KLF4 (Kruppel-Like Factor 4)-Dependent Perivascular Plasticity Contributes to Adipose Tissue inflammation.
KLF4 (Kruppel-Like Factor 4)-Dependent Perivascular Plasticity Contributes to Adipose Tissue inflammation.
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DOI：
10.1161/atvbaha.120.314703
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Owens GK
中科院分区：
文献类型：
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作者：
Bulut GB;Alencar GF;Owsiany KM;Nguyen AT;Karnewar S;Haskins RM;Waller LK;Cherepanova OA;Deaton RA;Shankman LS;Keller SR;Owens GK
平滑肌细胞和周细胞（SMC-P）在损伤和疾病进展过程中显示出显著的可塑性。在这里，我们测试了血管周围细胞产生Klf 4依赖性巨噬细胞（MIF 4）样细胞的假设，这些细胞增加了与饮食诱导的肥胖症（DIO）相关的脂肪组织炎症和代谢功能障碍。使用Myh 11-CreERT 2 eYFP小鼠和附睾脂肪组织的间质血管部分（SVF）的流式细胞术，我们观察到大部分SMC-P谱系示踪的eYFP+细胞表达M β标记物。然而，随后的单细胞RNA测序显示，这些细胞中的大多数没有可检测到的eYFP转录物。进一步的探索显示，在数千项先前的研究中用于产生条件性敲除或报告小鼠的花生油中的他莫昔芬的腹膜内注射导致附睾脂肪组织内的M β的自发荧光和错误鉴定为eYFP+的大量增加;以及意外的促炎后果。使用新产生的Myh 11-DreERT 2 tdTomato小鼠口服他莫昔芬，我们几乎消除了自发荧光的问题，并确定了8个血管周围细胞为主的簇，其中一半在DIO后发生了改变。鉴于血管周围细胞KLF 4可能具有有益或有害的作用，我们测试了其在肥胖相关脂肪组织炎症中的作用。虽然SMC-P特异性Klf 4敲除（SMC-P Klf 4 Δ/Δ）小鼠未受到DIO的保护，但它们在DIO后显示出葡萄糖耐量改善，并显示出附睾脂肪组织中促炎性M β细胞的显著减少和LYVE 1+淋巴内皮细胞的增加。脂肪组织微血管内的血管周细胞动态响应DIO，并以KLF 4依赖性方式调节组织炎症和代谢。
Smooth muscle cells and pericytes (SMC-P) display remarkable plasticity during injury and disease progression. Here, we tested the hypothesis that perivascular cells give rise to Klf4-dependent macrophage (MФ)-like cells that augment adipose tissue inflammation and metabolic dysfunction associated with diet-induced obesity (DIO). Using Myh11-CreERT2eYFP mice and flow cytometry of the stromovascular fraction (SVF) of epididymal adipose tissue we observed a large fraction of SMC-P lineage traced eYFP+ cells expressing MФ markers. Subsequent single cell RNA sequencing, however, showed that the majority of these cells had no detectable eYFP transcript. Further exploration revealed that intraperitoneal injection of tamoxifen in peanut oil, used for generating conditional knockout or reporter mice in thousands of previous studies, resulted in large increase in the autofluorescence and false identification of MФs within epididymal adipose tissue as being eYFP+; and unintended pro-inflammatory consequences. Using newly generated Myh11-DreERT2tdTomato mice given oral tamoxifen we virtually eliminated the problem with autofluorescence and identified eight perivascular cell dominated clusters, half of which were altered upon DIO. Given that perivascular cell KLF4 can have beneficial or detrimental effects, we tested its role in obesity associated adipose tissue inflammation. While SMC-P-specific Klf4 knockout (SMC-P Klf4Δ/Δ) mice were not protected from DIO, they displayed improved glucose tolerance upon DIO, and showed marked decreases in pro-inflammatory MФs and increases in LYVE1+ lymphatic endothelial cells in the epididymal adipose tissue. Perivascular cells within the adipose tissue microvasculature dynamically respond to DIO and modulate tissue inflammation and metabolism in a KLF4-dependent manner.