Macrophages and fibroblasts in cardiac fibrosis: interactions and transformation

Abstract

Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition, plays a central role in the progression of heart diseases such as myocardial infarction, heart failure, and hypertensive cardiomyopathy. The dynamic interplay between fibroblasts and macrophages is pivotal in regulating ECM remodeling and the fibrotic response. Fibroblasts, as primary ECM producers, undergo phenotypic changes during pathological conditions, transitioning into myofibroblasts that exacerbate fibrosis. Macrophages, both resident and non-resident, contribute to cardiac fibrosis by influencing fibroblast activation through cytokine secretion and direct cell interactions. Emerging evidence from preclinical studies highlights the transformation of macrophages into myofibroblast-like cells, known as macrophage-to-myofibroblast transformation (MMT), a key mechanism linking chronic inflammation to fibrosis. During MMT, macrophages acquire characteristics like myofibroblasts. This process is driven by signaling pathways such as TGF-β/Smad3, ALKBH5, and mineralocorticoid receptor (MR)/connective tissue growth factor (CTGF) pathways. Recent single-cell transcriptomics and lineage-tracing studies have provided deeper insights into the molecular regulation of MMT and its contribution to myocardial remodeling. Additionally, the balance between resident cardiac macrophages and monocyte-derived macrophages plays a crucial role in determining the fibrotic outcome following cardiac injury. This review discusses the cellular composition of the heart, the interactions between macrophages and fibroblasts, and the mechanisms driving MMT. By synthesizing these insights, we aim to evaluate MMT as a therapeutic target for mitigating cardiac fibrosis and improving clinical outcomes in cardiovascular diseases.

Keywords

Macrophage / macrophage-to-myofibroblast transition / cardiac fibrosis / myofibroblast

References

[1] Ban J, Ao L, He X, Zhao H, Li J. Advances in macrophage-myofibroblast transformation in fibrotic diseases. Front Immunol. 2024; 15: 1461919.

[2] Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020; 587: 555-66.

[3] Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007; 117: 568-75.

[4] Abe H, Takeda N, Isagawa T, Semba H, Nishimura S, Morioka MS, et al. Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nat Commun. 2019; 10: 2824.

[5] Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res. 2016; 365: 563-81.

[6] Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000; 101: 2981-8.

[7] Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021; 117: 1450-88.

[8] Greene SJ, Bauersachs J, Brugts JJ, Ezekowitz JA, Lam CSP, Lund LH, et al. Worsening Heart Failure: Nomenclature, Epidemiology, and Future Directions: JACC Review Topic of the Week. J Am Coll Cardiol. 2023; 81: 413-24.

[9] Yang B, Qiao Y, Yan D, Meng Q. Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis. Cells. 2024; 13: 764.

[10] Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nature Med. 2011; 17: 552-3.

[11] Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D’Antoni ML, Debuque R, et al. Revisiting Cardiac Cellular Composition. Circ Res. 2016; 118: 400-9.

[12] Sansonetti M, Waleczek FJG, Jung M, Thum T, Perbellini F. Resident cardiac macrophages: crucial modulators of cardiac (patho)physiology. Basic Res Cardiol. 2020; 115: 77.

[13] Haider N, Boscá L, Zandbergen HR, Kovacic JC, Narula N, González-Ramos S, et al. Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction. J Am Coll Cardiol. 2019; 74: 3124-35.

[14] Ham O, Jin W, Lei L, Huang HH, Tsuji K, Huang M, et al. Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril. Sci Rep. 2018; 8: 16087.

[15] Wei J, Xu Z, Yan X. The role of the macrophage-to-myofibroblast transition in renal fibrosis. Front Immunol. 2022; 13: 934377.

[16] Tang PM, Nikolic-Paterson DJ, Lan H. Macrophages: versatile players in renal inflammation and fibrosis. Nature Rev Nephrol. 2019; 15: 144-58.

[17] Yazdani S, Bansal R, Prakash J. Drug targeting to myofibroblasts: Implications for fibrosis and cancer. Adv Drug Deliv Rev. 2017; 121: 101-16.

[18] Jang H, Kim JI, Han SJ, Park KM. Recruitment and subsequent proliferation of bone marrow-derived cells in the postischemic kidney are important to the progression of fibrosis. Am J Physiol Renal Physiol. 2014; 306: F1451-61.

[19] Xia Y, Yan J, Jin X, Entman ML, Wang Y. The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis. Kidney Int. 2014; 86: 327-37.

[20] Wang Y, Jiang H, Pan J, Huang X, Wang Y, Huang H, et al. Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury. J Am Soc Nephrol. 2017; 28: 2053-67.

[21] Wang S, Meng X, Ng Y, Ma FY, Zhou S, Zhang Y, et al. TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget. 2016; 7: 8809-22.

