Abstract
Aging is a major risk factor in the development of chronic diseases, especially cardiovascular diseases. Age‐related organ dysfunction is strongly associated with the accumulation of senescent cells. Cardiac mesenchymal stromal cells (cMSCs), deemed part of the microenvironment, modulate cardiac homeostasis through their vascular differentiation potential and paracrine activity. Transcriptomic analysis of cMSCs identified age‐dependent biological pathways regulating immune responses and angiogenesis. Aged cMSCs displayed a senescence program characterized by Cdkn2a expression, decreased proliferation and clonogenicity, and acquisition of a senescence‐associated secretory phenotype (SASP). Increased CCR2‐dependent monocyte recruitment by aged cMSCs was associated with increased IL‐1ß production by inflammatory macrophages in the aging heart. In turn, IL‐1ß induced senescence in cMSCs and mimicked age‐related phenotypic changes such as decreased CD90 expression. The CD90+ and CD90‐ cMSC subsets had biased vascular differentiation potentials, and CD90+ cMSCs were more prone to acquire markers of the endothelial lineage with aging. These features were related to the emergence of a new cMSC subset in the aging heart, expressing CD31 and endothelial genes. These results demonstrate that cMSC senescence and SASP production are supported by the installation of an inflammatory amplification loop, which could sustain cMSC senescence and interfere with their vascular differentiation potentials.
Highlights
Aging represents a dominant risk factor for developing chronic dis‐ eases, especially cardiovascular diseases
By performing transcriptional expression analysis of cell‐sorted Cardiac mesenchymal stromal cells (cMSCs), we show that aged cMSCs acquire a senescent program including the expression of selective cell cycle regulators from the INK4 family and senescence‐associated secretory phenotype (SASP) factors involved in the regulation of the immune response
We show that aging is associated with specific changes in cardiac stroma microenvironment and coincides with the installation of a deleterious amplification loop promoting paracrine senescence of cMSCs and modifying their endothelial dif‐ ferentiation potential
Summary
Aging represents a dominant risk factor for developing chronic dis‐ eases, especially cardiovascular diseases. To verify that both the CD90‐ and CD90+ cMSCs belonged to the same cell population, we analyzed the expression of genes related to the cardiac mesenchymal lineage Both CD90‐ and CD90+ cMSCs subsets from young mice expressed higher levels of Tcf, Tbx, Tbx, Hand and Gata transcription factors compared with EC (Figure 5a), confirming the pro‐epicardial origin of both cMSC sub‐ sets (Chong et al, 2011; Noseda et al, 2015). We previ‐ ously observed that expression of Cdkn2a was up‐regulated during in vitro vascular differentiation of the entire cMSC pool and, nota‐ bly, in aged cMSCs in response to endothelial differentiation medium (Figure S2j) These results suggested that the preferential up‐regulation of Cdkn2a in the CD90+ cMSC subset with aging could favor, along with pro‐angiogenic factors such as Vegfa, the triggering of an endo‐ thelial differentiation program. This subset retained ex‐ pression of mesenchymal‐related genes, suggesting partial commit‐ ment to an endothelial cell fate
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