Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Abstract

SummaryHematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

Mechanisms and rejuvenation strategies for aged hematopoietic stem cells

“…Furthermore, the distance between HSCs and megakaryocytes regulates HSC proliferation and increases in β3adrenergic receptor (AR) mice and in natural aging. In 2019, Ho et al also identified disrupted β-adrenergic nerve signaling (increased β2-AR-interleukin (IL)-6 levels and decreased β3-AR-Nos1 activity) as an important determinant of niche alterations during aging, resulting in impaired lymphoid differentiation and myeloid expansion [113]. In addition, Frisch et al showed that dysfunction of aged marrow macrophages directed HSC platelet bias and that aged mice exhibited markedly more senescent neutrophils than young mice [11].…”

Highly multiplexed immune profiling throughout adulthood reveals kinetics of lymphocyte infiltration in the aging mouse prostate

“…Importantly, this age-related expansion of lymphocytes in the prostate happens in contrast to the agerelated myeloid bias of hematopoiesis (Mann et al, 2018). As mice age, different processes including bone marrow stem cell niche remodeling, inflammatory cytokines, and telomere dysfunction skew hematopoiesis towards myeloid lineages (Ergen et al, 2012;Ho et al, 2019;Ju et al, 2007). Aging is also associated with involution of the thymus, resulting in reduced production of naïve T cells (Palmer, 2013).…”

Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles

“…Age-related biased denervation and BM-niche remodeling lead to premature aging-like changes in murine HSCs [115]. The aging BM harbors not only reduced b3-AR signaling, but importantly also contains reduced endosteal HSC niches, which all lead to the aging-typical biased myelopoiesis [116]. Aging is also associated with a sharp decline in sex hormones and melatonin synthesis, accompanied by osteoporosis, anemia, and a major reduction in host immunity [37,117].…”