
1Institute of Molecular Medicine, Ulm University, Ulm, Germany; 2Department of Cardiothoracic and Vascular Surgery, Ulm University Hospital, Ulm, Germany and 3Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA
°AK current address: Zentrum für Integrative Psychiatrie, Lübeck Campus, Lübeck, Germany °RE current address: Herzzentrum, Uniklinik Köln, Köln, Germany
°MCF current address: Bellvitge Institute for Biomedical Research, IDIBELL, Barcelona, Spain
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 fre- quency 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 con- tributed 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 dis- played 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.
Introduction
Aging is associated with tissue degeneration, aging-related diseases and an increased susceptibility to infections.1,2 These hallmarks of aging have been linked to aging-related changes within somatic stem cell compartments, and primarily investigated in animal models like mice.3,4 One of the most extensively studied somatic stem cell-based system is the hematopoietic system. Hematopoietic stem cells (HSC) maintain blood homeostasis and show an age-related decline in overall function in mice,5 which includes an increase in myelopoiesis,6 accumulation of DNA damage,7 changes in epigenomic and transcriptional programs,8 decreased cell polarity and aberrant activity of the small RhoGTPase Cdc42.9 Although sig- nificant progress has been achieved in elucidating mechanisms of aging of murine HSC, it remains unclear whether these mechanisms can be simply extrapolated to other species, including humans. Early studies on HSC number and function in larger mammals showed, based on stochastic modeling, clear differences in HSC biology and aging to the murine model.10,11 These data suggested that HSC from non-human primates cycle more slowly and that fewer numbers of HSC clones actively contribute to hematopoiesis in humans at steady-state than in mice. This connotes that non-human primates and murine HSC may undergo different stress intensities such as the rate of accruing DNA damage and, as a result, may exhibit dissimilarities in aging.
Ferrata Storti Foundation
Haematologica 2022 Volume 107(2):393-402
Correspondence:
HARTMUT GEIGER,
hartmut.geiger@uni-ulm.de
Received: August 13, 2020. Accepted: December 22, 2020. Pre-published: January 14, 2021.
https://doi.org/10.3324/haematol.2020.269670 ©2022 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2022; 107(2)
393
ARTICLE