In vitro-derived insulin-producing cells modulate Th1 immune responses and induce IL-10 in streptozotocin-induced mouse model of pancreatic insulitis.

BACKGROUND: Insulitis is defined by the presence of immune cells infiltrating in the pancreatic islets that might progress into the complete ß-cell loss. The immunomodulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have attracted much attention. This study aimed to evaluate the possible immunomodulatory effects of rat BM-MSCs and MSCs-derived insulin-producing cells (IPCs) in a mouse model of pancreatic insulitis. METHODS: Insulitis was induced in BALB/c mice using five consecutive doses of streptozotocin. MSCs or IPCs were directly injected into the pancreas of mice and their effects on the expression of Th subsets-related genes were evaluated. RESULTS: Both BM-MSCs and IPCs significantly reduced the expression of pancreatic Th1-related IFN-γ (P < 0.001 and P < 0.05, respectively) and T-bet genes (both P < 0.001). Moreover, the expression of IL-10 gene was significantly increased in IPC-treated compared to BM-MSC- or PBS-treated mice (P < 0.001 both comparisons). CONCLUSIONS: BM-MSCs and IPCs could successfully suppress pathologic Th1 immune responses in the mouse model of insulitis. However, the marked increase in IL-10 gene expression by IPCs compared to BM-MSCs suggests that their simultaneous use at the initial phase of autoimmune diabetes might be a better option to reduce inflammation but these results need to be verified by further experiments.

A pilot study of family-based management of behavioral excesses in young Iranian children with autism spectrum disorder.

OBJECTIVE: Parent-mediated early behavioral interventions are considered as effective approaches in the treatment of children with Autism Spectrum Disorder (ASD). The majority of these interventions focus on social-communication deficits rather than behavioral excesses which severely irrupt child and family social life as well as the child's appearance behavior and learning processes. The study examines the effectiveness and feasibility of Family-based Management of Behavioral Excesses of Autism Program (FMBEAP) on Iranian families. METHOD: This pre-post and follow-up intervention study involved 17 parents of children with DSM-5 diagnosis of ASD recruited from Tehran Autism Center. All parents conducted FMBEAP on their children while receiving 10-weekly group supervision on top of everyday on-line individual coaching. The study's measures were Repetitive Behavior Scale-R, video-monitoring of child-parent Interaction, Clinical Global Impression-Improvement Scale, Parental Self-Efficacy and Parenting Stress Index-short form. The measures were applied to the sample three times: pre and post-intervention and at one-month follow-up. RESULTS: The Results showed high and low order behavioral excesses significantly decreased at post-intervention and the follow-up. 15 out of 17 children reached to recovered or highly recovered at post-test. Parents showed significant improvements in self-efficacy and parenting stress scales. The intervention was highly accepted by them. CONCLUSION: FMBEAP is shown to be a feasible, acceptable and effective intervention to improve autistic behavioral. The parents should also benefit from the program in terms of self-efficacy and parenting stress. FMBEAP is highly recommended for overcoming behavioral excesses along with those interventions focus on behavioral deficits in ASD.

A simple method for the generation of insulin producing cells from bone marrow mesenchymal stem cells.

To produce insulin-producing cells (IPCs) from bone marrow mesenchymal stem cells (BM-MSCs) using a simple and cost effective method. During the initial 7 days of three-dimensional (3D) culture, BM-MSCs were cultured on 1% agar or agarose to form multicellular spheroids. Spheroids and spheroid-derived single cells (SS and SSC, respectively) were cultured in the absence of any proteinaceous growth factor in a simple specific medium for a further 7 d. The insulin content of the differentiated cells was evaluated at the mRNA and protein levels. Furthermore, the expression of pancreatic beta cells-related genes other than INS as well as the in vitro responses of IPCs to different glucose concentrations were investigated. Cellular clusters generated on agar and SS conditions (agar+SS-IPCs) stained better with beta cell specific stains and were more reactive to serum-containing insulin reactive antibodies compared with agarose-SS-IPCs. Gene expression analysis revealed that in comparison to agarose + SS-IPCs, agar+SS-IPCs expressed significantly higher levels of INS-1, INS-2, PDX-1, NKX6.1, and XBP-1. Of interest, agar+SS-IPCs expressed 2215.3 ± 120.8-fold more INS-1 gene compared to BM-MSCs. The expression of ß-cell associated genes was also higher in agar+SS-IPCs compared to the agar+SSC-IPCs. Moreover, the expression of INS-1 gene was significantly higher in agar+SS-IPCs compared with agar+SSC-IPCs after culture in media with high concentration of glucose. Compared to the most expensive and time-consuming protocols, 3D culture of MSCs on agar followed by 2D culture of cellular clusters in a minimally supplemented high glucose media produced highly potent IPCs which may pay the way to the treatment of diabetic patients.

Neurogenic and mitotic effects of dehydroepiandrosterone on neuronal-competent marrow mesenchymal stem cells.

To establish whether dehydroepiandrosterone (DHEA) as a neurosteroid could enhance the rate of neuronal differentiation in neuronal-competent bone marrow mesenchymal stem cells (BM-MSCs), we added DHEA before and after plating the neurosphere-like aggregates. Flow cytometric analysis of Tubulin-III and Tau positive cells revealed that the percentages of these cells were increased significantly for the two markers following DHEA treatment at both stages. Moreover, Western blot analysis revealed that Tubulin-III protein was strongly induced by DHEA. The expression of neuronal specific genes such as Isl-1, Tubulin III, Pax6 and Nestin was also detected by RT-PCR analysis as well as BrdU incorporation and found to have increased significantly after DHEA induction. In conclusion, these results provide evidence that DHEA can affect neuronal-competent MSCs in inducing the expression of a comprehensive set of genes and proteins that define neuronal cells. DHEA was also able to induce the division of neuronal-competent MSCs, thereby increasing the number of cells with major neuronal characteristics. To our knowledge, this is the first report which shows that DHEA can induce the division and differentiation of MSCs into neurons in vitro and should provide an improved basis for new treatments using MSCs of a wide variety of neurological diseases.