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Cell stem cell

Cell stem cell

IF: 19.8
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A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration

Published:30 September 2024 DOI: 10.1016/j.stem.2024.09.001
Xiaocui Wei, Jingyang Qiu, Ruijun Lai, Tiantian Wei, Zhijie Lin, Shijiang Huang, Yuanjun Jiang, Zhanpeng Kuang, Hao Zeng, Yan Gong, Xiaoling Xie, Jun Yang, Yue Zhang, Sheng Zhang, Zhipeng Zou, Xuefei Gao, Xiaochun Bai

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 COL2A1mCherry and COL10A1eGFP 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.

Substances (38)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Phentolamine mesilate 65-28-1 C18H23N3O4S 420 suppliers $9.00-$2767.00
Phentolamine mesilate 65-28-1 C18H23N3O4S 420 suppliers $9.00-$2767.00
Phentolamine mesilate 65-28-1 C18H23N3O4S 420 suppliers $9.00-$2767.00
Phentolamine mesilate 65-28-1 C18H23N3O4S 420 suppliers $9.00-$2767.00
Phenylephrine 59-42-7 C9H13NO2 220 suppliers $23.30-$1654.38
Phenylephrine 59-42-7 C9H13NO2 220 suppliers $23.30-$1654.38
Phenylephrine 59-42-7 C9H13NO2 220 suppliers $23.30-$1654.38
Phenylephrine 59-42-7 C9H13NO2 220 suppliers $23.30-$1654.38
Yohimbine 146-48-5 C21H26N2O3 216 suppliers Inquiry
Yohimbine 146-48-5 C21H26N2O3 216 suppliers Inquiry

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