Abstract
Objective: To examine the effect of neurosteroids on human multipotent mesenchymal stromal cell (hMSCs) neuroglial differentiation. Materials and methods: Human MSCs were isolated and expanded in vitro. The expression of neurosteroid receptors by hMSCs was examined using immunocytochemistry and the effect of neurosteroids on the proliferation and differentiation of hMSCs was investigated using immunocytochemistry and the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) survival assay. Results: Human MSCs express receptors for neurosteroids. Nestin expression is decreased by neurosteroids. Neurosteroids also exert differential effects depending on the gender of the hMSC donor; dihydrotestosterone (DHT) was responsible for maximal A2B5 expression in hMSCs from male donors whereas 17-β estradiol (E2) exerted the greatest effect on differentiation of ‘female’ hMSCs. Maximal effects of E2 and DHT were observed at a concentration of 100nM, progesterone (PROG) at 250nM. The neurosteroid-induced increase in oligodendroglial differentiation was abrogated by specific receptor antagonists for E2, PROG and DHT. High concentrations of neurosteroids were toxic for hMSCs, irrespective of gender. Conclusions: These results suggest a significant role for neurosteroid hormones in the differentiation of hMSCs and may have important implications for the development of MSC transplantation therapy for multiple sclerosis and in autoimmune diseases.
Highlights
Neurosteroids are those steroid hormones which, independent of their origin, are capable of modifying neural activities [1]
Since the discovery of de novo synthesis of dehydroepiandrosterone sulpate (DHEAS) from cholesterol in the brain tissue by Baulieu in 1981 [2], the direct synthesis of the majority of the steroid hormones such as pregnenalone, progesterone and sex steroids, estradiol, testosterone and dihydrotestosterone and the presence of key enzymes for steroid synthesis have been demonstrated in CNS tissue [3,4]
A number of authors have reported the presence of neurosteroid hormone receptors on oligodendrocytes (OLG)
Summary
Neurosteroids are those steroid hormones which, independent of their origin, are capable of modifying neural activities [1]. They can act through classical/genomic or rapid/non-genomic pathways within the CNS. A number of authors have reported the presence of neurosteroid hormone receptors on oligodendrocytes (OLG). These are the cells responsible for synthesising and maintaining myelin in the CNS, and they form, together with myelin, the principal target for immune damage in Multiple Sclerosis (MS), the commonest acquired disease causing neurological disability in young adults. Neurosteroids exert effects on neural stem cells [15]
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