Li Jiaxuan, Tian Zhenyu, Zhang Tongxue, Jin Jiajia, Zhang Xinjie, Xie Panpan, Lin Haiyan, Gu Junfei, Wu Yingjie, Wang Xiaowei, Zhang Shucui, Yan Xuefang, Guo Dong, Wang Zhe, Zhang Qunye
Department of Cardiology, State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Hospital, Shandong Laboratory Animal Center, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, 250021, China.
Cell Mol Biol Lett. 2024 Dec 3;29(1):148. doi: 10.1186/s11658-024-00668-5.
Vasculopathy underlies diabetic complications, with perivascular adipose tissue (PVAT) playing crucial roles in its development. However, the changes in the cellular composition and function of PVAT, including the specific cell subsets and mechanisms implicated in type 2 diabetes mellitus (T2DM) vasculopathy, remain unclear.
To address the above issues, we performed single-cell RNA sequencing on the stromal vascular fraction (SVF) of PVAT from normal and T2DM rats. Then, various bioinformatics tools and functional experiments were used to investigate the characteristic changes in the cellular profile of diabetic PVAT SVF, their implications, and the underlying mechanisms.
Our study reveals the single-cell landscape of the SVF of PVAT, demonstrating its considerable heterogeneity and significant alterations in T2DM, including an enhanced inflammatory response and elevated proportions of macrophages and natural killer (NK) cells. Moreover, macrophages are critical hubs for cross-talk among various cell populations. Notably, we identified a decreased Pdpn macrophage subpopulation in the PVAT of T2DM rats and confirmed this in mice and humans. In vitro and in vivo studies demonstrated that Pdpn macrophages alleviated insulin resistance and modulated adipokine/cytokine expression in adipocytes via the Pla2g2d-DHA/EPA-GPR120 pathway. This subset also enhances the function of vascular endothelial and smooth muscle cells, inhibits vascular inflammation and oxidative stress, and improves vasodilatory function, thereby protecting blood vessels.
Pdpn macrophages exhibit significant vascular protective effects by alleviating insulin resistance and modulating adipokine/cytokine expression in PVAT adipocytes. This macrophage subtype may therefore play pivotal roles in mitigating vascular complications in T2DM. Our findings also underscore the critical role of immune-metabolic cross-talk in maintaining tissue homeostasis.
血管病变是糖尿病并发症的基础，血管周围脂肪组织（PVAT）在其发展过程中起关键作用。然而，PVAT的细胞组成和功能变化，包括参与2型糖尿病（T2DM）血管病变的特定细胞亚群和机制，仍不清楚。
为了解决上述问题，我们对正常和T2DM大鼠PVAT的基质血管部分（SVF）进行了单细胞RNA测序。然后，使用各种生物信息学工具和功能实验来研究糖尿病PVAT SVF细胞图谱的特征变化、其影响及潜在机制。
我们的研究揭示了PVAT的SVF单细胞图谱，证明了其相当大的异质性以及在T2DM中的显著改变，包括炎症反应增强以及巨噬细胞和自然杀伤（NK）细胞比例升高。此外，巨噬细胞是各种细胞群体之间相互作用的关键枢纽。值得注意的是，我们在T2DM大鼠的PVAT中鉴定出Pdpn巨噬细胞亚群减少，并在小鼠和人类中得到证实。体外和体内研究表明，Pdpn巨噬细胞通过Pla2g2d-DHA/EPA-GPR120途径减轻胰岛素抵抗并调节脂肪细胞中脂肪因子/细胞因子的表达。该亚群还增强血管内皮和平滑肌细胞的功能，抑制血管炎症和氧化应激，并改善血管舒张功能，从而保护血管。
Pdpn巨噬细胞通过减轻胰岛素抵抗和调节PVAT脂肪细胞中脂肪因子/细胞因子的表达，表现出显著的血管保护作用。因此，这种巨噬细胞亚型可能在减轻T2DM血管并发症中起关键作用。我们的研究结果还强调了免疫-代谢相互作用在维持组织稳态中的关键作用。
