# Improving cardiovascular disease modeling using human pluripotent stem cell-derived cardiac fibroblasts

> **NIH NIH F31** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $45,520

## Abstract

Project Summary: Annually, there are ~790,000 cases of myocardial infarction (MI) in the United States.
Typically, MI progresses into heart failure where patients have a high risk of mortality within 5 years after
diagnosis. While animal models provide a valuable model system of MI, interspecies differences lead to
inaccurate recapitulation of human myocardium. To address this, our lab originally developed 3D human
cardiac organoids through self-assembly of hPSC-CMs, human primary adult cardiac fibroblasts (adult-cFbs),
endothelial cells, and stromal cells. Further, we leveraged the oxygen diffusion limitation in 3D human cardiac
organoids along with chronic adrenergic stimulation to generate an organotypic model of post-MI hearts. The
human cardiac infarct organoids recapitulated transcriptional, structural and functional hallmarks of post-MI
myocardium. However, the use of primary, non-myocyte cell populations in our current organoids limit their
potential to mimic patient-specific myocardium. To develop human isogenic cardiac organoids, we are
collaborating with Dr. Sean Palecek at the University of Wisconsin-Madison to derive cardiac fibroblasts from
human pluripotent stem cells (hPSC) to replace adult-cFbs in our cardiac organoid model. Dr. Palecek’s lab has
developed expertise to direct hPSC differentiation into cardiac fibroblasts (hPSC-cFbs) in 2 different lineages:
epicardial-derived fibroblasts (hPSC-cFb(EpiC)s) and second heart field progenitor-derived fibroblasts (hPSC-
cFb(SHFP)s). While both lineages contribute to cardiac fibrosis and are functionally similar, in murine hearts,
the epicardium is the predominate source of ventricular cardiac fibroblasts while a small population arise
from the endocardium. In addition, the enhanced maturation may be needed for the hPSC-cFb(EpiC)s to
replace human adult-cFbs, as our preliminary data that showed that prolonged culture improved cell organization
of hPSC-cFb(SHFP)s in cardiac organoids when compared to that of adult-cFb organoids. The central
hypothesize of this proposal is that high passage hPSC-cFb(EpiC)s will best replicate adult-cFb transcriptomics
and functionality. The proposal is innovative in that, for the first time, we will identify a suitable hPSC-cFb
population to replace adult-cFbs to develop an isogenic 3D organotypic model of human myocardium. Our
long-term goal is to develop patient-specific cardiac organoids for in vitro disease modeling and drug testing.
Accordingly, we will pursue the following two Aims: 1) Determine the effectiveness of high passage hPSC-
cFb(EpiC)s to replicate the transcriptomics and functionality of adult cFbs, and 2) Determine the effectiveness
of human cardiac organoids composed of high passage hPSC-cFb(EpiC)s in modeling post-MI human
myocardium and responsiveness to anti-MI therapeutics. We also will perform single cell RNA-seq to examine
the heterogeneity of hPSC-cFb(EpiC)s in response to our infarction protocol. Completion of this study would
...

## Key facts

- **NIH application ID:** 10067745
- **Project number:** 1F31HL154665-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Charles Matthew Kerr
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067745

## Citation

> US National Institutes of Health, RePORTER application 10067745, Improving cardiovascular disease modeling using human pluripotent stem cell-derived cardiac fibroblasts (1F31HL154665-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10067745. Licensed CC0.

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