Fibroblast Fate Determination During Cardiac Reprogramming by Remodeling of Actin Filaments

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2022 Jun 10

PMID 35688153

Authors

Zhentao Zhang

Wenhui Zhang

Robert Blakes

Lauren J Sundby

Zengdun Shi

Don C Rockey

James M Ervasti

Young-Jae Nam

Affiliations

Soon will be listed here.

Abstract

Fibroblasts can be reprogrammed into induced cardiomyocyte-like cells (iCMs) by forced expression of cardiogenic transcription factors. However, it remains unknown how fibroblasts adopt a cardiomyocyte (CM) fate during their spontaneous ongoing transdifferentiation toward myofibroblasts (MFs). By tracing fibroblast lineages following cardiac reprogramming in vitro, we found that most mature iCMs are derived directly from fibroblasts without transition through the MF state. This direct conversion is attributable to mutually exclusive induction of cardiac sarcomeres and MF cytoskeletal structures in the cytoplasm of fibroblasts during reprogramming. For direct fate switch from fibroblasts to iCMs, significant remodeling of actin isoforms occurs in fibroblasts, including induction of α-cardiac actin and decrease of the actin isoforms predominant in MFs. Accordingly, genetic or pharmacological ablation of MF-enriched actin isoforms significantly enhances cardiac reprogramming. Our results demonstrate that remodeling of actin isoforms is required for fibroblast to CM fate conversion by cardiac reprogramming.

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References

Zhao Y, Londono P, Cao Y, Sharpe E, Proenza C, ORourke R . High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun. 2015; 6:8243. PMC: 4579788. DOI: 10.1038/ncomms9243. View

Riching A, Danis E, Zhao Y, Cao Y, Chi C, Bagchi R . Suppression of canonical TGF-β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis. J Mol Cell Cardiol. 2020; 153:44-59. PMC: 8809092. DOI: 10.1016/j.yjmcc.2020.12.005. View

Sanger J, Kang S, Siebrands C, Freeman N, Du A, Wang J . How to build a myofibril. J Muscle Res Cell Motil. 2006; 26(6-8):343-54. DOI: 10.1007/s10974-005-9016-7. View

Gautel M . The sarcomeric cytoskeleton: who picks up the strain?. Curr Opin Cell Biol. 2010; 23(1):39-46. DOI: 10.1016/j.ceb.2010.12.001. View

van Putten S, Shafieyan Y, Hinz B . Mechanical control of cardiac myofibroblasts. J Mol Cell Cardiol. 2015; 93:133-42. DOI: 10.1016/j.yjmcc.2015.11.025. View

Zhang Z, Zhang W, Nam Y . Stoichiometric optimization of Gata4, Hand2, Mef2c, and Tbx5 expression for contractile cardiomyocyte reprogramming. Sci Rep. 2019; 9(1):14970. PMC: 6800441. DOI: 10.1038/s41598-019-51536-8. View

Perrin B, Ervasti J . The actin gene family: function follows isoform. Cytoskeleton (Hoboken). 2010; 67(10):630-4. PMC: 2949686. DOI: 10.1002/cm.20475. View

Pellegrin S, Mellor H . Actin stress fibres. J Cell Sci. 2007; 120(Pt 20):3491-9. DOI: 10.1242/jcs.018473. View

Leask A . TGFbeta, cardiac fibroblasts, and the fibrotic response. Cardiovasc Res. 2006; 74(2):207-12. DOI: 10.1016/j.cardiores.2006.07.012. View

10.

Bektik E, Dennis A, Pawlowski G, Zhou C, Maleski D, Takahashi S . S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit. Int J Mol Sci. 2018; 19(5). PMC: 5983785. DOI: 10.3390/ijms19051364. View

11.

Song K, Nam Y, Luo X, Qi X, Tan W, Huang G . Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012; 485(7400):599-604. PMC: 3367390. DOI: 10.1038/nature11139. View

12.

Riedl J, Crevenna A, Kessenbrock K, Yu J, Neukirchen D, Bista M . Lifeact: a versatile marker to visualize F-actin. Nat Methods. 2008; 5(7):605-7. PMC: 2814344. DOI: 10.1038/nmeth.1220. View

13.

Hinz B . The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2009; 43(1):146-55. DOI: 10.1016/j.jbiomech.2009.09.020. View

14.

LeBleu V, Taduri G, OConnell J, Teng Y, Cooke V, Woda C . Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013; 19(8):1047-53. PMC: 4067127. DOI: 10.1038/nm.3218. View

15.

Umei T, Yamakawa H, Muraoka N, Sadahiro T, Isomi M, Haginiwa S . Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression. Int J Mol Sci. 2017; 18(8). PMC: 5578192. DOI: 10.3390/ijms18081805. View

16.

Clark K, McElhinny A, Beckerle M, Gregorio C . Striated muscle cytoarchitecture: an intricate web of form and function. Annu Rev Cell Dev Biol. 2002; 18:637-706. DOI: 10.1146/annurev.cellbio.18.012502.105840. View

17.

Hinz B, Celetta G, Tomasek J, Gabbiani G, Chaponnier C . Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001; 12(9):2730-41. PMC: 59708. DOI: 10.1091/mbc.12.9.2730. View

18.

Nam Y, Lubczyk C, Bhakta M, Zang T, Fernandez-Perez A, McAnally J . Induction of diverse cardiac cell types by reprogramming fibroblasts with cardiac transcription factors. Development. 2014; 141(22):4267-78. PMC: 4302916. DOI: 10.1242/dev.114025. View

19.

Jayawardena T, Egemnazarov B, Finch E, Zhang L, Payne J, Pandya K . MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012; 110(11):1465-73. PMC: 3380624. DOI: 10.1161/CIRCRESAHA.112.269035. View

20.

Hinz B, Gabbiani G, Chaponnier C . The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J Cell Biol. 2002; 157(4):657-63. PMC: 2173846. DOI: 10.1083/jcb.200201049. View