Mesenchymal Stem Cells Exposed to Persistently High Glucocorticoid Levels Develop Insulin-Resistance and Altered Lipolysis: A Promising In Vitro Model to Study Cushing’s Syndrome

Abstract

BackgroundIn Cushing’s syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, thus revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS.MethodsMSCs isolated from the abdominal skin of healthy subjects were treated thrice daily with GCs according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) versus persistently higher doses (Higher, Constant Exposure, HCE), aimed at mimicking either the physiological condition or CS, respectively. Subsequently, MSCs were stimulated with insulin and glucose thrice daily, resembling food uptake and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints over three days.ResultsLDE to GCs did not impair glucose uptake by MSCs, whereas HCE significantly decreased glucose uptake by MSCs only when prolonged. Persistent signs of IR occurred after 30 hours of HCE to GCs. Compared to LDE, MSCs experiencing HCE to GCs showed a downregulation of lipolysis-related genes in the acute period, followed by overexpression once IR was established.ConclusionsPreserving circadian GC rhythmicity is crucial to prevent the occurrence of metabolic alterations. Similar to mature adipocytes, MSCs suffer from IR and impaired lipolysis due to chronic GC excess: MSCs could represent a reliable model to track the mechanisms involved in GC-induced IR throughout cellular differentiation.

miRNAs, Mesenchymal Stromal Cells and Major Neoplastic and Inflammatory Skin Diseases: A Page Being Written: A Systematic Review

“…MSCs are multipotent cells residing in multiple tissues with the capacity for selfrenewal and differentiation into various cell types [9,10]. Our previous works confirmed that different pathologies, ranging from the dermatologic to the fibrotic ones [11][12][13][14][15][16][17][18][19][20], arise at the staminal level: MSCs show the same dysregulated pathological properties found in differentiated cells, opening up the hypothesis that the onset of the diseases could be backdated at the stem level.…”

STC2 Inhibits Hepatic Lipid Synthesis and Correlates with Intramuscular Fatty Acid Composition, Body Weight and Carcass Traits in Chickens

“…After stained for 1 h, they were washed three times with PBS and then photographed at 200× magnification. Intracellular Oil Red O was dissolved using 100% isopropyl alcohol for 5 min, and the content of lipid droplets was quantified spectrophotometrically by measuring the absorbance at 510 nm [38,39].…”

A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome

“…Scuteri et al [ 463 ], however, observed that incubating rat MSCs with rat islets was sufficient to differentiate the MSCs into PDX1-expressing and insulin-secreting cells, suggesting that factors secreted by islets (e.g., insulin) can affect the phenotype of the interacting MSCs. Although the direct effect of insulin as a single differentiation factor on MSCs has not yet been documented, insulin has been shown to increase glucose uptake and GLUT4 translocation in MSCs [ 464 ]. The ability of MSCs to adhere to the islets [ 463 ] and to home to the islets following transplantation, where it improves β-cell function, suggests a mutual interaction between the two cell types.…”