introduction
Cartilage tissue is composed of a single chondrocyte with a lack of vascular nerve distribution, and at the same time, chondrocytes have poor proliferative ability, which is extremely difficult to repair once damaged. Autologous chondrocyte transplantation is an ideal cell source for the treatment of cartilage defects, but the source of donor cells is limited, and it is easy to dedifferentiate during in vitro expansion and culture, and the expression of type II collagen (COL2A1), the main component of hyaline cartilage, is lost. Pluripotent stem cells or adult stem cells can regenerate cartilage through appropriate induction, but it is difficult to completely eliminate heterogeneous cells in the existing differentiation and expansion process, and it is easy to produce hypertrophic degeneration tendency, and the expression of X-type collagen (COL10A1) increases. Obtaining and maintaining the phenotype of chondrocytes is key to cartilage regenerative medicine research.
2024年9月30日，南方医科大学白晓春、高学飞研究组在Cell Stem Cell 上发表标题为A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration的研究论文，报道了通过构建人软骨类器官高通量筛选系统，发现靶向α2肾上腺素受体（α-AR）促进软骨分化并抑制软骨肥大的研究。 α2-AR抑制剂酚妥拉明（Phentolamine）是一种FDA批准的上市药物，能在体外抑制人软骨类器官及人软骨外植体的退变，并在体内促进内源性干细胞原位再生为透明软骨，避免了纤维软骨形成的命运。
In this study, cartilage organoids containing COL2A1mCherry and COL10A1eGFP dual fluorescent reporter genes were constructed based on human expanded potential stem cells (hEPSC). This organoid can monitor cartilage formation and hypertrophy in vitro in real time and has a similar hierarchical structure to human cartilage. Through high-throughput screening of more than 2,000 FDA-approved drug libraries, it was revealed that α-AR inhibitor phentolamine can induce chondrogenic formation and inhibit hypertrophy, while α2-AR agonists inhibit cartilage formation and stimulate hypertrophy. Mechanistic analysis revealed that the α2-AR signaling pathway produced secreted leukocyte protease inhibitors (SLPIs) through cGMP-dependent pathways, thereby inducing hypertrophic degeneration. In vivo studies have found that phentolamine can promote the regeneration of endogenous stem cells activated after cartilage defects and microfractures modeling in mice and small pigs to hyaline cartilage, avoiding fibrocartilage. In vivo transplantation of SLPI-knocked out cartilage organoids can maintain the hyaline cartilage phenotype and promote the repair of articular cartilage defects.
In summary, this work suggests that targeting α2-AR or SLPI is an effective strategy for cartilage regeneration. Phentolamine, a α-AR inhibitor, is a promising and clinically translatable treatment for cartilage injury.
模式图（Credit: Cell Stem Cell）
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https://doi.org/10.1016/j.stem.2024.09.001
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