A transient modified mRNA encoding Myc and cyclin T1 improves cardiac function after myocardial injury

Q: What is the clinical evidence from this study?

Population: Myocardial infarction (preclinical mouse models and human ESC-derived cardiomyocytes). Intervention: Transient localized expression of Myc and cyclin T1 via modified mRNA (modRNA) or tamoxifen-inducible transgenic system with AAV9-Ccnt1 and intramyocardial Cre modRNA vs. Control (Cre-negative/tdTomato mice or vehicle oil control). Primary outcome: Change in left ventricular ejection fraction (ΔEF%) at day 28 post-myocardial infarction.

Q: What does this research mean for the field?

Transient co-expression of Myc and cyclin T1 stimulates cardiomyocyte proliferation, promoting myocardial repair and functional recovery after myocardial infarction in mice. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Aleksandra Boikova; Gregory A. Quaife-Ryan; Christopher A. P. Batho; Rowda Dahir; Henrietta Cserné Szappanos; Harley Robinson; Elsa Lawrence; Camilla Ascanelli; Jin Seok Lee; Kypros Kyprianou Kokonos; Karin Jennbacken; Christopher R. Hunter; Patrícia Gonçalves‐Rodrigues; Gina Hyberg; Qing‐Dong Wang; Kenny M. Hansson; Adam Seaton; Maria Victoria Rodriguez Noci; Alby Biju; Silvia Da Pra; Gabriele D’Uva; Megan J. Bywater; Jasmin Straube; Kamil A. Sokolowski; Brian Wan-Chi Tse; Thomas Krieg; Ana Vujić; Mauro Giacca; Enzo R. Porrello; Sanjay Sinha; James E. Hudson; Catherine H. Wilson

doi:10.1038/s44161-026-00910-7

Key result

Myc and cyclin T1 expression limits post-MI LVEF decline by ~14 percentage points in mice.

Why the study?

The adult mammalian heart lacks regenerative capacity because cardiomyocytes fail to divide after damage, and although transgenic Myc and cyclin T1 expression drives cardiomyocyte proliferation, a translatable strategy for cardiac regeneration was needed.

Does transient, localized coexpression of Myc and cyclin T1 improve cardiomyocyte proliferation, myocardial repair, and cardiac function after myocardial infarction in adult mice?

Key Points

Investigate whether transient coexpression of Myc and cyclin T1 stimulates cardiomyocyte proliferation, promotes myocardial tissue repair, and restores cardiac function after myocardial infarction.
Assessed cardiac repair in transgenic Myh6-Cre;CMER adult mice treated with AAV9-cTnT-Ccnt1 and tamoxifen to induce transient MycERT2 and cyclin T1 coexpression following left anterior descending (LAD) coronary artery ligation.
Profiled transcriptional signatures using single-nucleus RNA sequencing (snRNA-seq) across juvenile, adult uninjured, and adult infarcted murine hearts.
Quantified cardiomyocyte cell cycle progression markers (Ki67, P-H3, Aurora B kinase) and apoptotic markers (cleaved caspase-3, TUNEL) 72 hours after myocardial infarction.
Transient Myc and cyclin T1 activation increased cardiomyocyte cell cycle entry at 72 hours post-infarction compared with vehicle controls: Ki67 positivity reached 25.1% versus 0.2%, P-H3 reached 6.9% versus 0.5%, and Aurora B kinase reached 4.4% versus 1.4%.
Cell cycle markers were substantially higher in the infarct border zone than the remote zone (Ki67: 25.1% vs. 6.2%; P-H3: 6.9% vs. 2.9%; Aurora B kinase: 4.4% vs. 0.6%), while cleaved caspase-3 and TUNEL staining remained low without altering cell death rates.

Structured PICO

Does transient, localized coexpression of Myc and cyclin T1 improve cardiomyocyte proliferation, myocardial repair, and cardiac function after myocardial infarction in adult mice?

