# Deciphering the Endothelial Cell-Cardiomyocyte Crosstalk in LMNA Cardiomyopathy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $393,500

## Abstract

Project Summary/Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the leading reason for heart
transplantation. Major gaps exist in our understanding of the pathophysiology of DCM and mutations in the
gene that encodes the nuclear envelope proteins lamin A and C (LMNA) are considered to be the most
common cause of DCM. However, the molecular mechanisms that underlie “cardiolaminopathy” remain
elusive, and it is unknown why mutations in this ubiquitously expressed gene have such a disproportionate
effect on the heart. Using induced pluripotent stem cell (iPSCs)-derived endothelial cells (iPSC-ECs), we
recently studied a family affected by DCM due to a frameshift variant in LMNA, which showed endothelial
dysfunction (Sayed et al. Science Translational Medicine, 2020). This EC dysfunction could be reversed by
upregulating Krüppel-like Factor 2 (KLF2) by treatment of iPSC-ECs with a subset of statins, including
lovastatin. Importantly, this improvement in EC dysfunction had a positive effect on co-cultured iPSC-
cardiomyocytes (iPSC-CMs) from cardiolaminopathy patients, indicating an intricate crosstalk between the ECs
and CMs in LMNA cardiomyopathy.
 Despite impressive progress, little attention has been given to the potential importance of cell-to-cell
signaling between ECs and CMs, despite the fact that ECs serve a paracrine function to enhance signaling in
CMs, especially in context to pharmacological stimulation. This knowledge gap impedes our comprehensive
understanding of organ dysfunction at a multi-cellular level. The overarching goal of our proposal is to use a
multidisciplinary approach that integrates human iPSCs, bioengineering tools, genome editing, and NGS to
gain novel insights into the pathogenesis of DCM. Using human iPSCs, we propose to decipher the impaired
cross-talk between ECs and CMs in LMNA cardiomyopathy and elucidate the beneficial class effects of statins
in improving the EC-CM signaling as a key factor in regulating cardiac function. We will pursue three specific
aims. In Aim 1: we will establish an experimental platform to study the genotype-phenotype association of
LMNA mutations on ECs and CMs. For this, we will recapitulate the EC-CM crosstalk in LMNA iPSC-derived
cells with 3D engineered heart tissues (EHTs). In Aim 2: we will decipher the mechanism of EC-CM crosstalk
in LMNA iPSC-derived EHTs using single-cell approaches (scRNA-seq and scATAC-seq). In Aim 3: we will
validate the key regulatory players of EC-CM crosstalk in LMNA cardiomyopathy by using CRISPR technology
and zebrafish animal model. We have provided compelling preliminary data to support the soundness of
our hypothesis-driven research proposal, and we are well positioned to achieve the project goals
within five years. If successful, our studies will provide a new paradigm for understanding the
pathogenesis and treatment of familial DCM.

## Key facts

- **NIH application ID:** 10486131
- **Project number:** 5R01HL158641-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nazish Sayed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,500
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486131

## Citation

> US National Institutes of Health, RePORTER application 10486131, Deciphering the Endothelial Cell-Cardiomyocyte Crosstalk in LMNA Cardiomyopathy (5R01HL158641-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10486131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*