# Stem cell oxygenation and ischemic tissue regeneration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $382,968

## Abstract

Program Director/Principal Investigator (Last, First, Middle): GUAN, JIANJUN
Project Summary
 Critical limb ischemia (CLI) is a severe peripheral artery disease with high rates of limb loss and mortality. It is
featured by low blood perfusion, extensive tissue ischemia, and degenerated skeletal muscle. Quick vascularization
to restore blood perfusion, and fast muscle regeneration to restore normal function, represent the optimal goals for
CLI treatment. Currently there is no efficient treatment available, although stem cell therapy is one of the most
promising strategies. Most of stem cell types promote vascularization and muscle regeneration mainly by paracrine
effects while some may also differentiate into endothelial and skeletal muscle cells. However, current stem cell
therapy experiences low efficacy largely due to inferior cell survival and paracrine effects under the extremely low
oxygen condition (<1%) of ischemic limbs. In this project, we propose a new cell delivery system that continuously
releases appropriate concentration of O2 to simultaneously improve stem cell survival and paracrine effects,
resulting in quick vascularization and muscle regeneration. Paracrine effects concurrently provide multiple growth
factors critical for vascularization and muscle regeneration, which cannot be readily achieved by growth factor
therapy.
 In our preliminary studies, we have created a hydrogel-based cell delivery system that releases O2. When tested
using bone marrow-derived mesenchymal stem cells (MSCs), the released O2 increased cell survival under
ischemic conditions in vitro without increasing reactive oxygen species (ROS) content. It also upregulated MSC
paracrine effects especially in terms of secreting proangiogenic/promyogenic growth factors like PDGF and IGF-1.
After implanting into ischemic limbs, the O2 releasing cell delivery system not only augmented MSC survival, but
also fully restored blood perfusion and muscle contractility in 4 weeks. The contribution of MSCs to vascularization
is mainly from paracrine effects as only a low percentage of cells were differentiated into endothelial cells.
Meanwhile, both MSC paracrine effects and myogenic differentiation contributed to muscle regeneration. These
preliminary data suggest that increasing both MSC survival and paracrine effects can significantly enhance
vascularization and muscle regeneration in ischemic limbs. Yet, cell survival and paracrine effects do not always
increase concurrently.
 Based on our preliminary studies and above discussion, we hypothesize that stem cell delivery systems with
optimal O2 release profiles that simultaneously increase MSC survival and paracrine effects, will significantly
accelerate vascularization and muscle regeneration in ischemic limbs.
 Aim #1 will test the hypothesis that optimal O2 release profiles will promote MSC survival and paracrine effects
under ischemic conditions.
 Aim #2 will test efficacy of the created cell delivery systems using a mo...

## Key facts

- **NIH application ID:** 9984512
- **Project number:** 5R01HL138353-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jianjun Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,968
- **Award type:** 5
- **Project period:** 2018-08-22 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984512

## Citation

> US National Institutes of Health, RePORTER application 9984512, Stem cell oxygenation and ischemic tissue regeneration (5R01HL138353-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984512. Licensed CC0.

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