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

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

PROVIDER: PRJNA1133672 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27030630_1.fastq.gz	Fastqsanger.gz
	SRR27030630_2.fastq.gz	Fastqsanger.gz
	SRR27030631_1.fastq.gz	Fastqsanger.gz
	SRR27030631_2.fastq.gz	Fastqsanger.gz
	SRR27030632_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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