Calr-mediated calcium buffering: a molecular barrier to in vivo cardiac reprogramming

Q: What is the clinical evidence from this study?

Study design: Editorial. Population: Myocardial infarction. Intervention: Calreticulin (Calr) knockdown vs. Control. Primary outcome: Cardiac reprogramming efficiency (fibroblast-to-cardiomyocyte conversion).

Q: What does this research mean for the field?

Calreticulin (Calr)-mediated calcium buffering acts as a molecular barrier to direct cardiac reprogramming, and its knockdown enhances fibroblast-to-cardiomyocyte conversion in vivo following myocardial infarction. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Johnny Kim; Hans R. Schöler; Kee-Pyo Kim

doi:10.1038/s41392-026-02901-3

August 7, 2026Signal Transduction and Targeted TherapyOpen Access

Calr-mediated calcium buffering: a molecular barrier to in vivo cardiac reprogramming

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Key result

Calreticulin (Calr) knockdown significantly enhanced direct cardiac reprogramming of fibroblasts into induced cardiomyocytes in vitro and in vivo following myocardial infarction.

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Why the study?

Does Calr knockdown enhance direct cardiac reprogramming of fibroblasts into induced cardiomyocytes following myocardial infarction?

Key Points

To identify molecular barriers that restrict direct in vivo reprogramming of cardiac fibroblasts into functional cardiomyocytes after myocardial infarction.
Screened 140 candidate genes using an in vivo Perturb-seq platform combining shRNA loss-of-function perturbations with single-cell transcriptome profiling.
Transplanted fibroblasts pre-transduced with doxycycline-inducible reprogramming factors (MGTMyoS) and shRNAs into infarcted hearts.
Evaluated functional and structural cardiomyocyte transdifferentiation in vitro, in human iPSC-derived cardiac fibroblasts, and in infarcted mouse hearts.
Calreticulin (Calr) was identified as a top-ranked barrier that is upregulated in fibroblasts within infarcted hearts.
Depletion of Calr elevated cytosolic Ca²⁺, triggering CaM–CaMKIIδ signaling to enhance MEF2C transcriptional activity and bypass exogenous Mef2c requirements.
Calr knockdown promoted fibroblast-to-cardiomyocyte conversion, generating mature rod-shaped induced cardiomyocytes, improving ventricular synchrony, and reducing fibrotic remodeling in vivo.

Structured PICO

Does Calr knockdown enhance direct cardiac reprogramming of fibroblasts into induced cardiomyocytes following myocardial infarction?

P

Population

Fibroblasts in the infarcted heart, human iPSC-derived cardiac fibroblasts, and primary fibroblasts isolated from myocardial infarction patients

I

Intervention

Calr knockdown combined with direct cardiac reprogramming factors (MGTMyoS / tdMGT)

O

Outcome

Fibroblast-to-cardiomyocyte conversion efficiency and functional maturationsurrogate

Limitations

The extent to which multiple identified barriers act synergistically or redundantly remains unclear
Long-term functional stability, electrophysiological coupling, and overall safety of induced cardiomyocytes require further investigation
Cellular and molecular immune circuitry regulating cardiac fate conversion needs further elucidation
Translation to large animal models and human in vivo systems is needed to validate clinical applicability
The therapeutic window for transdifferentiation of cardiac fibroblasts after MI needs to be defined
Extent to which multiple identified barriers act synergistically or redundantly remains unclear
Long-term functional stability, electrophysiological coupling, and overall safety of iCMs require further investigation
Translation to large animal models and human in vivo systems is essential
Therapeutic window for transdifferentiation of cardiac fibroblasts after MI remains undefined

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Implication

Calreticulin-mediated calcium buffering is a major molecular barrier to in vivo cardiac reprogramming, and its targeted suppression significantly enhances cardiac regeneration post-myocardial infarction.

Abstract

In a recent publication in Cell Stem Cell , Cai et al. 1 employed an in vivo Perturb-seq strategy to systematically identify molecular barriers that limit direct cardiac reprogramming following myocardial infarction (MI). This study provides a conceptual and technological framework for improving fibroblast-to-cardiomyocyte conversion in vivo and identifies a key regulatory pathway that can be targeted to enhance cardiac regeneration.

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Cite This Study

Kim et al. (2026) conducted an editorial in Myocardial infarction. Calreticulin (Calr) knockdown vs. Control was evaluated on Cardiac reprogramming efficiency (fibroblast-to-cardiomyocyte conversion). Calreticulin (Calr) knockdown significantly enhanced direct cardiac reprogramming of fibroblasts into induced cardiomyocytes in vitro and in vivo following myocardial infarction.

synapsesocial.com/papers/6a76da7cf12abadc79814c0a https://doi.org/10.1038/s41392-026-02901-3

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Calr-mediated calcium buffering: a molecular barrier to in vivo cardiac reprogramming

Figures

Key Points

Structured PICO

Limitations

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Implication

Abstract

Discussion

Cite This Study

Calr-mediated calcium buffering: a molecular barrier to in vivo cardiac reprogramming

Figures

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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