Mechanisms and rejuvenation strategies for aged hematopoietic stem cells

Abstract

Hematopoietic stem cell (HSC) aging, which is accompanied by reduced self-renewal ability, impaired homing, myeloid-biased differentiation, and other defects in hematopoietic reconstitution function, is a hot topic in stem cell research. Although the number of HSCs increases with age in both mice and humans, the increase cannot compensate for the defects of aged HSCs. Many studies have been performed from various perspectives to illustrate the potential mechanisms of HSC aging; however, the detailed molecular mechanisms remain unclear, blocking further exploration of aged HSC rejuvenation. To determine how aged HSC defects occur, we provide an overview of differences in the hallmarks, signaling pathways, and epigenetics of young and aged HSCs as well as of the bone marrow niche wherein HSCs reside. Notably, we summarize the very recent studies which dissect HSC aging at the single-cell level. Furthermore, we review the promising strategies for rejuvenating aged HSC functions. Considering that the incidence of many hematological malignancies is strongly associated with age, our HSC aging review delineates the association between functional changes and molecular mechanisms and may have significant clinical relevance.

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

“…HSC niches also undergo aging-related structural and functional changes which induce inflammatory challenges to HSCs [ 72 ]. Therefore, we might be able to rejuvenate aged HSCs by improving niche cell function and repressing inflammation in BM [ 12 , 190 ].…”

“…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 ].…”

Regulation of Hematopoietic Stem Cell Fate and Malignancy

“…Old bone marrow contains more HSCs than young bone marrow in both mice and humans [ 11 , 12 , 13 ]. This increase cannot compensate for the defects of aged HSCs and the aged HSC pool contained increased myeloid-dominant HSCs with a lower output of mature blood cells per HSC [ 14 , 15 ]. An increase in proliferation expanded the aged HSC subgroup and induced functional decline of HSCs [ 8 ].…”

“…HSC self-renewal involved in the maintenance or expansion of stem cell numbers following cellular division. Most HSCs are actively cycling during fetal life and old age, while HSCs in adulthood are often quiescent [ 15 , 46 , 47 , 48 ]. These phenomena were investigated by a serial transplantation assay, which showed that old HSCs had less self-renewal activity and generated smaller daughter clones in extended serial transplants than did their younger counterparts [ 14 ].…”

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

“…LncRNAs have been illustrated to play a pivotal role in the progression of cell fate and cancer development, including hematopoiesis and leukemogenesis [17,21,24,52]. They exert their functions via cotranscriptional regulation, gene expression modulation, scaffolding of protein complexes, and pairing with other RNAs [22,53].…”