Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

Jaeyeaon Cho; Sangsung Kim; Hyein Lee; Woongchan Rah; Hee Cheol Cho; Nam Kyun Kim; Seongho Bae; Dong Hoon Shin; Min Goo Lee; In Hyun Park; Yoshiaki Tanaka; Eric Shin; Hong Yi; Ji Woong Han; Patrick Tae Joon Hwang; Ho Wook Jun; Hun Jun Park; Kyuwon Cho; Sang Wook Lee; Jae Kyung Jung; Rebecca D. Levit; Mark A. Sussman; Richard P. Harvey; Young sup Yoon

doi:10.1038/s41551-021-00783-0

Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

Jaeyeaon Cho, Sangsung Kim, Hyein Lee, Woongchan Rah, Hee Cheol Cho, Nam Kyun Kim, Seongho Bae, Dong Hoon Shin, Min Goo Lee, In Hyun Park, Yoshiaki Tanaka, Eric Shin, Hong Yi, Ji Woong Han, Patrick Tae Joon Hwang, Ho Wook Jun, Hun Jun Park, Kyuwon Cho, Sang Wook Lee, Jae Kyung JungRebecca D. Levit, Mark A. Sussman, Richard P. Harvey, Young sup Yoon

BioMedical Science Institute

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

6 Citations (Scopus)

Abstract

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

Original language	English
Pages (from-to)	880-896
Number of pages	17
Journal	Nature biomedical engineering
Volume	5
Issue number	8
DOIs	https://doi.org/10.1038/s41551-021-00783-0
Publication status	Published - 2021 Aug

Bibliographical note

Funding Information:
We thank J. V. Taylor for sample preparations for TEM images and J. Mobley at the University of Alabama at Birmingham Comprehensive Cancer Center Mass Spectrometry/Proteomics Shared Facility for LC–MS analysis. This work was supported by grants from the National Heart, Lung, and Blood Institute (R01HL150877, R61HL154116, R01HL129511 and R01HL125391), an American Heart Association Transformative Project Award and the Bio and Medical Technology Development Program of the National Research Foundation grant funded by the Korean government (MSIT) (2020M3A9I4038454, 2020R1A2C3003784 and 2017R1D1A1B03036063).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41551-021-00783-0

Cite this

Cho, J., Kim, S., Lee, H., Rah, W., Cho, H. C., Kim, N. K., Bae, S., Shin, D. H., Lee, M. G., Park, I. H., Tanaka, Y., Shin, E., Yi, H., Han, J. W., Hwang, P. T. J., Jun, H. W., Park, H. J., Cho, K., Lee, S. W., ... Yoon, Y. S. (2021). Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts. Nature biomedical engineering, 5(8), 880-896. https://doi.org/10.1038/s41551-021-00783-0

@article{e721d3ca710444e9a2a60bfb956c8fb8,

title = "Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts",

abstract = "Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.",

author = "Jaeyeaon Cho and Sangsung Kim and Hyein Lee and Woongchan Rah and Cho, {Hee Cheol} and Kim, {Nam Kyun} and Seongho Bae and Shin, {Dong Hoon} and Lee, {Min Goo} and Park, {In Hyun} and Yoshiaki Tanaka and Eric Shin and Hong Yi and Han, {Ji Woong} and Hwang, {Patrick Tae Joon} and Jun, {Ho Wook} and Park, {Hun Jun} and Kyuwon Cho and Lee, {Sang Wook} and Jung, {Jae Kyung} and Levit, {Rebecca D.} and Sussman, {Mark A.} and Harvey, {Richard P.} and Yoon, {Young sup}",

note = "Funding Information: We thank J. V. Taylor for sample preparations for TEM images and J. Mobley at the University of Alabama at Birmingham Comprehensive Cancer Center Mass Spectrometry/Proteomics Shared Facility for LC–MS analysis. This work was supported by grants from the National Heart, Lung, and Blood Institute (R01HL150877, R61HL154116, R01HL129511 and R01HL125391), an American Heart Association Transformative Project Award and the Bio and Medical Technology Development Program of the National Research Foundation grant funded by the Korean government (MSIT) (2020M3A9I4038454, 2020R1A2C3003784 and 2017R1D1A1B03036063). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = aug,

doi = "10.1038/s41551-021-00783-0",

language = "English",

volume = "5",

pages = "880--896",

journal = "Nature Biomedical Engineering",

issn = "2157-846X",

publisher = "Nature Publishing Group",

number = "8",

}

Cho, J, Kim, S, Lee, H, Rah, W, Cho, HC, Kim, NK, Bae, S, Shin, DH, Lee, MG, Park, IH, Tanaka, Y, Shin, E, Yi, H, Han, JW, Hwang, PTJ, Jun, HW, Park, HJ, Cho, K, Lee, SW, Jung, JK, Levit, RD, Sussman, MA, Harvey, RP & Yoon, YS 2021, 'Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts', Nature biomedical engineering, vol. 5, no. 8, pp. 880-896. https://doi.org/10.1038/s41551-021-00783-0

TY - JOUR

T1 - Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

AU - Cho, Jaeyeaon

AU - Kim, Sangsung

AU - Lee, Hyein

AU - Rah, Woongchan

AU - Cho, Hee Cheol

AU - Kim, Nam Kyun

AU - Bae, Seongho

AU - Shin, Dong Hoon

AU - Lee, Min Goo

AU - Park, In Hyun

AU - Tanaka, Yoshiaki

AU - Shin, Eric

AU - Yi, Hong

AU - Han, Ji Woong

AU - Hwang, Patrick Tae Joon

AU - Jun, Ho Wook

AU - Park, Hun Jun

AU - Cho, Kyuwon

AU - Lee, Sang Wook

AU - Jung, Jae Kyung

AU - Levit, Rebecca D.

AU - Sussman, Mark A.

AU - Harvey, Richard P.

AU - Yoon, Young sup

N1 - Funding Information: We thank J. V. Taylor for sample preparations for TEM images and J. Mobley at the University of Alabama at Birmingham Comprehensive Cancer Center Mass Spectrometry/Proteomics Shared Facility for LC–MS analysis. This work was supported by grants from the National Heart, Lung, and Blood Institute (R01HL150877, R61HL154116, R01HL129511 and R01HL125391), an American Heart Association Transformative Project Award and the Bio and Medical Technology Development Program of the National Research Foundation grant funded by the Korean government (MSIT) (2020M3A9I4038454, 2020R1A2C3003784 and 2017R1D1A1B03036063). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/8

Y1 - 2021/8

N2 - Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

AB - Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.

UR - http://www.scopus.com/inward/record.url?scp=85113349878&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85113349878&partnerID=8YFLogxK

U2 - 10.1038/s41551-021-00783-0

DO - 10.1038/s41551-021-00783-0

M3 - Article

C2 - 34426676

AN - SCOPUS:85113349878

SN - 2157-846X

VL - 5

SP - 880

EP - 896

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

IS - 8

ER -

Regeneration of infarcted mouse hearts by cardiovascular tissue formed via the direct reprogramming of mouse fibroblasts

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this