# The interplay between mesenchymal stem cell secretome and fibroblast differentiation in the confined microenvironment of idiopathic pulmonary fibrosis

> **NIH NIH F31** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $13,237

## Abstract

PROJECT SUMMARY/ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a chronic disease of the lung characterized by the differentiation of resident
fibroblasts into contractile myofibroblasts that deposit excessive extracellular matrix (ECM). There are no
effective treatments for IPF, and the median survival time after diagnosis is approximately 3 years. Increased
matrix deposition is a hallmark of IPF that increases the stiffness of lung tissue, thereby encouraging fibroblast
differentiation into myofibroblasts and furthering disease progression. Increased matrix deposition concomitantly
increases the degree of confinement experienced by cells, yet the role of confinement in fibroblast differentiation
is unknown. Mesenchymal stem cell (MSC) injection is currently being targeted as a potential therapeutic for IPF
in clinical trials. However, some studies indicate that MSC therapy worsens outcome, yielding conflicting results.
Studies have suggested that protective effects are due to MSC secreted factors, which are often collected from
MSCs cultured in 2D on standard tissue culture plastic. It has been shown that manipulating the MSC
microenvironment alters the MSC secretome, yet the effect of confinement on the MSC secretome is unknown.
We hypothesize that a) increasing confinement experienced by fibroblasts will encourage their differentiation into
myofibroblasts, and b) increasing confinement experienced by MSCs will increase their protective effects on
fibroblasts, inhibiting myofibroblast differentiation. To investigate this hypothesis, we propose two Specific Aims:
1) Evaluate the effect of matrix composition and degree of confinement on fibroblast to myofibroblast
differentiation, and the role cell mechanics play in this process, and 2) Evaluate the effect of MSC secreted
factors in various degrees of confinement on differentiation of fibroblasts to myofibroblasts and matrix deposition
by fibroblasts and myofibroblasts. For aim 1) fibroblasts will be cultured within confining devices and their
differentiation into myofibroblasts will be characterized via α-SMA immunofluorescence staining and gene and
protein expression analysis of characteristic myofibroblast markers. Traction forces and chromosome
condensation will be investigated as potential players in the differentiation mechanism. For aim 2) MSCs will be
cultured within confining devices and their secreted factors collected. These secreted factors will be applied to
fibroblasts, and fibroblast to myofiroblast differentiation will again be characterized. Extracellular vesicles will be
investigated as a potential contributor to the therapeutic effects of MSC secretions. Thus, we aim to determine
the role of confinement and ligand presentation in lung fibroblast and myofibroblast mechanics, and their
response to MSC secretions. Successful completion of these aims will improve understanding of IPF progression
and improve methods of MSC culture for use in IPF treatments. Broadly, this research w...

## Key facts

- **NIH application ID:** 9918156
- **Project number:** 5F31HL145991-02
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Mary Doolin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $13,237
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918156

## Citation

> US National Institutes of Health, RePORTER application 9918156, The interplay between mesenchymal stem cell secretome and fibroblast differentiation in the confined microenvironment of idiopathic pulmonary fibrosis (5F31HL145991-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9918156. Licensed CC0.

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