# Human iPSCs for Elucidating Stress-mediated Paracrine Signaling in Dilated Cardiomyopathy

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $64,926

## Abstract

PROJECT SUMMARY
Dilated cardiomyopathy (DCM) is among the most common forms of inherited heart disease, characterized by
systolic dysfunction and ventricular chamber enlargement. Although DCM is often associated with mutations in
myocyte-specific genes that impair contractile function, pathological hallmarks also include non-myocyte
dysfunction, including cardiac fibrosis and endotheliopathy. Fibrosis in particular correlates with the extent of
DCM progression and is an important indicator of adverse patient outcomes (e.g., heart failure), suggesting that
cardiomyocyte (CM) dysfunction and aberrant activation of fibroblasts could be causally coupled. Potential
pathological crosstalk signaling between the two cell types seems increasingly plausible given that diseased or
stressed CMs have been shown to produce remarkably distinct secretory profiles compared to control CMs.
However, precise mechanisms of intercellular communication in the heart remain unclear, in part because the
human cardiac secretome to date has been poorly defined, hampered by the difficulty of distinguishing proteins
secreted by the heart versus other organs in patient plasma.
Here, I will leverage iPSC-derived engineered heart tissue (iPSC-EHT), genome-editing technology, and cutting-
edge proteomics to test the hypothesis that stress-induced CM secretome signaling promotes fibroblast
activation and fibrosis in DCM pathogenesis. To achieve this, I will first generate iPSC-derived cardiomyocytes
(iPSC-CMs) from DCM patients that carry mutations in three common sarcomeric genes, along with genome-
edited isogenic lines. The iPSC-CMs will be used to create 3D iPSC-EHTs, which will enable enhanced CM
maturation as well as examination of cellular responses to electrical stimulation and/or increased mechanical
load. The secreted proteins and exosomes from healthy versus diseased iPSC-EHTs will then be
comprehensively profiled under defined conditions using high-throughput proteomics platforms. To elucidate
mechanisms and downstream effects of potential crosstalk signaling, activation of iPSC-derived cardiac
fibroblasts (iPSC-CFs) will be examined by treatment with conditioned media and by co-culture assays.
Successful completion of the proposed studies will lead to new mechanistic insights into DCM pathogenesis,
and help identify novel therapeutic targets that can disrupt pathological signaling in DCM.

## Key facts

- **NIH application ID:** 9991266
- **Project number:** 1F32HL152483-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Sangkyun Cho
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991266

## Citation

> US National Institutes of Health, RePORTER application 9991266, Human iPSCs for Elucidating Stress-mediated Paracrine Signaling in Dilated Cardiomyopathy (1F32HL152483-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9991266. Licensed CC0.

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