Ali, S. R., Ranjbarvaziri, S., Talkhabi, M., Zhao, P., Subat, A., Hojjat, A., et al. (2014). Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ. Res. 115 (7), 625–635. doi:10. 1161/CIRCRESAHA.115.303794
Cai, C. L., Martin, J. C., Sun, Y., Cui, L., Wang, L., Ouyang, K., et al. (2008). A myocardial lineage derives from Tbx18 epicardial cells. Nature 454 (7200), 104–108. doi:10.1038/nature06969
Cao, J., and Poss, K. D. (2018). The epicardium as a hub for heart regeneration. Nat. Rev. Cardiol. 15 (10), 631–647. doi:10.1038/s41569-018-0046-4
Carbone, A. M., Borges, J. I., Suster, M. S., Sizova, A., Cora, N., Desimine, V. L., et al. (2022). Regulator of G-protein signaling-4 attenuates cardiac adverse remodeling and neuronal norepinephrine release-promoting free fatty acid receptor FFAR3 signaling. Int. J. Mol. Sci. 23 (10), 5803. doi:10.3390/ijms23105803
Chen, Y., Yang, S., Lovisa, S., Ambrose, C. G., McAndrews, K. M., Sugimoto, H., et al. (2021). Type-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta. Nat. Commun. 12 (1), 7199. doi:10.1038/s41467-021-27563-3
Cho, S., Discher, D. E., Leong, K. W., Vunjak-Novakovic, G., and Wu, J. C. (2022). Challenges and opportunities for the next generation of cardiovascular tissue engineering. Nat. Methods 19 (9), 1064–1071. doi:10.1038/s41592-022-01591-3
Clarke, H. C., Kocher, H. M., Khwaja, A., Kloog, Y., Cook, H. T., and Hendry, B. M. (2003). Ras antagonist farnesylthiosalicylic acid (FTS) reduces glomerular cellular proliferation and macrophage number in rat thy-1 nephritis. J. Am. Soc. Nephrol. 14 (4), 848–854. doi:10.1097/01.asn.0000057543.55318.8b
Downward, J. (2003). Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3 (1), 11–22. doi:10.1038/nrc969
Doyle, M. J., Lohr, J. L., Chapman, C. S., Koyano-Nakagawa, N., Garry, M. G., and Garry, D. J. (2015). Human induced pluripotent stem cell-derived cardiomyocytes as a model for heart development and congenital heart disease. Stem Cell Rev. Rep. 11 (5), 710–727. doi:10.1007/s12015-015-9596-6
Frantz, C., Stewart, K. M., and Weaver, V. M. (2010). The extracellular matrix at a glance. J. Cell Sci. 123 (24), 4195–4200. doi:10.1242/jcs.023820
Fu, X., Liu, Q., Li, C., Li, Y., and Wang, L. (2020). Cardiac fibrosis and cardiac fibroblast lineage-tracing: Recent advances. Front. Physiol. 11, 416. doi:10.3389/ fphys.2020.00416
Gimenez, A., Duch, P., Puig, M., Gabasa, M., Xaubet, A., and Alcaraz, J. (2017). Dysregulated collagen homeostasis by matrix stiffening and TGF-β1 in fibroblasts from idiopathic pulmonary fibrosis patients: Role of FAK/Akt. Int. J. Mol. Sci. 18 (11), E2431. doi:10.3390/ijms18112431
Gittenberger-de Groot, A. C., Vrancken Peeters, M. P., Mentink, M. M., Gourdie, R. G., and Poelmann, R. E. (1998). Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circ. Res. 82 (10), 1043–1052. doi:10.1161/01.res.82.10.1043
Graham-Brown, M. P., Patel, A. S., Stensel, D. J., March, D. S., Marsh, A. M., McAdam, J., et al. (2017). Imaging of myocardial fibrosis in patients with end-stage renal disease: Current limitations and future possibilities. Biomed. Res. Int. 2017, 5453606. doi:10.1155/2017/5453606
Hall, C., Gehmlich, K., Denning, C., and Pavlovic, D. (2021). Complex relationship between cardiac fibroblasts and cardiomyocytes in health and disease. J. Am. Heart Assoc. 10 (5), e019338. doi:10.1161/JAHA.120.019338