[22] Meng X, Wang S, Huang X, Yang C, Xiao J, Zhang Y, et al. Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis. 2016; 7: e2495.

[23] Yang H, Cheng H, Dai R, Shang L, Zhang X, Wen H. Macrophage polarization in tissue fibrosis. PeerJ. 2023; 11: e16092.

[24] Wang W, Xiao D, Lin L, Gao X, Peng L, Chen J, et al. Antifibrotic Effects of Tetrahedral Framework Nucleic Acids by Inhibiting Macrophage Polarization and Macrophage-Myofibroblast Transition in Bladder Remodeling. Adv Healthc Mater. 2023; 12: e2203076.

[25] Afjeh-Dana E, Naserzadeh P, Moradi E, Hosseini N, Seifalian AM, Ashtari B. Stem Cell Differentiation into Cardiomyocytes: Current Methods and Emerging Approaches. Stem Cell Rev Rep. 2022; 18: 2566-92.

[26] Hall C, Gehmlich K, Denning C, Pavlovic D. Complex Relationship Between Cardiac Fibroblasts and Cardiomyocytes in Health and Disease. J Am Heart Assoc. 2021; 10: e019338.

[27] Yap J, Irei J, Lozano-Gerona J, Vanapruks S, Bishop T, Boisvert WA. Macrophages in cardiac remodelling after myocardial infarction. Nat Rev Cardiol. 2023; 20: 373-85.

[28] Khan SU, Huang Y, Ali H, Ali I, Ahmad S, Khan SU, et al. Single-cell RNA Sequencing (scRNA-seq): Advances and Challenges for Cardiovascular Diseases (CVDs). Curr Probl Cardiol. 2024; 49: 102202.

[29] Lu J, Sheng Y, Qian W, Pan M, Zhao X, Ge Q. scRNA-seq data analysis method to improve analysis performance. IET Nanobiotechnol. 2023; 17: 246-56.

[30] Koenig AL, Shchukina I, Amrute J, Andhey PS, Zaitsev K, Lai L, et al. Single-cell transcriptomics reveals cell-type-specific diversification in human heart failure. Nat Cardiovasc Res. 2022; 1: 263-80.

[31] Reichart D, Lindberg EL, Maatz H, Miranda AMA, Viveiros A, Shvetsov N, et al. Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science. 2022; 377: eabo1984.

[32] Litviňuková M, Talavera-López C, Maatz H, Reichart D, Worth CL, Lindberg EL, et al. Cells of the adult human heart. Nature. 2020; 588: 466-72.

[33] Michel NA, Ljubojevic-Holzer S, Bugger H, Zirlik A. Cellular Heterogeneity of the Heart. Front Cardiovasc Med. 2022; 9: 868466.

[34] Tucker NR, Chaffin M, Fleming SJ, Hall AW, Parsons VA, Bedi KC Jr, et al. Transcriptional and Cellular Diversity of the Human Heart. Circulation. 2020; 142: 466-82.

[35] Peet C, Ivetic A, Bromage DI, Shah AM. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res. 2020; 116: 1101-12.

[36] Komal S, Han S, Cui L, Zhai M, Zhou Y, Wang P, et al. Epigenetic Regulation of Macrophage Polarization in Cardiovascular Diseases. Pharmaceuticals (Basel). 2023; 16: 141.

[37] Hilgendorf I, Gerhardt LMS, Tan TC, Winter C, Holderied TAW, Chousterman BG, et al. Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res. 2014; 114: 1611-22.

[38] Mia MM, Cibi DM, Ghani SABA, Song W, Tee N, Ghosh S, et al. YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biol. 2020; 18: e3000941.

[39] Huang C, Dai D, Xie H, Zhu Z, Hu J, Su M, et al. Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair. Circ Res. 2020; 127: 953-73.

[40] Glinton KE, Ma W, Lantz C, Grigoryeva LS, DeBerge M, Liu X, et al. Macrophage-produced VEGFC is induced by efferocytosis to ameliorate cardiac injury and inflammation. J Clin Invest. 2022; 132: e140685.

[41] Yang L, Han Y, Jaffré F, Nilsson-Payant BE, Bram Y, Wang P, et al. An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts. Circ Res. 2021; 129: 33-46.

[42] Ma P, Liu J, Qin J, Lai L, Heo GS, Luehmann H, et al. Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis. Circulation. 2024; 149: 48-66.

[43] Kang M, Jia H, Feng M, Ren H, Gao J, Liu Y, et al. Cardiac macrophages in maintaining heart homeostasis and regulating ventricular remodeling of heart diseases. Front Immunol. 2024; 15: 1467089.

