# FAS Controls Exosome-Mediated miRNA Transfer in MSC-Based Therapy

> **NIH NIH R00** · UNIVERSITY OF PENNSYLVANIA · 2021 · $240,032

## Abstract

Project Description
Systemic sclerosis/scleroderma (SSc) is a connective tissue disease characterized by vascular, immune and
fibrotic changes in the skin and internal organs. SSc patients are known to have high prevalence of osteopenia,
but the pathophysiological mechanism causing this osteoporosis in SSc patients is unknown. Systemic infusion
of mesenchymal stem cells (MSCs) yields a therapeutic effect in a variety of autoimmune diseases; however,
the reasons behind this MSC-based therapy are not fully understood. As a secretome, MSCs release large
amounts of cytokines and small vesicles for immunoregulation and communication with surrounding cells. The
goal of this proposal is to investigate how small vesicles are controlled by a set of membrane traffic proteins for
cell component reuse in MSC transplantation (MSCT). My preliminary data show that MSCT significantly
rescues disease phenotypes in SSc mice through rebuilding tissue homeostasis and lineage commitment of
host MSCs. miRNA-151-5p is reused by recipient MSCs through exosome trafficking resulting in markedly
recovered lineage selection of host MSCs. A micro-vesicle trafficking complex assembled in donor MSCs
regulated exocytosis for exosome-mediated miRNA transfer. In addition, developmental endothelial locus-1
(Del-1), an immune suppressive molecule, expresses in MSCs and releases via exosomes to inhibit neutrophil
migration. The central hypothesis of this proposal is that cell component transferred from donor to
recipient MSCs ameliorates autoimmune disease phenotypes through FAS-assembled exocytotic
machinery. During the K99 phase, I will explore the efficacy of MSCT in SSc mice and uncover the interplay
between immune cells and tissue-specific stem cells to elucidate the pathophysiological mechanism of SSc
(Aim 1; K99). Since miRNA-151-5p has been identified to transfer from donor to recipient MSCs, I will
determine the function of miRNA-151-5p in MSC differentiation and use miRNA-151-5p gene therapy in SSc
mice (Aim 2; K99). During the R00 phase, I will determine the role of the exosome in MSCT by direct infusion
of exosomes for disease treatment and examine the role of the exocytosis molecule Rab27a in regulation of
exosome release. I will identify a novel micro-vesicle trafficking complex from MSCs and determine its function
in controlling cell component reuse (Aim 3; R00). Finally, I will examine the therapeutic effect of Del-1, which
can be released via exosomes from donor MSCs to restrain cytokine production and disease phenotypes (Aim
4; R00). Upon successful completion of the Specific Aims, this translational study will extend our knowledge of
SSc pathogenesis and describe detailed mechanisms of MSC-based therapy. Under my primary mentorship of
Drs. Hajishengallis and Shi, the training plan will provide the opportunity to extend and develop the necessary
knowledge and skills within a collaborative environment. An identified outstanding mentorship team and
collaborators will...

## Key facts

- **NIH application ID:** 10114905
- **Project number:** 5R00DE025915-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Chi-Der Chen
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $240,032
- **Award type:** 5
- **Project period:** 2019-04-03 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114905

## Citation

> US National Institutes of Health, RePORTER application 10114905, FAS Controls Exosome-Mediated miRNA Transfer in MSC-Based Therapy (5R00DE025915-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114905. Licensed CC0.

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