Heras-Bautista, C. O., Mikhael, N., Lam, J., Shinde, V., Katsen-Globa, A., Dieluweit, S., et al. (2019). Cardiomyocytes facing fibrotic conditions re-express extracellular matrix transcripts. Acta Biomater. 89, 180–192. doi:10.1016/j.actbio. 2019.03.017
Ieda, M., Tsuchihashi, T., Ivey, K. N., Ross, R. S., Hong, T. T., Shaw, R. M., et al. (2009). Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev. Cell 16 (2), 233–244. doi:10.1016/j.devcel.2008.12.007
Jellis, C., Martin, J., Narula, J., and Marwick, T. H. (2010). Assessment of nonischemic myocardial fibrosis. J. Am. Coll. Cardiol. 56 (2), 89–97. doi:10. 1016/j.jacc.2010.02.047
Jiang, W., Xiong, Y., Li, X., and Yang, Y. (2021). Cardiac fibrosis: Cellular effectors, molecular pathways, and exosomal roles. Front. Cardiovasc. Med. 8, 715258. doi:10.3389/fcvm.2021.715258
Kafri, M., Kloog, Y., Korczyn, A. D., Ferdman-Aronovich, R., Drory, V., Katzav, A., et al. (2005). Inhibition of Ras attenuates the course of experimental autoimmune neuritis. J. Neuroimmunol. 168 (1-2), 46–55. doi:10.1016/j. jneuroim.2005.07.008
Kahan, B. D., Podbielski, J., Napoli, K. L., Katz, S. M., Meier-Kriesche, H. U., and Van Buren, C. T. (1998). Immunosuppressive effects and safety of a sirolimus/ cyclosporine combination regimen for renal transplantation. Transplantation 66 (8), 1040–1046. doi:10.1097/00007890-199810270-00013
Kania, G., Blyszczuk, P., and Eriksson, U. (2009). Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends cardiovasc. Med. 19 (8), 247–252. doi:10. 1016/j.tcm.2010.02.005
Katzav, A., Kloog, Y., Korczyn, A. D., Niv, H., Karussis, D. M., Wang, N., et al. (2001). Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS). Clin. Exp. Immunol. 126 (3), 570–577. doi:10. 1046/j.1365-2249.2001.01674.x
Khalil, H., Kanisicak, O., Prasad, V., Correll, R. N., Fu, X., Schips, T., et al. (2017). Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 127 (10), 3770–3783. doi:10.1172/JCI94753
Kurose, H. (2021). Cardiac fibrosis and fibroblasts. Cells 10 (7), 1716. doi:10.3390/ cells10071716
Lewis-Israeli, Y. R., Wasserman, A. H., Gabalski, M. A., Volmert, B. D., Ming, Y., Ball, K. A., et al. (2021). Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease. Nat. Commun. 12 (1), 5142. doi:10.1038/s41467-021-25329-5
Ma, Z. G., Yuan, Y. P., Wu, H. M., Zhang, X., and Tang, Q. Z. (2018). Cardiac fibrosis: New insights into the pathogenesis. Int. J. Biol. Sci. 14 (12), 1645–1657. doi:10.7150/ijbs.28103
Miao, R., Lu, Y., Xing, X., Li, Y., Huang, Z., Zhong, H., et al. (2016). Regulator of G-protein signaling 10 negatively regulates cardiac remodeling by blocking mitogen-activated protein kinase-extracellular signal-regulated protein kinase 1/ 2 signaling. Hypertension 67 (1), 86–98. doi:10.1161/HYPERTENSIONAHA.115. 05957
Mikawa, T., and Fischman, D. A. (1992). Retroviral analysis of cardiac morphogenesis: Discontinuous formation of coronary vessels. Proc. Natl. Acad. Sci. U. S. A. 89 (20), 9504–9508. doi:10.1073/pnas.89.20.9504
Mikawa, T., and Gourdie, R. G. (1996). Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev. Biol. 174 (2), 221–232. doi:10.1006/dbio. 1996.0068
Molina, J. R., and Adjei, A. A. (2006). The Ras/Raf/MAPK pathway. J. Thorac. Oncol. 1 (1), 7–9. doi:10.1097/01243894-200601000-00004
