Protective effect of M-CSF on the subpopulation composition of monocytes in vitro in ischemic heart disease

Background. Coronary artery disease (CAD) is characterized by abnormalities in the subpopulation composition of blood monocytes, which has specific features in ischemic cardiomyopathy (ICM), but its regulation by lineage-specific M-CSF has not been studied.

Aim: To determine the nature of changes in monocyte numbers and their subpopulation composition in vitro in the presence of M-CSF in patients with CAD, both with and without ICM.

Material and Methods. 22 patients with CAD (11 with ICM and 11 without ICM) and 10 healthy donors were examined. Their monocytes were cultured for 6 days with and without the addition of 50 ng/ml M-CSF. In both samples, flow cytometry was used to assess the proportion of classical CD14⁺⁺CD16^–, intermediate CD14⁺⁺CD16⁺, non-classical CD14⁺CD16⁺⁺, and transitional CD14⁺CD16^– forms relative to the total number of monocytes (CD14^++/+ cells).

Results. In patients with coronary artery disease (CAD), regardless of ICM, the proportion of intermediate forms (and, in ICM, the total number of CD14^++/+ cells) in native monocyte culture is reduced relative to healthy individuals. M-CSF inhibits the decline of intermediate monocytes in in vitro cell culture in patients with CAD, both with and without cardiomyopathy. In ICM, this is accompanied by an increase (to normal) in the proportion of non-classical cells and the total number of monocytes in the culture.

Conclusion. M-CSF in CAD normalizes the subpopulation composition and number of monocytes in vitro, which is impaired to a greater extent in patients with ICM, in whom non-classical and intermediate forms exhibit increased sensitivity to it.

1. Pastena P., Frye J.T., Ho C. et al. Ischemic cardiomyopathy: epidemiology, pathophysiology, outcomes, and therapeutic options. Heart Fail. Rev. 2024;29(1):287–299. https://doi.org/10.1007/s10741-023-10377-4

2. Mori D., Miyagawa S., Matsuura R. et al. Pioglitazone strengthen therapeutic effect of adipose-derived regenerative cells against ischemic cardiomyopathy through enhanced expression of adiponectin and modulation of macrophage phenotype. Cardiovasc. Diabetol. 2019;18(1):39. https://doi.org/10.1186/s12933-019-0829-x

3. Chumakova S.P., Shipulin V.M., Urazova O.I. et al. Ischemic cardiomyopathy: blood monocytes and mediators of their differentiation. Bulletin of the Russian Academy of Medical Sciences. 2019;74(6):396–404. (In Russ.). https://doi.org/10.15690/vramn1185. EDN: MOGXIH

4. Urazova O.I, Chumakova S.P., Vins M.V. et al. Characteristics of humoral regulation of differentiation of bone marrow monocyte subpopulations in patients with ischemic cardiomyopathy. International Journal of Biomedicine. 2019;9(2):91–96. https://doi.org/10.21103/Article9(2)_OA1. EDN: CLBORY

5. Kapellos T.S., Bonaguro L., Gemünd I. et al. Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front. Immunol. 2019;10:2035. https://doi.org/10.3389/fimmu.2019.02035

6. Wang Q., Ismahil M.A., Zhu Y. et al. CD206(+)IL-4Ralpha(+) macrophages are drivers of adverse cardiac remodeling in ischemic cardiomyopathy. Circulation. 2025;152(4):257–273. https://doi.org/10.1161/CIRCULATIONAHA.124.072411

7. Ruder A.V., Wetzels S.M.W., Temmerman L. et al. Monocyte heterogeneity in cardiovascular disease. Cardiovasc. Res. 2023;119(11):2033–2045. https://doi.org/10.1093/cvr/cvad069

8. Ushach I., Zlotnik A. Biological role of granulocyte macrophage colonystimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J. Leukoc. Biol. 2016;100(3):481–448. https://doi.org/10.1189/jlb.3RU0316-144R

9. Inoue K., Qin Y., Xia Y. et al. Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass. Elife. 2023;12:e82118. https://doi.org/10.7554/eLife.82118

10. Williams H., Mack C., Baraz R. et al. Monocyte differentiation and heterogeneity: inter-subset and interindividual differences. Int. J. Mol. Sci. 2023;24(10):8757. https://doi.org/10.3390/ijms24108757

11. Peet C., Ivetic A., Bromage D.I., Shah A.M. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc. Res. 2020;116(6):1101–1112. https://doi.org/10.1093/cvr/cvz336

12. Felker G.M., Shaw L.K., O'Connor C.M. A standardized definition of ischemic cardiomyopathy for use in clinical research. J. Am. Coll. Cardiol. 2002;39(2):210–218. https://doi.org/10.1016/s0735-1097(01)01738-7

13. Pilling D., Fan T., Huang D. et al. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One. 2009;4(10):e7475. https://doi.org/10.1371/journal.pone.0007475

14. Lopes-Coelho F., Silva F., Gouveia-Fernandes S. et al. Monocytes as endothelial progenitor cells (EPCs), another brick in the wall to disentangle tumor angiogenesis. Cells. 2020;9(1):107. https://doi.org/10.3390/cells9010107

15. Denisenko O.A., Chumakova S.P., Urazova O.I. Endothelial progenitor cells: Origin and role of angiogenesis in cardiovascular diseases. Siberian Journal of Clinical and Experimental Medicine. 2021;36(2):23–29. (In Russ.). https://doi.org/10.29001/2073-8552-2021-36-2-23-29. EDN: UJDHLQ

16. Stelmashenko A.I., Belyaeva S.A., Karpov R.M., Andreev S.L. Assessment of the state of the extracellular matrix of the myocardium in patients with ischemic cardiomyopathy. Morphological almanac named after V.G. Koveshnikov. 2021;19(4):65–71. (In Russ.). EDN: CPVJHJ

17. Patel A.A., Zhang Y., Fullerton J.N. et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J. Exp. Med. 2017;214(7):1913–1923. https://doi.org/10.1084/jem.20170355

18. Orozco S.L., Canny S.P., Hamerman J.A. Signals governing monocyte differentiation during inflammation. Curr. Opin. Immunol. 2021;73:16–24. https://doi.org/10.1016/j.coi.2021.07.00

19. Brach M.A., Henschler R., Mertelsmann R.H., Herrmann F. Regulation of M-CSF expression by M-CSF: role of protein kinase C and transcription factor NF kappa B. Pathobiology. 1991;59(4):284–288. https://doi.org/10.1159/000163664

20. Zhuang L., Zong X., Yang Q. et al. Interleukin-34-NF-κB signaling aggravates myocardial ischemic/reperfusion injury by facilitating macrophage recruitment and polarization. EBioMedicine. 2023;95:104744. https://doi.org/10.1016/j.ebiom.2023.104744