Human Aging Alters the Spatial Organization between CD34+ Hematopoietic Cells and Adipocytes in Bone Marrow

Abstract

Summary Age-related clonal hematopoiesis is a major risk factor for myeloid malignancy and myeloid skewing is a hallmark of aging. However, while it is known that non-cell-autonomous components of the microenvironment can also influence this risk, there have been few studies of how the spatial architecture of human bone marrow (BM) changes with aging. Here, we show that BM adiposity increases with age, which correlates with increased density of maturing myeloid cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) and an increased proportion of HSPCs adjacent to adipocytes. However, NGFR+ bone marrow stromal cell (NGFR+ BMSC) density and distance to HSPCs and vessels remained stable. Interestingly, we found that, upon aging, maturing myeloid cell density increases in hematopoietic areas surrounding adipocytes. We propose that increased adjacency to adipocytes in the BM microenvironment may influence myeloid skewing of aging HSPCs, contributing to age-related risk of myeloid malignancies.

Human, mouse, and dog bone marrow show similar mesenchymal stromal cells within a distinctive microenvironment

“…However, both subpopulations may have transcriptomic differences to support the more myeloid/lymphoid bias hematopoiesis, respectively. Our data correlate with recent observations that the frequencies of mouse LepR+ BMSCs [14] and human CD271+ BMSCs [1] did not change with aging. However, changes in the functional properties of BMSCs [26] and in the subpopulation frequencies and their distribution with aging [27] have been reported.…”

“…Offprint requests to: Dr Eugenia Flores-Figueroa, Princess Margaret Cancer Research Tower Q4 X X, Oncology Hospital, 101 College Street, 9th Floor, Toronto, ON M5G 1L7, Canada;; E-mail: eugenia. flores-figueroa@uhnresearch.ca 1 Current affiliation: Princess Margaret Cancer Research Tower, Toronto, ON, Canada. 2 BML, JED, and EFF designed the research and wrote the article.…”

Maternal Western-Style Diet Impairs Bone Marrow Development and Drives a Hyperinflammatory Phenotype in Hematopoietic Stem and Progenitor Cells in Fetal Rhesus Macaques

“…Heightened inflammatory responses by BM stromal macrophages could modulate the development of myeloid progenitors leading to “immune-tolerant phenotype” in mature monocytes. Recent studies from our and other laboratories have shown that BM adipocytes may potentiate myeloid-biased differentiation of HSPCs in adult rhesus macaques (Robino et al, 2020) and humans (Aguilar-Navarro et al, 2020). Future studies will identify adipocyte-derived molecules that control myelopoiesis.…”

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

“…The microenvironment niche for HSCs has been studied for young mice [ 260 ], but more in-depth studies of the aged BM microenvironment is warranted, especially in context of oxygen content [ 260 ], as we noted [ 1 ]. There is a report of the rejuvenation of progenitors from old mice when placed into and exposed to a young BM environment [ 261 ], and a more recent report demonstrated that degeneration of adrenergic nerves in BM affects aging of the HSC niche [ 262 ], and that aging in humans alters the special organization between populations of CD34 + cells (contains mainly HPCs, but also a small percentage of HSCs) and adipocytes in the BM [ 263 ]; this is of potential relevance as increased adiposity is associated with the aged BM microenvironment and can alter the functionality of surrounding cells. MSCs showed aging related expression of cxcr4 [ 264 ], a “homing” HSC/HPC receptor, but this has not yet been evaluated under conditions of hypoxia collection and processing such as in [ 40 , 41 ].…”