CD90 serves as differential modulator of subcutaneous and visceral adipose-derived stem cells by regulating AKT activation that influences adipose tissue and metabolic homeostasis

Abstract

BackgroundWhite 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.MethodsS-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.ResultsCompared 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.ConclusionsCD90 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.

Adipose Extracellular Vesicles: Messengers From and to Macrophages in Regulating Immunometabolic Homeostasis or Disorders

“…Therefore, ADSCs are currently recognized as promising therapeutic candidates for tissue repair and regeneration ( 7 , 8 ). The proliferation and adipogenesis of ADSCs are essential for the maintenance of metabolic homeostasis particularly in adipose tissue, as supported by our previous study showing distinct metabolic influences on WAT homeostasis by ADSCs from different anatomic locations ( 41 , 42 ). Notably, human or mouse ADSCs showed strong capacity for immunomodulation through actively participating in both innate and adaptive immunity, such as promoting macrophage polarization toward anti-inflammatory phenotypes or inducing regulatory T cell differentiation.…”

Adipose‐derived stromal cells for nonhealing wounds: Emerging opportunities and challenges

“…Additionally, V‐AD‐MSCs show a reduction of CD90, which could mediate metabolic disorder. S‐AD‐MSCs express a high level of CD90 and show an increase in proliferation, mitotic clonal expansion, and adipogenic differentiation, together with AKT activation and G1‐S phase transition, which may contribute to metabolic homeostasis via preventing adipocyte hypertrophy in SAT 159 …”

In Vitro Cultures of Adipose-Derived Stem Cells: An Overview of Methods, Molecular Analyses, and Clinical Applications

“…However, different functions of visceral and subcutaneous ASCs are thought to be regulated by the key protein CD90, often anchored to the glycosylphosphatidylinositol of cells playing a key role in proliferation, mitotic clonal expansion, and homeostasis of adipose tissue and metabolism. CD90 was differently expressed in visceral and subcutaneous ASCs and further analysis could lead to advances in the treatments of multiple metabolic disorders [47].…”