Moore-Morris, T., Cattaneo, P., Puceat, M., and Evans, S. M. (2016). Origins of cardiac fibroblasts. J. Mol. Cell. Cardiol. 91, 1–5. doi:10.1016/j.yjmcc.2015.12.031
Morelon, E., Mamzer-Bruneel, M. F., Peraldi, M. N., and Kreis, H. (2001). Sirolimus: A new promising immunosuppressive drug. Towards a rationale for its use in renal transplantation. Nephrol. Dial. Transpl. 16 (1), 18–20. doi:10.1093/ ndt/16.1.18
Nagano, J., Iyonaga, K., Kawamura, K., YamAshitA, A., IcHiyasu, H., OkamoTo, T., et al. (2006). Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. Eur. Respir. J. 27 (3), 460–469. doi:10.1183/09031936.06.00070705
Nevo, Y., Aga-Mizrachi, S., Elmakayes, E., Yanay, N., Ettinger, K., Elbaz, M., et al. (2011). The Ras antagonist, farnesylthiosalicylic acid (FTS), decreases fibrosis and improves muscle strength in dy/dy mouse model of muscular dystrophy. PLoS One 6 (3), e18049. doi:10.1371/journal.pone.0018049
Nicoletti, A., and Michel, J. B. (1999). Cardiac fibrosis and inflammation: Interaction with hemodynamic and hormonal factors. Cardiovasc. Res. 41 (3), 532–543. doi:10.1016/s0008-6363(98)00305-8
Piersma, B., Bank, R. A., and Boersema, M. (2015). Signaling in fibrosis: TGF- beta, WNT, and YAP/TAZ converge. Front. Med. 2, 59. doi:10.3389/fmed.2015. 00059
Plosker, G. L., and Foster, R. H. (2000). Tacrolimus: A further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 59 (2), 323–389. doi:10.2165/00003495-200059020-00021
Reif, S., Aeed, H., Shilo, Y., Reich, R., Kloog, Y., Kweon, Y. O., et al. (2004). Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. J. Hepatol. 41 (2), 235–241. doi:10.1016/j.jhep.2004.04.010
Reif, S., Weis, B., Aeed, H., Gana-WeisM.ZaideL, L., Avni, Y., et al. (1999). The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats. J. Hepatol. 31 (6), 1053–1061. doi:10.1016/s0168-8278(99) 80318-3
Rinn, J. L., Bondre, C., Gladstone, H. B., Brown, P. O., and Chang, H. Y. (2006). Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet. 2 (7), e119. doi:10.1371/journal.pgen.0020119
Roger, V. L., Go, A. S., Lloyd-Jones, D. M., Benjamin, E. J., Berry, J. D., Borden, W. B., et al. (2012). Heart disease and stroke statistics--2012 update: A report from the American heart association. Circulation 125 (1), e2–e220. doi:10.1161/CIR. 0b013e31823ac046
Rokni, M., Sadeghi Shaker, M., Kavosi, H., Shokoofi, S., Mahmoudi, M., and Farhadi, E. (2022). The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: An updated review with therapeutic implications. Arthritis Res. Ther. 24 (1), 108. doi:10.1186/s13075-022-02787-w
Ruiz-Villalba, A., Romero, J. P., Hernandez, S. C., Vilas-Zornoza, A., Fortelny, N., Castro-Labrador, L., et al. (2020). Single-cell RNA sequencing analysis reveals a crucial role for CTHRC1 (collagen triple helix repeat containing 1) cardiac fibroblasts after myocardial infarction. Circulation 142 (19), 1831–1847. doi:10. 1161/CIRCULATIONAHA.119.044557
Sallam, K., Thomas, D., Gaddam, S., Lopez, N., Beck, A., Beach, L., et al. (2022). Modeling effects of immunosuppressive drugs on human hearts using induced pluripotent stem cell-derived cardiac organoids and single-cell RNA sequencing. Circulation 145 (17), 1367–1369. doi:10.1161/CIRCULATIONAHA.121.054317
Schafer, S., Viswanathan, S., Widjaja, A. A., Lim, W. W., Moreno-Moral, A., DeLaughter, D. M., et al. (2017). IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552 (7683), 110–115. doi:10.1038/nature24676
