Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China.
Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong, People's Republic of China.
Stem Cell Res Ther. 2019 Nov 28;10(1):355. doi: 10.1186/s13287-019-1459-7.
White adipose tissue includes subcutaneous and visceral adipose tissue (SAT and VAT) with different metabolic features. SAT protects from metabolic disorders, while VAT promotes them. The proliferative and adipogenic potentials of adipose-derived stem cells (ADSCs) are critical for maintaining adipose tissue homeostasis through driving adipocyte hyperplasia and inhibiting pathological hypertrophy. However, it remains to be elucidated the critical molecules that regulate different potentials of subcutaneous and visceral ADSCs (S-ADSCs, V-ADSCs) and mediate distinct metabolic properties of SAT and VAT. CD90 is a glycosylphosphatidylinositol-anchored protein on various cells, which is also expressed on ADSCs. However, its expression patterns and differential regulation on S-ADSCs and V-ADSCs remain unclear.
S-ADSCs and V-ADSCs were detected for CD90 expression. Proliferation, colony formation, cell cycle, mitotic clonal expansion, and adipogenic differentiation were assayed in S-ADSCs, V-ADSCs, or CD90-silenced S-ADSCs. Glucose tolerance test and adipocyte hypertrophy were examined in mice after silencing of CD90 in SAT. CD90 expression and its association with CyclinD1 and Leptin were analyzed in adipose tissue from mice and humans. Regulation of AKT by CD90 was detected using a co-transfection system.
Compared with V-ADSCs, S-ADSCs expressed high level of CD90 and showed increases in proliferation, mitotic clonal expansion, and adipogenic differentiation, together with AKT activation and G1-S phase transition. CD90 silencing inhibited AKT activation and S phase entry, thereby curbing proliferation and mitotic clonal expansion of S-ADSCs. In vivo CD90 silencing in SAT inhibited S-ADSC proliferation, which caused adipocyte hypertrophy and glucose intolerance in mice. Furthermore, CD90 was highly expressed in SAT rather than in VAT in human and mouse, which had positive correlation with CyclinD1 but negative correlation with Leptin. CD90 promoted AKT activation through recruiting its pleckstrin homology domain to plasma membrane.
CD90 is differentially expressed on S-ADSCs and V-ADSCs, and plays critical roles in ADSC proliferation, mitotic clonal expansion, and hemostasis of adipose tissue and metabolism. These findings identify CD90 as a crucial modulator of S-ADSCs and V-ADSCs to mediate distinct metabolic features of SAT and VAT, thus proposing CD90 as a valuable biomarker or target for evaluating ADSC potentials, monitoring or treating obesity-associated metabolic disorders.
白色脂肪组织包括皮下脂肪组织和内脏脂肪组织（SAT 和 VAT），它们具有不同的代谢特征。SAT 可预防代谢紊乱，而 VAT 则会促进代谢紊乱。脂肪来源干细胞（ADSCs）的增殖和成脂潜能对于通过驱动脂肪细胞增生和抑制病理性肥大来维持脂肪组织的稳态至关重要。然而，调节皮下和内脏 ADSC（S-ADSCs、V-ADSCs）不同潜能的关键分子，以及介导 SAT 和 VAT 不同代谢特性的关键分子仍有待阐明。CD90 是一种在各种细胞上表达的糖基磷脂酰肌醇锚定蛋白，也在 ADSCs 上表达。然而，其在 S-ADSCs 和 V-ADSCs 上的表达模式及其差异调节尚不清楚。
检测 S-ADSCs 和 V-ADSCs 上 CD90 的表达。在 S-ADSCs、V-ADSCs 或沉默 CD90 的 S-ADSCs 中检测增殖、集落形成、细胞周期、有丝分裂克隆扩张和脂肪生成分化。在沉默 SAT 中的 CD90 后，在小鼠中进行葡萄糖耐量试验和脂肪细胞肥大检测。分析来自小鼠和人类的脂肪组织中 CD90 的表达及其与细胞周期蛋白 D1 和瘦素的关系。使用共转染系统检测 AKT 受 CD90 的调节。
与 V-ADSCs 相比，S-ADSCs 表达高水平的 CD90，并表现出增殖、有丝分裂克隆扩张和脂肪生成分化增加，同时伴有 AKT 激活和 G1-S 期转变。沉默 CD90 抑制 AKT 激活和 S 期进入，从而抑制 S-ADSCs 的增殖和有丝分裂克隆扩张。体内沉默 SAT 中的 CD90 可抑制 S-ADSC 的增殖，导致小鼠脂肪细胞肥大和葡萄糖耐量受损。此外，CD90 在人类和小鼠的 SAT 中高表达，而在 VAT 中低表达，与 CyclinD1 呈正相关，与 Leptin 呈负相关。CD90 通过将其 pleckstrin 同源结构域募集到质膜上来促进 AKT 激活。
CD90 在 S-ADSCs 和 V-ADSCs 上的表达存在差异，在 ADSC 增殖、有丝分裂克隆扩张和脂肪组织稳态及代谢中发挥关键作用。这些发现表明 CD90 是调节 S-ADSCs 和 V-ADSCs 的关键调节剂，介导 SAT 和 VAT 的不同代谢特征，从而提出 CD90 是评估 ADSC 潜能、监测或治疗肥胖相关代谢紊乱的有价值的生物标志物或靶标。
