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  3. A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration

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

  • Cell Stem Cell. 2024 Sep 27:S1934-5909(24)00315-1. doi: 10.1016/j.stem.2024.09.001.
Xiaocui Wei 1,  Jingyang Qiu 2,  Ruijun Lai 3,  Tiantian Wei 2,  Zhijie Lin 2,  Shijiang Huang 2,  Yuanjun Jiang 2,  Zhanpeng Kuang 4,  Hao Zeng 2,  Yan Gong 2,  Xiaoling Xie 2,  Jun Yang 2,  Yue Zhang 2,  Sheng Zhang 2,  Zhipeng Zou 2,  Xuefei Gao 5,  Xiaochun Bai 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
  • 4 Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 5 Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, Guangdong, China. Electronic address: xgao2019@smu.edu.cn.
  • 6 State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China. Electronic address: baixc15@smu.edu.cn.
PMID: 39353427 DOI: 10.1016/j.stem.2024.09.001
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.

Keywords

cartilage regeneration; drug screening; human expanded pluripotent stem cells; hypertrophic cartilaginous organoid; secretory leukocyte protease inhibitor; α-adrenergic receptor.

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