Skip to main content
  • Research highlight
  • Open access
  • Published:

OSKM-mediated reversible reprogramming of cardiomyocytes regenerates injured myocardium


Cellular reprogramming has rapidly become a promising methodology to generate new cardiomyocytes from non-cardiomyocyte cell types. Using the transient expression of OSKM factors, Chen et al. demonstrate a unique reprogramming strategy involving the modulation of the resident adult cardiomyocyte identity to an immature proliferative state (Science 373:1537–40, 2021). This OSKM-mediated reversion results in the adoption by adult murine cardiomyocytes of a transcriptional profile similar to cardiomyocytes found in developing hearts, as well as increased proliferative capacity of these reprogrammed cardiomyocytes compared to mature cardiomyocytes. Furthermore, this novel approach enhances the regeneration of adult murine hearts post-myocardial injury. Although concerns and questions remain, the encouraging results of this study advance the field of cardiac regeneration by providing a new technique to generate cardiomyocytes as well as insights into cardiomyocyte dedifferentiation and its relation to proliferation.

Main text

The high global prevalence of cardiac injury and disease has made finding new sources for cardiomyocytes an ever-evolving area of research. Numerous approaches to repair injured cardiac tissue have been developed and range from bioengineering-focused therapies, to stem cell-based strategies, to direct manipulation of cell signaling pathways. The ultimate goal for these methodologies is to generate new cardiomyocytes and/or replace damaged ones with the aim of improving heart function. Direct and indirect (via iPSC route) reprogramming-based methods are attractive options for generating new cardiomyocytes from non-cardiomyocyte cell types and have shown promise as potential therapeutic tools for heart regeneration (Ieda et. al 2010; Qian et. al 2012; Shiba et al. 2016; Song et al. 2012; Wang et al. 2021). However, the excitement concerning these conversion techniques is tempered by the difficulty of creating fully functional and mature cardiomyocytes in vitro, as these methods generally yield cardiomyocytes of a relative immature phenotype in a dish. Utilizing native cardiomyocytes to create cardiomyocytes has always been a tantalizing proposal because of the potential to generate a cell type that is either identical or very similar to the desired adult cardiomyocyte. Furthermore, the well-characterized regenerative capacity of neonatal cardiomyocytes in murine injury models highlights the underlying potential for adult cardiomyocytes to generate new cardiomyocytes if they can re-acquire their regenerative capabilities that are loss during cardiac maturation.

In a recent paper by Chen et. al, the authors explore the possibility of reverting murine adult cardiomyocytes into a more immature state by forced-expression of OSKM factors (Oct4, Sox2, Klf4, and c-Myc) in murine cardiomyocytes, and investigate whether this reversion process allows resident cardiomyocytes to proliferate post-myocardial infarction (Chen et. al 2021). This de-differentiation reprogramming strategy resulted in decreased scar formation post-myocardial infarction, and demonstrated the potential for improving adult cardiomyocyte proliferative capacity by changing their maturation state through transient expression of OSKM in cardiomyocytes. The authors methodically evaluated how to best utilize this reprogramming strategy post-myocardial injury as well as its impact on mice of various ages. Bioinformatical analyses demonstrated that the reprogrammed identity of the affected cardiomyocytes are similar to cardiomyocytes found in developing murine hearts. However, this reprogramming approach faces similar hurdles as other methods, such as reprogramming heterogeneity and the question of what should be the final desired cardiomyocyte identity after reprogramming in order to achieve both the creation of new cardiomyocytes as well as functional improvement after cardiac injury.

Investigation of the different intermediary states resulting from OSKM factor-mediated reversible reprogramming would provide exciting insights into the molecular mechanisms behind this de-differentiation process as well as how the OSKM factors guide cardiomyocytes to regain their proliferation capabilities. Single cell genomics has allowed for the visualization of the heterogeneity of reprogrammed cells in other reprogramming methodologies and has shown the presence of multiple intermediary states between the starting cell type and final identity (Stone et al. 2019; Zhou et al. 2019). In the case of this reversible reprogramming, there is potential to see cardiomyocytes in various states of dedifferentiation, ranging from fully de-differentiated pluripotent cells to unaffected cardiomyocytes. Further evaluation could determine whether certain intermediary states may be more beneficial to cardiac regeneration than others. As shown in other reprogramming-related studies, unsuccessful reprogramming or the creation of undesired cell types can lead to negative functional consequences such as arrythmias or improperly formed muscle tissue. Single cell genomics would also allow for more detailed analysis into how closely OSKM-reprogrammed cardiomyocytes revert back to their original identity and would potentially highlight ways to improve this method.

