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Aged bone marrow myeloid and mesenchymal cells develop unique senescence phenotypes

ABSTRACT: Cellular senescence was originally characterized in mesenchymal cells and subsequently this concept was extended to immune cells. However, the extent to which immune cells differ from mesenchymal cells in their senescence phenotype, or “senotype”, is unclear. Here, we evaluated the senotypes of bone marrow/bone immune versus mesenchymal cells. Among immune cells, myeloid cells exhibited the highest expression of p16. However, targeted clearance of p16+ myeloid cells using LysM-Cre x p16-LOX-ATTAC mice only had minor effects on age-related bone loss in male mice, with no effects in females. After clearance, p16+ myeloid cells were only transiently reduced, unlike when targeting p16+ mesenchymal cells. In the same bones, aged myeloid cells demonstrated lower expression of senescence markers than mesenchymal cells and, when induced in culture, the senescence phenotype of myeloid cells differed substantially from that of mesenchymal cells. Our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE294362 | GEO | 2026/01/07

REPOSITORIES: GEO

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Project description:Cellular senescence is a heterogeneous phenotype that has primarily been characterized in non-hematopoietic cells. The extent to which immune cells differ from mesenchymal cells in their senescence phenotype, or “senotype”, is unclear. Here, we applied single-cell transcriptomic and proteomic technologies with both global and cell-specific senolytic mouse models to test the extent to which cellular senescence occurs in immune cells in the bone marrow of aging mice and placed these findings in the context of aged bone mesenchymal cells. In the bone marrow, myeloid-lineage cells exhibited the highest expression of the senescence marker, p16, among all immune cell types, while also exhibiting high levels of inflammatory markers. Targeted clearance of p16+ myeloid cells in aged mice using the LysM-Cre x p16-LOX-ATTAC model reduced levels of senescence-associated markers in monocyte-lineage cells, yet only had minor effects on age-related bone loss in male mice, with no effect in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time period. This led to a lack of long-lasting reduction in senescent cell burden, in contrast to when targeting bone mesenchymal cell types. In vitro, myeloid lineage cells failed to undergo growth arrest under genotoxic stress, potentially explaining their rapid repopulation in vivo . To further understand how DNA damage influences senescence in myeloid cells versus mesenchymal cells, we performed senescence induction using etoposide treatment on primary mouse bone marrow-derived macrophages (BMDMs) and mesenchymal bone marrow stromal cells (BMSCs) in side-by-side in vitro experiments. Although BMDMs upregulated mRNA transcripts for p16 and p21 in response to senescence induction, these increases were considerably lower in magnitude as compared to BMSCs. Furthermore, in contrast to BMSCs, BMDMs did not develop a transcriptional profile of senescence development. Collectively, our findings indicate that myeloid-lineage cells express the most robust features of senescence of all immune cells in the bone marrow but differ substantially in their senotype relative to mesenchymal cells in the aging skeleton. Specifically, while aged bone marrow myeloid cells express features of senescence, they do not possess the full senescent phenotype of aged mesenchymal cells. Thus, our findings point to fundamental differences in the senotypes of aged immune versus mesenchymal cells that warrants further investigation across tissues.

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Aged bone marrow myeloid and mesenchymal cells develop unique senescence phenotypes

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