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Haematologica 2020 Volume 105(1):38-46
Microenvironmental contributions to hematopoietic stem cell aging
Ya-Hsuan Ho1,2 and Simón Méndez-Ferrer1,2
1Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge and 2National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
ABSTRACT
Hematopoietic stem cell (HSC) aging was originally thought to be essentially an HSC-autonomous process, which is the focus of another review in the same issue of Haematologica. However, studies on the microenvironment that maintains and regulates HSC (HSC niche) over the past 20 years have suggested that microenvironmental aging con- tributes to declined HSC function over time. The HSC niches comprise a complex and dynamic molecular network of interactions across multiple cell types, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, neuro-glial cells and mature hematopoietic cells. Upon aging, functional changes in the HSC niches, such as microenviron- mental senescence, imbalanced bone marrow mesenchymal stromal cell differentiation, vascular remodeling, changes in adrenergic signaling and inflammation, coordinately and dynamically influence the fate of HSC and their downstream progeny. The end result is lymphoid deficiency and myeloid skewing. During this process, aged HSC and their derivatives remodel the niche to favor myeloid expansion. Therefore, the crosstalk between HSC and the microenvironment is indispensable for the aging of the hematopoietic system and might represent a therapeutic target in age- related pathological disorders.
Introduction to hematopoietic stem cell aging
Adult hematopoiesis takes place in the bone marrow (BM), where hematopoietic stem cells (HSC) can self-renew, proliferate and differentiate to replenish the blood and immune systems. Given that most HSC are quiescent under homeostasis, mature blood and immune cell production is believed to derive mainly under steady state from progenitor cells (rather than HSC), which differentiate to produce mature blood cells. Cumulative studies have demonstrated that HSC are heteroge- neous and contain subsets with distinct myeloid, platelet or lymphoid-biased potentials, although the existence of lymphoid-biased HSC has long been debated and remains controversial.1-5 Additionally, recent studies have shown that HSC can bypass the intermediate steps to generate mature progenies under certain condi- tions, such as chronic inflammation and aging.
Upon aging, HSC increase in number but their functions are impaired, character- ized by reduced regenerative and homing capacity, loss of cell polarity, and myeloid-biased differentiation at the expense of lymphopoiesis.6-9 These changes were initially thought to cause only cell-intrinsic dysregulation,10 such as epigenetic deregulation,11 replication stress,12 deficient DNA repair,13 and transition from canonical to non-canonical Wnt signaling.14 Old HSC also suffer metabolic changes,15,16 impaired autophagy17 and altered protein homeostasis,18 which con- tribute to the decline of their regenerative potential. However, current studies are revealing that the BM microenvironment may contribute to HSC aging. This hypothesis is supported by an elegant study in which old HSC transplanted into young recipients exhibited reduced myeloid output as compared those transplant- ed into old recipients, suggesting that the old BM microenvironment contributes to myeloid skewing.19 This review will cover microenvironmental contributions to
Correspondence:
YA-HSUAN HO
yhh29@medschl.cam.ac.uk
SIMÓN MÉNDEZ-FERRER
sm2116@cam.ac.uk
Received: July 8, 2019.
Accepted: November 14, 2019. Pre-published: December 5, 2019.
doi:10.3324/haematol.2018.211334
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/38
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