This study also raises an interesting question on what should be the desired end product of cardiomyocyte reprogramming for cardiac regeneration. While other reprogramming strategies seek to create mature cardiomyocytes to replace damaged ones, this study seeks to obtain an earlier stage of cardiomyocyte identity which may result in increased proliferation potential at the expense of losing key functional attributes. This may explain why this technique yields new cardiomyocytes but does not result in significant improvement of cardiac function after myocardial infarction. What is necessary and not for a reprogrammed cardiomyocyte to remain a cardiomyocyte in both identity and function is a topic that warrants further evaluation as new regenerative techniques are added to the toolbox. Along the same lines, it would be interesting to see if this OSKM-mediated reversion is cardiomyocyte-specific or if the approach can be used to generate other cell types such as neurons or hepatocytes. Because this de-differentiation reprogramming is unique from other reprogramming techniques in its use of generic reprogramming genes rather than cell-type specific genes, it would be intriguing to assess whether this transition to a proliferative immature state is unique to cardiomyocytes.

Another potential impact of this study is the ability to identify signaling pathways and genes that regulate the acquisition and silencing of the regenerative properties of immature cardiomyocytes. These genetic targets could be future focal points for manipulation in adult cardiomyocytes in order to increase their proliferation potential. Previous studies have shown that more targeted approaches for increasing adult cardiomyocyte proliferation have therapeutic promise. Several research groups have shown that members of the cyclin family of proteins are promising candidates (Mohamed et al. 2018; Pasumarthi et al. 2005; Shapiro et al. 2014). Other groups have evaluated proteins involved in the Hippo pathway as well as transcription factors like Gata4 and Meis1 (Mahmoud et al., 2013; Malek Mohammadi et al., 2017). All of these approaches have shown varying degrees of promise in allowing cardiomyocytes to enter a more proliferative state, thus they may benefit from application of knowledge obtained from OSKM-mediated reversible reprogramming in order to further hone in on specific pathways. Understanding the roadmap of de-differentiation during OSKM reprogramming can also be used to help other reprogramming methods to create more matured cardiomyocytes.

While there remains some interesting questions regarding this reversible OSKM-mediated reprogramming, this study provides foundational knowledge on the potential uses and limits of OSKM factors to modulate adult cardiomyocyte identity and achieve more regenerative cardiac tissue. OSKM-mediated identity reversion may, in the end, be a too powerful or non-specific methodology to modulate the maturation of cardiomyocytes, but the molecular pathways affected by this approach may ultimately be the key to unlocking the regenerative potential of adult cardiomyocytes and regenerating injured hearts

Availability of data and materials

Not applicable.


  • Chen Y, et al. Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice. Science. 2021;373:1537–40.

    Article  CAS  Google Scholar 

  • Ieda M, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;142:375–86.

    Article  CAS  Google Scholar 

  • Mahmoud AI, et al. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature. 2013;497:249–53.

    Article  CAS  Google Scholar 

  • Malek Mohammadi M, et al. The transcription factor GATA 4 promotes myocardial regeneration in neonatal mice. EMBO Mol Med. 2017;9:265–79.

    Article  CAS  Google Scholar 

  • Mohamed TMA, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell. 2018;173:104-116.e12.

    Article  CAS  Google Scholar 

  • Pasumarthi KBS, Nakajima H, Nakajima HO, Soonpaa MH, Field LJ. Targeted expression of cyclin D2 results in cardiomyocyte DNA synthesis and infarct regression in transgenic mice. Circ Res. 2005;96:110–8.

    Article  CAS  Google Scholar 

  • Qian L, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593–8.

    Article  CAS  Google Scholar 

  • Shapiro SD, et al. Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes. Sci Transl Med. 2014;6(224):224ra27.

    Article  Google Scholar 

  • Shiba Y, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016;538:388–91.

    Article  CAS  Google Scholar 

  • Song K, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485:599–604.

    Article  CAS  Google Scholar 

  • Stone NR, et al. Context-specific transcription factor functions regulate epigenomic and transcriptional dynamics during cardiac reprogramming. Cell Stem Cell. 2019;25:87-102.e9.

    Article  CAS  Google Scholar 

  • Wang H, Yang Y, Liu J, Qian L. Direct cell reprogramming: approaches, mechanisms and progress. Nat Rev Mol Cell Biol. 2021;22:410–24.

    Article  Google Scholar 

  • Zhou Y, et al. Single-cell transcriptomic analyses of cell fate transitions during human cardiac reprogramming. Cell Stem Cell. 2019;25:149-164.e9.

    Article  CAS  Google Scholar 

Download references


Not applicable.


Not applicable.

Author information

Authors and Affiliations



All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Li Qian.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Dr. Li Qian is an editorial board member of the journal, and not involved in the review and decision making process of the article.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farber, G., Liu, J. & Qian, L. OSKM-mediated reversible reprogramming of cardiomyocytes regenerates injured myocardium. Cell Regen 11, 6 (2022).

Download citation

  • Accepted:

  • Published:

  • DOI: