Institute for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
Department of Internal Medicine and Nutrition, Institute for Medicine, Gothenburg University, Gothenburg, Sweden.
Stem Cells. 2023 Jun 15;41(6):658-671. doi: 10.1093/stmcls/sxad031.
Articular cartilage has a limited capacity for self-repair and clinical approaches to cartilage regeneration are needed. The only such approach developed to date involves an expansion of primary autologous chondrocytes in culture, followed by their reimplantation into a cartilage defect. However, because of the formation of fibrocartilage instead of hyaline cartilage, the outcome is often not satisfactory. It happens due to the de-differentiation of chondrocytes during the expansion step. Indeed, articular chondrocytes are non-proliferative and require partial or complete dedifferentiation before actively proliferating. In recent years stem/progenitor cells in articular cartilage (artSPCs) have been described. These cells maintain their own population and renew articular cartilage in sexually mature mice. artSPCs can, theoretically, be superior to chondrocytes, for repairing damaged cartilage. Accordingly, here, we searched for conditions that allow rapid expansion of both artSPCs and chondrocytes with simultaneous preservation of their ability to form hyaline cartilage. Among the modulators of Wnt, Notch, and FGF signaling and of cell adhesion screened, only fibronectin and modulators of the Notch pathway promoted the rapid expansion of artSPCs. Surprisingly, both inhibition and activation of the pathway had this effect. However, only inhibition of Notch during expansion facilitated the chondrogenic potential of both artSPCs and primary chondrocytes, whereas activation of this pathway abrogated this potential entirely. This effect was the same for murine and human cells. Our present observations indicate that Notch signaling is the major regulator of the chondrogenic capacity of both artSPCs and chondrocytes during their expansion.
关节软骨自我修复能力有限，因此需要临床方法来促进软骨再生。迄今为止，唯一开发的此类方法涉及在培养中扩增原代自体软骨细胞，然后将其重新植入软骨缺损部位。然而，由于形成纤维软骨而不是透明软骨，因此结果通常并不令人满意。这是由于软骨细胞在扩增过程中去分化所致。事实上，关节软骨细胞是非增殖性的，在积极增殖之前需要部分或完全去分化。近年来，关节软骨中的干细胞/祖细胞（artSPCs）已被描述。这些细胞在性成熟的小鼠中维持自身群体并更新关节软骨。理论上，artSPCs 可以优于软骨细胞，用于修复受损的软骨。因此，在这里，我们寻找允许快速扩增 artSPCs 和软骨细胞同时保持形成透明软骨能力的条件。在筛选的 Wnt、Notch 和 FGF 信号传导和细胞黏附调节剂中，只有纤连蛋白和 Notch 途径调节剂促进了 artSPCs 的快速扩增。令人惊讶的是，该途径的抑制和激活都具有这种效果。然而，只有在扩增过程中抑制 Notch 才能促进 artSPCs 和原代软骨细胞的软骨形成潜力，而激活该途径则完全消除了这种潜力。这种效应对鼠和人细胞都是一样的。我们目前的观察结果表明，Notch 信号传导是扩增过程中 artSPCs 和软骨细胞软骨形成能力的主要调节因子。
