Myeloid Skew Arises from Age-Related Changes in Bone Marrow Niches

Hematopoietic stem cells (HSCs) resident in bone marrow generate immune cells, and their activity is thus vital to the correct function of the immune system. Like all stem cell populations, HSCs are sustained by a niche of supporting cells. One of the interesting questions relating to the aging of stem cells and the decline of stem cell activity in later life is whether this is a problem inherent to the stem cells themselves, or it arises from change and damage in the niche. There is evidence for both to be the case, but it is possible to argue that, until extreme old age, the loss of activity is more a matter of the niche than actual incapacity on the part of stem cells.

One of the ways in which HSC behavior changes with age, and that alters the immune system for the worse, is that ever more myeloid and ever fewer lymphoid daughter cells are created. This myeloid skew is a well studied phenomenon, but as for all complex systems in the body, the causes and their relations to one another are much debated. Here, researchers discuss some specific mechanisms in the HSC niches in the bone marrow that may contribute to this phenomenon.

Hematopoietic aging is characterized by expansion of hematopoietic stem cells (HSCs) with impaired function, such as reduced engraftment, quiescence, self-renewal, unfolded protein response, and lymphoid differentiation potential, leading to myeloid-biased output both in mice and humans. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged HSCs and/or their microenvironment predispose to these malignancies remains unclear.

Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological or 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 bone marrow microenvironment promotes myelopoiesis in premature and physiological aging.

During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased bone marrow 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 or premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.