Skelly, D. A., Squiers, G. T., McLellan, M. A., Bolisetty, M. T., Robson, P., Rosenthal, N. A., et al. (2018). Single-cell transcriptional profiling reveals cellular diversity and intercommunication in the mouse heart. Cell Rep. 22 (3), 600–610. doi:10.1016/j.celrep.2017.12.072
Smith, C. L., Baek, S. T., Sung, C. Y., and Tallquist, M. D. (2011). Epicardial- derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ. Res. 108 (12), e15–e26. doi:10.1161/CIRCRESAHA. 110.235531
Stone, N. R., Gifford, C. A., Thomas, R., Pratt, K. J. B., Samse-Knapp, K., Mohamed, T. M. A., et al. (2019). Context-specific transcription factor functions regulate epigenomic and transcriptional dynamics during cardiac reprogramming. Cell Stem Cell 25 (1), 87–102. doi:10.1016/j.stem.2019.06.012
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131 (5), 861–872. doi:10.1016/j.cell.2007.11.019
Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (4), 663–676. doi:10.1016/j.cell.2006.07.024
Taroni, J. N., Greene, C. S., Martyanov, V., Wood, T. A., Christmann, R. B., Farber, H. W., et al. (2017). A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med. 9 (1), 27. doi:10. 1186/s13073-017-0417-1
Thomas, D., de Jesus Perez, V. A., and Sayed, N. (2022). An evidence appraisal of heart organoids in a dish and commensurability to human heart development in vivo. BMC Cardiovasc. Disord. 22 (1), 122. doi:10.1186/s12872-022-02543-7
Thomas, T. P., and Grisanti, L. A. (2020). The dynamic interplay between cardiac inflammation and fibrosis. Front. Physiol. 11, 529075. doi:10.3389/fphys.2020. 529075
Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E., and Blaxall, B. C. (2016). Cardiac fibrosis: The fibroblast awakens. Circ. Res. 118 (6), 1021–1040. doi:10.1161/ CIRCRESAHA.115.306565
Tulek, B., Kiyan, E., Toy, H., Kiyici, A., Narin, C., and Suerdem, M. (2011). Anti- inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats. Clin. Invest. Med. 34 (6), E341. doi:10.25011/cim. v34i6.15894
Turhan, A. G., Hwang, J. W., Chaker, D., Tasteyre, A., Latsis, T., Griscelli, F., et al. (2021). iPSC-derived organoids as therapeutic models in regenerative medicine and oncology. Front. Med. 8, 728543. doi:10.3389/fmed.2021.728543
Vancheri, C. (2012). Idiopathic pulmonary fibrosis: An altered fibroblast proliferation linked to cancer biology. Proc. Am. Thorac. Soc. 9 (3), 153–157. doi:10.1513/pats.201203-025AW
Wagner, A. J., Malinowska-Kolodziej, I., Morgan, J. A., Qin, W., Fletcher, C. D. M., Vena, N., et al. (2010). Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: Targeting the pathogenic activation of mTORC1 in tumors. J. Clin. Oncol. 28 (5), 835–840. doi:10.1200/JCO.2009.25. 2981
Wang, L., Yu, P., Zhou, B., Song, J., Li, Z., Zhang, M., et al. (2020). Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function. Nat. Cell Biol. 22 (1), 108–119. doi:10.1038/s41556-019-0446-7
Zeisberg, M., and Kalluri, R. (2013). Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 304 (3), C216–C225. doi:10.1152/ajpcell.00328.2012
Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., et al. (2008). Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454 (7200), 109–113. doi:10.1038/nature07060
Zhu, F., Li, Y., Zhang, J., Piao, C., Liu, T., Li, H. H., et al. (2013). Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One 8 (9), e74535. doi:10.1371/journal.pone.0074535