P

Population

Preclinical study in adult mouse models of myocardial infarction induced by LAD ligation and human embryonic stem cell-derived cardiomyocytes, followed for up to 28 days.

I

Intervention

Transient and localized expression of Myc (or tamoxifen-inducible MycERT2 activated via intraperitoneal tamoxifen on days 1 and 2 post-MI) and cyclin T1 (Ccnt1) via systemic adeno-associated virus (AAV9-cTnT-Ccnt1 injected at 4 weeks of age) and/or direct intramyocardial injection of modified mRNA (modRNA, including 100 µg Cre modRNA or Myc and Ccnt1 modRNA) immediately after MI.

C

Comparator

Control mice receiving vehicle control (oil intraperitoneal injection) or lacking Cre recombinase (Cre-negative CMER mice or tdTomato control mice injected with AAV9-Ccnt1, 100 µg Cre modRNA, and tamoxifen).

O

Outcome

Cardiomyocyte proliferation (assessed by Ki67, phospho-histone H3, and Aurora B kinase positivity at 72 hours post-MI) and functional cardiac recovery (change in left ventricular ejection fraction [ΔEF%] and scar area at 28 days post-MI).surrogate

Main Result

Absolute Event Rate: -9% vs -23%

Transient, localized coexpression of Myc and cyclin T1 via modified mRNA stimulates adult cardiomyocyte proliferation and restores left ventricular function after myocardial infarction in mice without the lethal toxicity observed with global cardiac expression.

Limitations

Preclinical animal and in vitro cell model study
Global whole-heart expression of Myc and cyclin T1 after myocardial infarction resulted in 88% mortality (7/8 mice) within 3 to 7 days due to uncontrolled cardiomyocyte proliferation and potential arrhythmia
Sustained or global whole-heart expression of MycERT2 and cyclin T1 following MI resulted in 88% (7/8) mortality within 3 to 7 days, likely due to uncontrolled proliferation, sarcomere disassembly, or arrhythmogenic risk (reductions in Scn5a and Gja1).
Intramyocardial injection of Cre modRNA resulted in rare extracardiac recombination in the liver (0.14% of cells) and spleen (0.27% of cells).

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Implication

Hypothesis-generating for Myc-cyclin T1 in post-MI repair; leaves open translation to human cardiac regeneration.

Abstract

Myc is an evolutionarily conserved transcription factor that is necessary for the restoration of tissues in multiple regenerative species. The adult mammalian heart lacks regenerative capacity and cardiomyocytes fail to divide following damage-induced signaling. Transgenic expression of Myc and cyclin T1 can drive substantial adult cardiomyocyte proliferation to replace lost cardiomyocytes. Here, using transgenic models and a prototypical mRNA therapeutic, we show that Myc and cyclin T1 require transient induction for cardiomyocyte proliferation that leads to myocardial repair and functional recovery after myocardial infarction in mice. This research provides a strategy to translate Myc–cyclin T1 coexpression for cardiac regeneration to address serious unmet needs in the treatment of cardiovascular disease.

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Cite This Study

Boikova et al. (2026) studied Myocardial infarction (preclinical mouse models and human ESC-derived cardiomyocytes). Transient localized expression of Myc and cyclin T1 via modified mRNA (modRNA) or tamoxifen-inducible transgenic system with AAV9-Ccnt1 and intramyocardial Cre modRNA vs. Control (Cre-negative/tdTomato mice or vehicle oil control) was evaluated on Change in left ventricular ejection fraction (ΔEF%) at day 28 post-myocardial infarction. Localized transient expression of Myc and cyclin T1 attenuated left ventricular ejection fraction decline at 28 days post-MI compared to control (-9%±3% vs -23%±3%) in mice.

synapsesocial.com/papers/6af3463ebdf2424ebd04f7cd https://doi.org/10.1038/s44161-026-00910-7

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A transient modified mRNA encoding Myc and cyclin T1 improves cardiac function after myocardial injury

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

A transient modified mRNA encoding Myc and cyclin T1 improves cardiac function after myocardial injury

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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