Fibroblast fate determination during cardiac reprogramming by remodeling of actin filaments

Zhentao Zhang; Wenhui Zhang; Robert Blakes; Lauren J. Sundby; Zengdun Shi; Don C. Rockey; James M. Ervasti; Young Jae Nam

doi:10.1016/j.stemcr.2022.05.004

Fibroblast fate determination during cardiac reprogramming by remodeling of actin filaments

Zhentao Zhang, Wenhui Zhang, Robert Blakes, Lauren J. Sundby, Zengdun Shi, Don C. Rockey, James M. Ervasti, Young Jae Nam

Metabolic and Systems Biology (TMED)

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1604-1619
Number of pages	16
Journal	Stem Cell Reports
Volume	17
Issue number	7
DOIs	https://doi.org/10.1016/j.stemcr.2022.05.004
State	Published - Jul 12 2022

Bibliographical note

Funding Information:
High-content imaging analysis was performed in the Vanderbilt High-Throughput Screening (HTS) Core Facility. The HTS Core receives support from the Vanderbilt Institute of Chemical Biology and the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ). We appreciate the technical assistance by Dr. Boris Hinz. We thank Dr. Russell Addis for the TroponinT-GCaMP5-Zeo reporter construct. This work was supported by Gilead Sciences Research Scholars Program and NIH ( R01 HL146524 ) to Y.-J.N., NIH ( R01 AR049899 ) to J.M.E., and AHA ( 20POST35210170 ) to Z.Z.

Publisher Copyright:
© 2022 The Author(s)

Keywords

actin
cardiomyocyte
fibroblast
heart
myofibroblast
reprogramming
stress fiber

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10.1016/j.stemcr.2022.05.004

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title = "Fibroblast fate determination during cardiac reprogramming by remodeling of actin filaments",

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.",

keywords = "actin, cardiomyocyte, fibroblast, heart, myofibroblast, reprogramming, stress fiber",

author = "Zhentao Zhang and Wenhui Zhang and Robert Blakes and Sundby, {Lauren J.} and Zengdun Shi and Rockey, {Don C.} and Ervasti, {James M.} and Nam, {Young Jae}",

note = "Funding Information: High-content imaging analysis was performed in the Vanderbilt High-Throughput Screening (HTS) Core Facility. The HTS Core receives support from the Vanderbilt Institute of Chemical Biology and the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ). We appreciate the technical assistance by Dr. Boris Hinz. We thank Dr. Russell Addis for the TroponinT-GCaMP5-Zeo reporter construct. This work was supported by Gilead Sciences Research Scholars Program and NIH ( R01 HL146524 ) to Y.-J.N., NIH ( R01 AR049899 ) to J.M.E., and AHA ( 20POST35210170 ) to Z.Z. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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AU - Zhang, Zhentao

AU - Zhang, Wenhui

AU - Blakes, Robert

AU - Sundby, Lauren J.

AU - Shi, Zengdun

AU - Rockey, Don C.

AU - Ervasti, James M.

AU - Nam, Young Jae

N1 - Funding Information: High-content imaging analysis was performed in the Vanderbilt High-Throughput Screening (HTS) Core Facility. The HTS Core receives support from the Vanderbilt Institute of Chemical Biology and the Vanderbilt-Ingram Cancer Center ( P30 CA68485 ). We appreciate the technical assistance by Dr. Boris Hinz. We thank Dr. Russell Addis for the TroponinT-GCaMP5-Zeo reporter construct. This work was supported by Gilead Sciences Research Scholars Program and NIH ( R01 HL146524 ) to Y.-J.N., NIH ( R01 AR049899 ) to J.M.E., and AHA ( 20POST35210170 ) to Z.Z. Publisher Copyright: © 2022 The Author(s)

PY - 2022/7/12

Y1 - 2022/7/12

N2 - 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.

AB - 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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KW - cardiomyocyte

KW - fibroblast

KW - heart

KW - myofibroblast

KW - reprogramming

KW - stress fiber

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Fibroblast fate determination during cardiac reprogramming by remodeling of actin filaments

Abstract

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