Small molecules promote tendon regeneration by targeting endogenous stem cells
Ended Project Grant Awarded Last action
- Award ID
- R41AR079360
- Recipient
-
WNT Scientific LLC UEI CZVHJRF9T6H3
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $756,393
Award facts
- Assistance listing
- 93.846 Arthritis, Musculoskeletal and Skin Diseases Research
- Completion date
- Funding
-
- $504,262.00 Federal
- $252,131.00 Non-federal
- Place of performance
- New York, USA
Award details come from USAspending.gov.
Description
- 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 S1 receptor (S1R) 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.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $0 | $0 | |
| Amendment | $252,131 | $0 | |
| Original award | $252,131 | $252,131 |
Quick answers
Who received award R41AR079360?
R41AR079360 was awarded to WNT Scientific LLC by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on September 5, 2021.
How much is award R41AR079360 worth?
$756,393 has been obligated on R41AR079360: $504,262 in federal funding and $252,131 in non-federal funding.
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