Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, 310000, Zhejiang Province, People's Republic of China.
Orthopedic Research Institute of Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
Stem Cell Res Ther. 2022 Mar 25;13(1):127. doi: 10.1186/s13287-022-02758-7.
Osteoarthritis (OA) is a debilitating disease that inflicts intractable pain, a major problem that humanity faces, especially in aging populations. Stem cells have been used in the treatment of many chronic diseases, including OA. Cartilage progenitor/stem cells (CPSCs) are a type of stem cells with the ability to self- renew and differentiate. They hold a promising future for the understanding of the progression of OA and for its treatment. Previous studies have reported the relationship between mitochondrial dynamics and mesenchymal stem cell (MSC) proliferation, differentiation and aging. Mitochondrial dynamic and morphology change during stem cell differentiation.
This study was performed to access the relationship between mitochondrial dynamics and chondrogenic differentiation of CPSCs. Mitochondrial fusion and fission levels were measured during the chondrogenic differentiation process of CPSCs. After that, we used mitochondrial fusion promoter to induce fusion in CPSCs and then the chondrogenic markers were measured. Transmission electron microscopy (TEM) and confocal microscopy were used to capture the mass and fusion status of mitochondria. Lentiviruses were used to detect the role of mitofusin 2 (Mfn2) in CPSC chondrogenic differentiation. In vivo, Mfn2 was over-expressed in sheets of rat CPSCs, which were then injected intra-articularly into the knees of rats.
Mitochondrial fusion markers were upregulated during the chondrogenic induction process of CPSCs. The mass of mitochondria was higher in differentiated CPSC, and the fusion status was obvious relative to un-differentiated CPSC. Chondrogenesis of CPSCs was upregulated with the induction by mitochondrial fusion promoter. Mfn2 over-expression significantly increased chondrocyte-specific gene expression and reversed OA through NOTCH2 signal pathway.
Our study demonstrated that the mitochondrial fusion promotes chondrogenesis differentiation of CPSCs. Mfn2 accelerates the chondrogenesis differentiation of CPSCs through Notch2. In vivo, Mfn2-OE in sheets of rCPSCs ameliorated OA in the rat model.
骨关节炎（OA）是一种使人虚弱的疾病，会造成难以忍受的疼痛，这是人类面临的一个主要问题，尤其是在老龄化人口中。干细胞已被用于治疗许多慢性疾病，包括 OA。软骨祖细胞/干细胞（CPSCs）是一种具有自我更新和分化能力的干细胞。它们为理解 OA 的进展和治疗提供了广阔的前景。先前的研究报告了线粒体动力学与间充质干细胞（MSC）增殖、分化和衰老之间的关系。线粒体动力学和形态在干细胞分化过程中发生变化。
本研究旨在探讨线粒体动力学与 CPSCs 软骨分化的关系。在 CPSCs 的软骨分化过程中测量线粒体融合和裂变水平。然后，我们使用线粒体融合促进剂诱导 CPSCs 融合，然后测量软骨形成标志物。透射电子显微镜（TEM）和共聚焦显微镜用于捕获线粒体的质量和融合状态。慢病毒用于检测线粒体融合蛋白 2（Mfn2）在 CPSC 软骨分化中的作用。在体内，过表达 Mfn2 大鼠 CPSCs 薄片，然后将其关节内注射到大鼠膝关节中。
在 CPSCs 的软骨诱导过程中，线粒体融合标志物上调。分化的 CPSC 中线粒体的质量更高，与未分化的 CPSC 相比融合状态更为明显。线粒体融合诱导剂可上调 CPSCs 的软骨形成。Mfn2 过表达显著增加软骨细胞特异性基因表达，并通过 NOTCH2 信号通路逆转 OA。
本研究表明，线粒体融合促进 CPSCs 的软骨分化。Mfn2 通过 Notch2 加速 CPSCs 的软骨分化。在体内，rCPSCs 薄片中的 Mfn2-OE 改善了大鼠模型中的 OA。
