AI Article Synopsis
- This study focuses on improving cartilage regeneration using stem cells by addressing issues like off-target differentiation and hypertrophic tendencies.
- Researchers created a system to monitor chondrogenesis and hypertrophy in real-time using stem cells with specific genetic markers and tested over 2,000 FDA-approved drugs.
- They discovered that the drug phentolamine promoted cartilage growth and avoided degeneration, suggesting the α2-AR/SLPI pathway as a potential target for effective cartilage regeneration.
Article Abstract
Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1 and COL10A1 double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.
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| http://dx.doi.org/10.1016/j.stem.2024.09.001 | DOI Listing |
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