# Human Mesenchymal Stem Cell Microvesicles for the Treatment of Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $689,069

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute respiratory distress syndrome remains a devastating syndrome affecting more than 200,000 patients
annually in the U.S. with a mortality rate approaching 40%. Currently, there are no pharmacological treatments
available that reduce mortality. Consequently, innovative therapies are needed. In various preclinical models of
acute lung injury, mesenchymal stem cells (MSC) have been shown to secrete multiple paracrine factors that
can reduce lung endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and
inhibit bacterial growth, ultimately decreasing mortality. Despite a favorable safety profile in early clinical trials,
however, MSC have the capacity for spontaneous malignant transformation following multiple passages in
culture as well as the ability to promote tumor growth in small animal models. In the prior grant period, we
found that microvesicles (MV) released by human MSCs were as biologically active as the parent stem cells in
both inflammatory and infectious causes of acute lung injury. Once considered cellular debris, MVs, anuclear
circular membrane bound vesicles 50 nm to 200 nm in size that are constitutively released by many cell types,
are now recognized as important mechanisms for cell-cell communication. Our overall hypothesis for the
current proposal is that MSC MVs are biologically active, and its therapeutic activity in severe bacterial
pneumonia is mediated through transfer of mRNAs, microRNAs, proteins and/or organelles from the
MVs to the injured alveolus. In Aim 1, we will further uncover the therapeutic mechanisms by studying the
effect of human MSC MVs on lipid metabolism and the activity of ATP-binding cassette transporter, multidrug
resistance associated protein (MRP)1, in mice injured with severe pneumonia. We hypothesize that MSC MVs
will inhibit MRP1 activity in monocytes/macrophages and decrease the enzymatic conversion and secretion of
leukotriene (LT)A4 to LTC/D/E4, leukotrienes involved in lung protein permeability, and increase the conversion
into LTB4, leukotriene involved in bacterial killing. In Aim 2, we will test the effect of human MSC MV on net
fluid transport in both a novel ex vivo perfused human lung injured with severe bacterial pneumonia and in
primary cultures of human alveolar epithelial type II cells injured by an inflammatory insult. We hypothesize
that MSC MVs will prevent pulmonary edema formation by restoring the apical membrane expression of the
major epithelial sodium channel, αENaC. In Aim 3, we will determine if human MSC MVs are therapeutic in a
sheep model of sepsis following smoke inhalation and Pseudomonas aeruginosa pneumonia. We hypothesize
that MSC MVs will improve oxygenation (PaO2/FiO2) by restoring alveolar fluid clearance, reducing lung protein
permeability and alveolar inflammation, increasing bacterial killing, and decreasing pulmonary vascular
pressure by releasing nitric oxide and restoring the glycocalyx layer on th...

## Key facts

- **NIH application ID:** 9861107
- **Project number:** 5R01HL113022-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jae Woo Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $689,069
- **Award type:** 5
- **Project period:** 2012-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861107

## Citation

> US National Institutes of Health, RePORTER application 9861107, Human Mesenchymal Stem Cell Microvesicles for the Treatment of Acute Lung Injury (5R01HL113022-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861107. Licensed CC0.

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