Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF

Mentkowski, K.; Lee, I.-H.; Rohde, D.; Paccalet, A.; Seung, H.; Kumowski, N.; Schloss, M. J.; Carpenito-Kronenfeld, M.; Kaushal, V.; Jain, R.; Memcaj, X.; Wiebe, J.; Momin, N.; Pabel, S.; Muse, C. G.; Tuy, K.; Ung, S.; Roh, J.; Swirski, F. K.; Scadden, D.; van Galen, P.; Kreso, A.; Naxerova, K. N.; Hulsmans, M.; Nahrendorf, M.

doi:10.1101/2025.03.28.645924

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bioRxiv · 10.1101/2025.03.28.645924

Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF

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Abstract

During the genesis of heart failure, the myocardium recruits an abundance of bone marrow-derived leukocytes, primarily monocytes, with various disease-promoting functions. Increased hematopoiesis fuels these unfavorable changes in cardiac leukocyte origin, number and phenotype. Here we examine hematopoietic niche cells, which regulate blood progenitor proliferation and systemic monocyte supply, in obese, hypertensive mice that develop heart failure with preserved ejection fraction (HFpEF). Single cell transcriptomics revealed that in HFpEF, stromal bone marrow niche cells expand and respond strongly to IFN{gamma}. Deleting the IFN{gamma} receptor in stromal cells of Prrx1CreERT2;Ifngr1fl/fl mice reduced hematopoietic progenitor proliferation and systemic monocytes in both the steady state and HFpEF and also increased the canonical hematopoietic maintenance factor CXCL12, resulting in reduced fibrosis and improved diastolic function. CD8+ T cells in adipose tissue were a major source of IFN{gamma} in mice with HFpEF; their depletion restored CXCL12 expression and lowered monocyte numbers. ScRNA-seq in mice with ischemic heart disease uncovered a diverging marrow response. These data indicate that in HFpEF, adipose tissue, bone marrow and adaptive and innate immune cells conspire to expand harmful macrophage subsets in the heart.

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Mentkowski, K., Lee, I.-H., Rohde, D., Paccalet, A., Seung, H., Kumowski, N., Schloss, M. J., Carpenito-Kronenfeld, M., Kaushal, V., Jain, R., Memcaj, X., Wiebe, J., Momin, N., Pabel, S., Muse, C. G., Tuy, K., Ung, S., Roh, J., Swirski, F. K., Scadden, D., van Galen, P., Kreso, A., Naxerova, K. N., Hulsmans, M., Nahrendorf, M.. 2025-04-02. Bone marrow mesenchymal stromal cells mediate cellular inflammation in HFpEF. https://doi.org/10.1101/2025.03.28.645924

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