Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands

Abstract

Hematopoietic stem cells (HSCs), which govern the production of all blood lineages, transition through a series of functional states characterized by expansion during fetal development, functional quiescence in adulthood, and decline upon aging. We describe central features of HSC regulation during ontogeny to contextualize how adaptive responses over the life of the organism ultimately form the basis for HSC functional degradation with age. We particularly focus on the role of cell cycle regulation, inflammatory response pathways, epigenetic changes, and metabolic regulation. We then explore how the knowledge of age-related changes in HSC regulation can inform strategies for the rejuvenation of old HSCs.

Keywords: aging; development; epigenetic; hematopoietic stem cells; inflammation; metabolism; niche regulation; quiescence; rejuvenation.

Figure 1.. Dynamic responses of HSCs to organismal demands throughout the lifespan.

During development, HSCs primary function is to establish the adult blood system, with fetal HSCs residing in the fetal liver and engaging in oxidative phosphorylation to allow for rapid expansion. During adulthood, HSCs act to maintain organismal health and immunity via functional quiescence, a primarily glycolytic resting state that allows quick entry into the cell cycle in response to organismal demands. During aging, dysfunctional HSCs expand, survive, and maintain quiescence despite maladaptive oxidative metabolism and chronic inflammation in a degraded BM niche environment that promotes aberrant differentiation.

Figure 2.. Cell-intrinsic and cell-extrinsic features of HSC aging.

Old HSCs display many altered cell-intrinsic features including epigenetic drift, DNA damage, replication stress, deregulated proteostasis, mitochondrial dysfunction, and altered autophagy regulation. These cell-intrinsic changes are compounded by cell-extrinsic changes in the aged BM microenvironment including loss of specific niche cells (i.e., periarteriolar mesenchymal stromal cells (MSC), osteoblastic progenitors (OPr), osteoblasts), and accumulation of other cell types that contribute to an inflammatory milieu (i.e., inflammatory MSCs, macrophages, megakaryocytes) rich in pro-inflammatory factors (i.e., IL-1, IFNs, TNF-α, etc.). Old HSCs are also influenced by other niche changes, including altered innervation, increased adiposity, and leaky vasculature. Together, these features of HSC aging contribute to their functional decline.

Figure 3.. Antagonistic pleiotropy of HSC features during young adulthood and old age.

Many features of HSCs, such as pro-survival mechanisms, stress response mechanisms, quiescence, cellular memory, and response to niche factors, are beneficial for optimal HSC function and response to organismal demands in young adulthood but become detrimental and maladaptive during aging.