# Mitochondria-rich microvesicles for restoration of intracellular bioenergetics

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $386,937

## Abstract

PROJECT SUMMARY/ABSTRACT
Induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) have generated great excitement for their
promise to regenerate the injured myocardium. In pre-clinical studies, we have demonstrated that iCMs have
significant functional benefit; however, substantial challenges remain, including ventricular arrhythmia,
teratoma formation, and poor engraftment in the host myocardium. Furthermore, reliable regeneration of the
injured myocardium has yet to be seen. While no effective strategy for permanent restoration has emerged,
paracrine factors appear to underlie the beneficial effects of iCM therapy. Recently, we discovered the
mitochondria-rich extracellular vesicles (M-EVs), which are secreted from the iCMs. These M-EVs effectively
repair the injured cardiomyocytes and myocardium through restoration of intracellular bioenergetics. The
paracrine effect is achieved by mitochondrial transfer and biogenesis to augment ATP production.
This proposal will re-shape the future of heart failure (HF) therapeutics. There is clear clinical indication and need
to improve the high mortality and morbidity of HF patients. The shortcoming of current standard of care may be
due to the unmet need in understanding the bioenergetic imbalance in HF. The disruption of the balance
between energy supply and demand underlies the pathogenesis of HF. Cardiac tissues from patients with
hypertrophic, dilated, or ischemic cardiomyopathy all exhibit structural abnormalities of mitochondria and
diminished ATP production despite increased metabolic energy demands in the failing heart. Although
peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) serves as a master regulator of
mitochondrial biogenesis and function, PGC-1α levels are decreased in the myocardium of the HF patients.
Insufficient energy generation results in the loss of cardiomyocyte contractility, myocardial dysfunction, and,
ultimately, decompensated HF. Proteomic analysis of M-EVs demonstrated a novel cluster of 6 enriched M-EV
proteins (PC), which interact with PGC-1α. PC was found to up-regulate energy metabolism, including oxidative
phosphorylation, fatty acid metabolism, and glycolysis. Therefore, we hope to develop an innovative therapy
that targets the intracellular bioenergetics directly through the following 3 Specific Aims:
Specific Aim 1 – Confirm the role of enriched M-EV protein cluster (PC) in mitochondrial biogenesis.
Specific Aim 2: Determine the mechanism of the protective effects of M-EVs in an in vitro iCM model of
hypoxic injury.
Specific Aim 3: Assess the functional benefits of mitochondrial augmentation and/or biogenesis in an in
vivo mouse model of chronic myocardial injury.
Upon conclusion of this study, the bioenergetic mechanism of mitochondrial augmentation and biogenesis will be
confirmed in M-EVs for significant and sustained restoration of the injured myocardium.

## Key facts

- **NIH application ID:** 10586699
- **Project number:** 1R01HL156945-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PHILLIP CHUNG-MING YANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $386,937
- **Award type:** 1
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586699

## Citation

> US National Institutes of Health, RePORTER application 10586699, Mitochondria-rich microvesicles for restoration of intracellular bioenergetics (1R01HL156945-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10586699. Licensed CC0.

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