Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches
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REVIEW
Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches Lei Zhang1, Ryan Mack1, Peter Breslin1,2 and Jiwang Zhang1,3*
Abstract Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated. Keywords: HSCs, Aging, Replication stress Background The primary functions of blood cells are transporting oxygen to tissues by red blood cells (RBCs), antagonizing infections caused by pathogenic agents (macrophages and neutrophils), maintaining coagulatory hemostasis (platelets), and confronting and responding adaptively to internal and external antigenic affronts (T and B lymphocyte-mediated immune defense). In the adult human, ~ 4–5 × 1011 blood cells are lost every day due to cellular aging or damage. To replenish the loss of blood cells, approximately the same numbers of blood cells must be produced from bone marrow (BM) hematopoietic progenitors daily [1–3]. Normal homeostatic multi-lineage blood cell regeneration, including immunerelated tissue, is primarily maintained through multipotent hematopoietic progenitors (MPPs), which become exhausted over time, whereas lifetime hematopoiesis and immunity are maintained by self-renewable hematopoietic stem cells (HSCs) that are localized within specialized BM microenvironments called HSC niches [4–9]. *Correspondence: [email protected] 1 Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA Full list of author information is available at the end of the article
Like most other tissue-specific stem cells, HSCs are vulnerable to aging-related stress and gradually lose their self-renewal and hematopoietic regenerative capacities (HRC) [10–12]. The process of aging in HSCs is driven by both cell-intrinsic and extrinsic factors, which lead to a reduction in blood cell production and impairment of immune system function [13–16]. Consequently, elderly populations experience higher incidences of anemia, arterial thrombosis, and myeloid and lymphoid malignancies (such as age-related clonal hematopoiesis, myelodysplastic syndromes, acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma and non-Hodgkin’s lymphoma) [17–19]. In addition, this population may experience declining adaptive immunity, autoimmunity, vaccine failure, and experience increased
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