Abstract
A major hurdle in cardiac cell therapy is the lack of a bona fide autologous stem-cell type that can be expanded long-term and has authentic cardiovascular differentiation potential. Here we report that a proliferative cell population with robust cardiovascular differentiation potential can be generated from mouse or human fibroblasts via a combination of six small molecules. These chemically induced cardiovascular progenitor cells (ciCPCs) self-renew long-term in fully chemically defined and xeno-free conditions, with faithful preservation of the CPC phenotype and of cardiovascular differentiation capacity in vitro and in vivo. Transplantation of ciCPCs into infarcted mouse hearts improved animal survival and cardiac function up to 13 weeks post-infarction. Mechanistically, activated fibroblasts revert to a plastic state permissive to cardiogenic signals, enabling their reprogramming into ciCPCs. Expanded autologous cardiovascular cells may find uses in drug discovery, disease modelling and cardiac cell therapy.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are provided with this paper. The RNA-sequencing data are available from the NCBI GEO database, via the accession number GSE159081. Source data are provided with this paper.
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Acknowledgements
We thank Y. Zhou (University of North Carolina) for technical support and all lab members for helpful discussion. N.C. was funded by the National Key R&D Program of China (2018YFA0109100 and 2018YFA050830), the National Natural Science Foundation of China (92057113, 82061148011 and 31771508), and the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029). J.W. was funded by the National Key R&D Program of China (2018YFA0109600) and the National Natural Science Foundation of China (81700233). Z.Z. was funded by the National Key R&D Program of China (2019YFA0111500).
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J.W., S.G. and N.C. conceived the project, carried out the experiments and wrote the manuscript. Zihao Chen, W.C. and T.X. performed bioinformatics analysis. F.L., H.X., Z.L., L.W., Zhongyan Chen, D.C., X.C., F.Z., Z.Z. and M.Z. performed data analysis, provided materials or assisted with the experiments.
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Nature Biomedical Engineering thanks Ke Cheng, Timothy Kamp and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Video 1
Beating cluster generated after MEF-derived ciCPCs were cultured in cardiac differentiation conditions for 7 d.
Supplementary Video 2
Beating cluster generated after TTF-derived ciCPCs were cultured in cardiac differentiation conditions for 7 d.
Supplementary Video 3
Beating cluster generated after HFF-derived ciCPCs were cultured in cardiac differentiation conditions for 14 d.
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Wang, J., Gu, S., Liu, F. et al. Reprogramming of fibroblasts into expandable cardiovascular progenitor cells via small molecules in xeno-free conditions. Nat. Biomed. Eng 6, 403–420 (2022). https://doi.org/10.1038/s41551-022-00865-7
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DOI: https://doi.org/10.1038/s41551-022-00865-7
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