# Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells

> **NIH NIH R41** · WNT SCIENTIFIC, LLC · 2021 · $252,131

## Abstract

Abstract
Tendon and ligament injuries represent an acute healthcare burden in the United States, costing >$30 billion
annually. Tendon injuries frequently result in scar-like tissue with inferior physical properties - however no
regenerative therapy exists to date. Recently, we have identified and characterized perivascular (CD146+)
tendon stem/progenitor cells (TSCs) that play an essential role in tendon healing via FAK and ERK1/2
signaling.
In our preliminary study, we screened small molecules from a library of FAK and ERK1/2 agonists and
identified Oxotremorine M (Oxo-M) and PPBP maleate (4-PPBP) that stimulated TSCs toward regenerative
tendon healing. Oxo-M and 4-PPBP were originally developed for treating neuronal diseases but have never
been tested in the musculoskeletal system. In vitro, a combination of Oxo-M and 4-PPBP induced significant
increases in the expression of tendon-related genes involved in tendon repair. Oxo-M and 4-PPBP showed
no cytotoxicity up to 10X working doses. Western blot and siRNA knockdown (KD) confirmed that FAK and
ERK1/2 signaling regulate Oxo -M & 4-PPBP-induced tenogenic differentiation of TSCs. In vivo, direct
topical delivery of Oxo-M and 4-PPBP onto full-transected rat patellar tendons (PT) significantly improved
tendon healing, as observed histologically as densely reorganized collagen fibrils, and functionally as
significantly enhanced tensile strength. This process was guided by a rapid but transient increase in the
number endogenous TSCs undergoing tenogenic differentiation. In addition, Oxo-M and 4-PPBP specifically
targeted CD146+ TSCs through muscarinic acetylcholine receptors (AChRs) and σ1 receptor (σ1R)
pathways, with minimal effect on other types of tendon cells. These findings demonstrate a novel and
promising activity of the combination of Oxo-M and 4-PPBP in tendon healing by specifically targeting
endogenous TSCs.
The overall objectives of this STTR grant are to develop a reliable and effective small molecule-based
regenerative therapy for tendon injuries by transiently activating regenerative pathways of endogenous
TSCs and repair tendon tears. The overarching goal of the STTR phase I grant is to optimize the
combination of Oxo-M and 4-PPBP, the 2 compounds and determine their drugability in combination. The 2
aims of the phase I STTR are to obtain robust proof-of-concept and preliminary safety data to establish
technical merit, feasibility, and commercial potential of the innovative technology.

## Key facts

- **NIH application ID:** 10258102
- **Project number:** 1R41AR079360-01
- **Recipient organization:** WNT SCIENTIFIC, LLC
- **Principal Investigator:** Mo Chen
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $252,131
- **Award type:** 1
- **Project period:** 2021-09-05 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258102

## Citation

> US National Institutes of Health, RePORTER application 10258102, Small Molecules Promote Tendon Regeneration by Targeting Endogenous Stem Cells (1R41AR079360-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10258102. Licensed CC0.

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