[44] Chen C, Wang J, Liu C, Hu J. Cardiac resident macrophages: key regulatory mediators in the aftermath of myocardial infarction. Front Immunol. 2023; 14: 1207100.

[45] Zaman R, Hamidzada H, Kantores C, Wong A, Dick SA, Wang Y, et al. Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress. Immunity. 2021; 54: 2057-71.e6.

[46] Zhang H, Xu A, Sun X, Yang Y, Zhang L, Bai H, et al. Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-Induced Cardiomyopathy Through the SR-A1-c-Myc Axis. Circ Res. 2020; 127: 610-27.

[47] An T, Guo M, Wang Z, Liu K. Tissue-Resident Macrophages in Cardiovascular Diseases: Heterogeneity and Therapeutic Potential. Int J Mol Sci. 2025; 26: 4524.

[48] Hu S, Yang M, Huang S, Zhong S, Zhang Q, Ding H, et al. Different Roles of Resident and Non-resident Macrophages in Cardiac Fibrosis. Front Cardiovasc Med. 2022; 9: 818188.

[49] Vendrov AE, Xiao H, Lozhkin A, Hayami T, Hu G, Brody MJ, et al. Cardiomyocyte NOX4 regulates resident macrophage-mediated inflammation and diastolic dysfunction in stress cardiomyopathy. Redox Biol. 2023; 67: 102937.

[50] Shinde AV, Frangogiannis NG. Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol. 2014; 70: 74-82.

[51] Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014; 71: 549-74.

[52] Hulsmans M, Sam F, Nahrendorf M. Monocyte and macrophage contributions to cardiac remodeling. J Mol Cell Cardiol. 2016; 93: 149-55.

[53] Dick SA, Macklin JA, Nejat S, Momen A, Clemente-Casares X, Althagafi MG, et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat Immunol. 2019; 20: 29-39.

[54] Uhlig M, Billig S, Wienhold J, Schumacher D. Pro-Fibrotic Macrophage Subtypes: SPP1+ Macrophages as a Key Player and Therapeutic Target in Cardiac Fibrosis? Cells. 2025; 14: 345.

[55] Das A, Sinha M, Datta S, Abas M, Chaffee S, Sen CK, et al. Monocyte and macrophage plasticity in tissue repair and regeneration. Am J Pathol. 2015; 185: 2596-606.

[56] Oh H, Kwon O, Kong MJ, Park KM, Baek J. Macrophages promote Fibrinogenesis during kidney injury. Front Med (Lausanne). 2023; 10: 1206362.

[57] Oh H, Park HE, Song MS, Kim H, Baek J. The Therapeutic Potential of Anticoagulation in Organ Fibrosis. Front Med (Lausanne). 2022; 9: 866746.

[58] Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013; 10: 15-26.

[59] Peters T, Sindrilaru A, Hinz B, Hinrichs R, Menke A, Al-Azzeh EAD, et al. Wound-healing defect of CD18-/- mice due to a decrease in TGF-beta1 and myofibroblast differentiation. EMBO J. 2005; 24: 3400-10.

[60] Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007; 74: 184-95.

[61] Ceccato TL, Starbuck RB, Hall JK, Walker CJ, Brown TE, Killgore JP, et al. Defining the Cardiac Fibroblast Secretome in a Fibrotic Microenvironment. J Am Heart Assoc. 2020; 9: e017025.

[62] Buechler MB, Fu W, Turley SJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021; 54: 903-15.

[63] Fernando MR, Giembycz MA, McKay DM. Bidirectional crosstalk via IL-6, PGE2 and PGD2 between murine myofibroblasts and alternatively activated macrophages enhances anti-inflammatory phenotype in both cells. Br J Pharmacol. 2016; 173: 899-912.

[64] Jivraj N, Phinikaridou A, Shah AM, Botnar RM. Molecular imaging of myocardial infarction. Basic Res Cardiol. 2014; 109: 397.

[65] Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012; 110: 159-73.

[66] Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014; 11: 255-65.

[67] Meziani L, Mondini M, Petit B, Boissonnas A, Thomas de Montpreville V, Mercier O, et al. CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages. Eur Respir J. 2018; 51: 1702120.

[68] Baek J. The Impact of Versatile Macrophage Functions on Acute Kidney Injury and Its Outcomes. Front Physiol. 2019; 10: 1016.

[69] McKleroy W, Lee T, Atabai K. Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013; 304: L709-21.

[70] Vi L, Baht GS, Soderblom EJ, Whetstone H, Wei Q, Furman B, et al. Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice. Nat Commun. 2018; 9: 5191.

[71] Zhang W, Lavine KJ, Epelman S, Evans SA, Weinheimer CJ, Barger PM, et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc. 2015; 4: e001993.

