# Role of RBP in programming and reprogramming of cardiac fibroblasts

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $662,922

## Abstract

Cardiac fibroblasts (CFs) are the major cardiac cell type responsible for producing extracellular matrix (ECM)
proteins, forming a structural scaffold crucial for supporting cardiac tissue during development and homeostasis.
CFs are also known for their high plasticity, enabling them to swiftly respond to injuries and pathological
conditions. Under such circumstances, CFs are rapidly activated and become transdifferentiated into
myofibroblasts that produce and secrete an excessive amount of ECM components, ultimately leading to fibrotic
scarring that disrupts tissue compliance and accelerates the progression toward heart failure.
 The transformation of CFs into myofibroblasts requires wholesale programming of the CF transcriptome. Yet,
in addition to transcriptional regulation, post-transcriptional regulation by RNA-binding proteins (RBPs) has
emerged as a critical regulatory layer for controlling gene expression. RBPs actively regulate every step of mRNA
life cycle, including splicing, stability, and translation. In our preliminary studies, we found that one of RBPs,
Ybx1, was significantly upregulated during CF to myofibroblast conversion and further discovered a potentially
important role of this RBP in myofibroblast formation. Specifically, we found that Tcf21:MerCreMer mediated
ablation of Ybx1 inhibits the transformation of CFs into myofibroblasts and reduces cardiac fibrosis.
 While the conversion CFs to myofibroblasts is inherently pathological, the extensive pool and plasticity of
resident CFs has been recently harnessed for cardiac regeneration whereby CFs are reprogrammed into induced
cardiomyocytes (iCMs) by local delivery of three cardiac transcription factors (TFs) - Gata4, Mef2c, Tbx5
(abbreviated as GMT). Building upon our intriguing finding that depletion of Ybx1 attenuates CF to myofibroblast
conversion and reduces cardiac fibrosis, we posed the question whether Ybx1 ablation enhances GMT-mediated
iCM reprogramming. Indeed, our preliminary study indicates that, compared to MGT-mediated iCM
reprogramming, delivery of GMT with Ybx1 depletion enhances iCM induction, further attenuating cardiac fibrosis
and improves heart function following MI.
 Combining these two lines of investigation and the corresponding preliminary data, in this proposal we will
leverage our series of unique tools, reagents, and animal models to address our hypothesis that Ybx1 activity
exerts a significant influence on the fate switch involving CFs, specifically the transformation of CFs into
myofibroblasts and the reprogramming of CFs into iCMs, which can be leveraged for reducing fibrotic scarring
and regenerating lost myocardium after MI.

## Key facts

- **NIH application ID:** 10942226
- **Project number:** 1R01HL174774-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jiandong Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $662,922
- **Award type:** 1
- **Project period:** 2024-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942226

## Citation

> US National Institutes of Health, RePORTER application 10942226, Role of RBP in programming and reprogramming of cardiac fibroblasts (1R01HL174774-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10942226. Licensed CC0.

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