PDF(Pubmed)
Abstract：
Osteoarthritis (OA) affects multiple tissues in the knee joint, including the synovium and intra-articular adipose tissue (IAAT) that are attached to each other. However, whether these two tissues share the same progenitor cells and hence function as a single unit in joint homeostasis and diseases is largely unknown. Single-cell transcriptomic profiling of synovium and infrapatellar fat pad (IFP), the largest IAAT, from control and OA mice revealed five mesenchymal clusters and predicted mesenchymal progenitor cells (MPCs) as the common progenitors for other cells: synovial lining fibroblasts (SLFs), myofibroblasts (MFs), and preadipocytes 1 and 2. Histologic examination of joints in reporter mice having Dpp4-CreER and Prg4-CreER that label MPCs and SLFs, respectively, demonstrated that Dpp4+ MPCs reside in the synovial sublining layer and give rise to Prg4+ SLFs and Perilipin+ adipocytes during growth and OA progression. After OA injury, both MPCs and SLFs gave rise to MFs, which remained in the thickened synovium at later stages of OA. In culture, Dpp4+ MPCs possessed mesenchymal progenitor properties, such as proliferation and multilineage differentiation. In contrast, Prg4+ SLFs did not contribute to adipocytes in IFP and Prg4+ cells barely grew in vitro. Taken together, we demonstrate that the synovium and joint fat pad are one integrated functional tissue sharing common mesenchymal progenitors and undergoing coordinated changes during OA progression.
Both synovium and intra-articular adipose tissue (IAAT) in knee joint play a critical role in joint health and osteoarthritis (OA) progression. Recent single-cell RNA-sequencing studies have been performed on the mouse and human synovium. However, IAATs residing in close proximity to the synovium have not been studied yet. Our study reveals mesenchymal cell heterogeneity of synovium/infrapatellar fat pad (Syn/IFP) tissue and their OA responses. We identify Dpp4+ multipotent progenitors as a source that give rise to Prg4+ lining layer fibroblasts in the synovium, adipocytes in the IFP, and myofibroblasts in the OA Syn/IFP tissue. Our work demonstrates that Syn/IFP is a functionally connected tissue that shares common mesenchymal progenitors and undergoes coordinated OA changes. This novel insight advances our knowledge of previously understudied joint tissues and provides new directions for drug discovery to treat joint disorders.
Both synovium and intra-articular adipose tissue (IAAT) in knee joint play a critical role in joint health and osteoarthritis (OA) progression. Recent single-cell RNA-sequencing studies have been performed on the mouse and human synovium. However, IAATs residing in close proximity to the synovium have not been studied yet. Our study reveals mesenchymal cell heterogeneity of synovium/infrapatellar fat pad (Syn/IFP) tissue and their OA responses. We identify Dpp4+ multipotent progenitors as a source that give rise to Prg4+ lining layer fibroblasts in the synovium, adipocytes in the IFP, and myofibroblasts in the OA Syn/IFP tissue. Our work demonstrates that Syn/IFP is a functionally connected tissue that shares common mesenchymal progenitors and undergoes coordinated OA changes. This novel insight advances our knowledge of previously understudied joint tissues and provides new directions for drug discovery to treat joint disorders.
摘要：
骨关节炎（OA）影响膝关节的多个组织，包括彼此附着的滑膜和关节内脂肪组织(IAAT)。然而,这两种组织是否共享相同的祖细胞，因此在关节内稳态和疾病中作为一个单元起作用，在很大程度上是未知的。滑膜和髌下脂肪垫（IFP）的单细胞转录组学分析，最大的IAAT,来自对照和OA小鼠的显示五个间充质簇和预测的间充质祖细胞（MPCs）作为其他细胞的常见祖细胞：滑膜内衬成纤维细胞（SLFs），肌成纤维细胞（MFs），和前脂肪细胞1和2。具有标记MPC和SLF的Dpp4-CreER和Prg4-CreER的报告小鼠的关节的组织学检查，分别,证明Dpp4MPCs位于滑膜亚衬层中，并在生长和OA进展期间产生Prg4SLF和Perilipin脂肪细胞。OA损伤后,MPC和SLF都产生了MF，在OA的后期保留在增厚的滑膜中。在文化中,Dpp4+MPCs具有间充质祖细胞特性，如增殖和多谱系分化。相比之下,Prg4+SLF对IFP中的脂肪细胞没有贡献,并且Prg4+细胞在体外几乎不生长。一起来看,我们证明滑膜和关节脂肪垫是一个整合的功能组织，共享共同的间充质祖细胞，并在OA进展过程中发生协调变化。
膝关节中的滑膜和关节内脂肪组织(IAAT)在关节健康和骨关节炎(OA)进展中起关键作用。最近的单细胞RNA测序研究已经在小鼠和人类滑膜上进行。然而,尚未研究靠近滑膜的IAAT。我们的研究揭示了滑膜/髌下脂肪垫（Syn/IFP）组织的间充质细胞异质性及其OA反应。我们确定Dpp4+多能祖细胞是滑膜中产生Prg4+衬里层成纤维细胞的来源，IFP中的脂肪细胞，和OASyn/IFP组织中的肌成纤维细胞。我们的工作表明，Syn/IFP是一种功能连接的组织，共享共同的间充质祖细胞并经历协调的OA变化。这种新颖的见解增进了我们对先前未被研究的关节组织的了解，并为治疗关节疾病的药物发现提供了新的方向。
膝关节中的滑膜和关节内脂肪组织(IAAT)在关节健康和骨关节炎(OA)进展中起关键作用。最近的单细胞RNA测序研究已经在小鼠和人类滑膜上进行。然而,尚未研究靠近滑膜的IAAT。我们的研究揭示了滑膜/髌下脂肪垫（Syn/IFP）组织的间充质细胞异质性及其OA反应。我们确定Dpp4+多能祖细胞是滑膜中产生Prg4+衬里层成纤维细胞的来源，IFP中的脂肪细胞，和OASyn/IFP组织中的肌成纤维细胞。我们的工作表明，Syn/IFP是一种功能连接的组织，共享共同的间充质祖细胞并经历协调的OA变化。这种新颖的见解增进了我们对先前未被研究的关节组织的了解，并为治疗关节疾病的药物发现提供了新的方向。