[72] Wu L, Ong S, Talor MV, Barin JG, Baldeviano GC, Kass DA, et al. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med. 2014; 211: 1449-64.

[73] Anzai A, Choi JL, He S, Fenn AM, Nairz M, Rattik S, et al. The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J Exp Med. 2017; 214: 3293-310.

[74] Heinrichs D, Knauel M, Offermanns C, Berres M, Nellen A, Leng L, et al. Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74. Proc Natl Acad Sci U S A. 2011; 108: 17444-9.

[75] Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013; 229: 298-309.

[76] Meng X, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016; 12: 325-38.

[77] Vierhout M, Ayoub A, Naiel S, Yazdanshenas P, Revill SD, Reihani A, et al. Monocyte and macrophage derived myofibroblasts: Is it fate? A review of the current evidence. Wound Repair Regen. 2021; 29: 548-62.

[78] Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014; 159: 1312-26.

[79] Nikolic-Paterson DJ, Wang S, Lan HY. Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int Suppl (2011). 2014; 4: 34-8.

[80] Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol. 2011; 43: 154-62.

[81] Cao Q, Wang Y, Zheng D, Sun Y, Wang C, Wang XM, et al. Failed renoprotection by alternatively activated bone marrow macrophages is due to a proliferation-dependent phenotype switch in vivo. Kidney Int. 2014; 85: 794-806.

[82] Evans S, Butler JR, Mattila JT, Kirschner DE. Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation. PLoS Comput Biol. 2020; 16: e1008520.

[83] Xiong Y, Chang Y, Hao J, Zhang C, Yang F, Wang Z, et al. Eplerenone Attenuates Fibrosis in the Contralateral Kidney of UUO Rats by Preventing Macrophage-to-Myofibroblast Transition. Front Pharmacol. 2021; 12: 620433.

[84] Sinha M, Sen CK, Singh K, Das A, Ghatak S, Rhea B, et al. Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. Nat Commun. 2018; 9: 936.

[85] Zhuang T, Chen M, Wu R, Wang J, Hu X, Meng T, et al. ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice. Nat Commun. 2024; 15: 1995.

[86] Tang PM, Zhang Y, Xiao J, Tang PC, Chung JY, Li J, et al. Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition. Proc Natl Acad Sci U S A. 2020; 117: 20741-52.

[87] Shen S, Zhang M, Wang X, Liu Q, Su H, Sun B, et al. Single-cell RNA sequencing reveals S100a9^hi macrophages promote the transition from acute inflammation to fibrotic remodeling after myocardial ischemia‒reperfusion . Theranostics. 2024; 14: 1241-59.

[88] Cho HH, Rhee S, Cho DI, Jun JH, Heo H, Cho SH, et al. IKKε-deficient macrophages impede cardiac repair after myocardial infarction by enhancing the macrophage-myofibroblast transition. Exp Mol Med. 2024; 56: 2052-64.

[89] Zhang Y, Wu Y, Li M, Mijiti A, Cheng L. Identification of macrophage driver genes in fibrosis caused by different heart diseases based on omics integration. J Transl Med. 2024; 22: 839.

[90] Han Y, Xian Y, Shimosawa T, Chang Y, Xu Q. PS-B03-10: Eplerenone inhibits ICAM-1 from macrophages and macrophage-to-myofibroblast transition in type 4 cardiorenal syndrome rats induced with UUO. J Hypertens. 2023; 41: e358-9.

[91] Han Y, Xian Y, Gao X, Qiang P, Hao J, Yang F, et al. Eplerenone inhibits the macrophage-to-myofibroblast transition in rats with UUO-induced type 4 cardiorenal syndrome through the MR/CTGF pathway. Int Immunopharmacol. 2022; 113: 109396.

[92] Wang Q, Yang Y. Mineralocorticoid receptor antagonists promote renal immunosenescence. Int Urol Nephrol. 2025.

[93] Wu P, Zhang W, Guan H, Jin T, Jia J, Luo B, et al. Macrophage erythropoietin signaling promotes macrophage-myofibroblast transformation and fibroblast-myofibroblast differentiation. Biochem Biophys Res Commun. 2024; 734: 150783.

[94] Fendt BM, Hirschmann A, Bruns M, Camarillo-Retamosa E, Ospelt C, Vogetseder A. Protein atlas of fibroblast specific protein 1 (FSP1)/S100A4. Histol Histopathol. 2023; 38: 1391-401.

[95] Jin C, Chen Y, Wang Y, Li J, Liang J, Zheng S, et al. Single-cell RNA sequencing reveals special basal cells and fibroblasts in idiopathic pulmonary fibrosis. Sci Rep. 2024; 14: 15778.