الفهرس 
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Abstract
Diabetes mellitus (DM) is a major public health problem worldwide. The standard treatment of type1DM is by providing exogenous insulin therapy several times daily via injection or pump. Recently regenerative therapy via transplantation of mesenchymal stem cells (MSCs) provides an effective strategy to protect against tissue injury. Many factors act as obstacles to the best regenerative results by MSCs implantation as increasing apoptotic and oxidative processes due to hyperglycemic state during the period of treatment, Hence, we studied combination therapy with MSCs to overcome these obstacles. Previous studies discussed the effects of insulin, resveratrol and MSCs on diabetes separately or dual therapy only. The aim of work: -This study aimed to study the effects of MSCs transplantation on the pancreas of diabetic rats (type 1) as a separate treatment and in combination treatment with resveratrol and insulin. Material and methods: -This study was conducted on sixty-two male albino rats. Ten rats were used for obtaining AD-MSCs from the rat’s inguinal pad of fat. The fifty-two rats were divided into two major groups. group I (16 rats) represented the control groups. group II (36 rats) represented the diabetic group. These rats were injected with a Streptozotocin for induction of diabetes. This group was further subdivided into six subgroups (6 rats for each). GIIa was an untreated diabetic group that did not receive any treatment. GIIb was a diabetic group that received long-acting insulin analog once daily, GIIc was a diabetic group that received resveratrol l5-10 mg/kg body weight dissolved in saline solution, GIId was a diabetic group that received AD-MSCs alone they received 1x10⁶ of cultured rat ADMSCs via tail vein. GIIe was a diabetic group that received AD-MSCs and resveratrol in a combination, and GIIf was a diabetic group that received AD-MSCs, resveratrol, and insulin in triple combination treatment. All rats were sacrificed after four weeks after measuring fasting blood glucose level by glucometer. The pancreas was subjected to light and electron microscopic examination. Immune histo-chemical staining for PCNA and caspase-3 were performed as well. The morphometric examinations were used for measuring the diameter of the islets, Area % of collagen fibers in Masson’s trichrome stained sections, and area % of PCNA and caspas-3 immunoreactivity. Statistical analysis for morphometric results and the level of fasting blood glucose (FBG) was done. Results: -Under light and electron microscopic examinations, the sections of the control rats showed closely packed lobules of normal pancreatic acini surrounding well-packed endocrine islets of Langerhans. The islets consist of clusters of large beta cells that were centrally placed and appeared with a rounded regular euchromatic nucleus with a prominent nucleolus and numerous cytoplasmic secretory granules having a condensed cores surrounded by a large halo. Its mitochondria, and Golgi apparatus appear regular. Normal Alpha cells lie peripherally containing homogeneous electron-dense granules with no or very narrow surrounding hallo. The cells were separated by blood capillaries. The acini are formed of pyramidal cells with basal nuclei and apical acidophilic cytoplasm. The Untreated Diabetic group (GIIa) showed shrunken islets of Langerhans that lost their normal architecture with distortion of its outline and many lytic vacuoles appeared. In the ultrastructural sections distorted β cells appeared with irregular pyknotic nuclei and rarified vacuolated cytoplasm. There was a decrease and degeneration of its secretory granules, swollen degenerated mitochondria, and dilated cisternae of Golgi apparatus. Insulin treated Diabetic group (group IIb) showed slight improvement in comparison with group (GIIa). Few cells appeared regenerated with normal polygonal appearance but still, islets of Langerhans appeared shrunk with many degenerated cells that appeared with a dark pyknotic nuclei with vacuolated cytoplasm. Some distorted mitochondria and dilated cisternae of Golgi apparatus appeared. The light and electron microscopic examinations results of Resveratrol treated Diabetic group (group IIc) resembles that of insulin treated group. The islets of Langerhans appeared distorted with irregular outlines and degenerative changes appeared as lytic vacuoles and rarefied areas between cells. In the ultrastructural sections some cells showed dark pyknotic nuclei and others appeared as normal polygonal cells. H & E sections of AD-MSCs treated Diabetic group (GIId) showed improvement in the architecture of the islets of Langerhans with intact boundaries except for the presence of a few vacuoles between the cells of the islets. Beta cells appeared nearly normal, pale polygonal cells, Alpha cells appeared with dense nuclei and acidophilic cytoplasm at the periphery. Scanty cells appeared with pyknotic nuclei and vacuolated cytoplasm. In the ultrastructural sections, cells appeared with a nearly normal nucleus. And the secretory granules are numerous. Few vacuoles and dilated cisterns of the rough endoplasmic reticulum could be seen, others restored their regular appearance. H & E sections of MSCs +Res.- treated Diabetic group (group IIe) showed marked improvement in the morphological appearance when compared with the previous groups. The islets of Langerhans appeared with adequate size and regular outlines there were no vacuolation. The islet cells were arranged in well-packed cords. In the ultrastructural sections the β cell appeared with a normal nucleus and the secretory granules were numerous. normal lamellar mitochondria and Golgi apparatus could be seen. The pancreatic sections of MSCs+ Res. +insulin treated group (GIIf) showed the same observations in the group (GIIe) by the light and electron microscopic examinations with more increase in size and cellular density. The Masson’s trichrome stained sections of untreated Diabetic group showed increased deposition of irregularly arranged collagen fibers inside the islet of Langerhans and between acini, around pancreatic ducts, and blood vessels. While Insulin and resveratrol treated groups showed moderate collagen fibers deposition. AD-MSCs showed mild collagen fibers deposition. (MSCs+ Res.) and (MSCs +Res. + insulin) treated Diabetic showed fine collagen fibers deposition. Immune histo-chemical stained sections for PCNA showed weak positive reaction in control group and untreated diabetic groups. Resveratrol and insulin treated groups showed mild immune reactivity while AD-MSCs treated groups showed a moderate positive immune reaction. In (MSCs+ Res.) and (MSCs +Res. + insulin) treated Groups there were marked positive PCNA immune reactivity. Immune histo-chemical stained sections for caspas-3 showed marked positive reaction in untreated diabetic groups. Resveratrol and insulin treated groups showed moderate immune reactivity while AD-MSCs treated groups showed a mild positive immune reaction. In (MSCs+ Res.) and (MSCs +Res. + insulin) treated Diabetic Groups there were scanty positive PCNA immune reactivity. The morphometric and statistical results illustrated that the mean diameter of the islet in AD-MSCs treated group (GIId) showed a significant increase when compared with GIIa, GIIb, and GIIc. While AD-MSCs+ Res. Treated group showed a significant increase (P< 0.05) when compared with GIIa, GIIb, GIIc, and GIId. And a significant decrease (P< 0.05) when compared with GIIf. (AD-MSCs+ Res.+ insulin) treated group had a non-significant change compared with the control group. Mean area % of collagen deposition of Mason’s trichrome and Mean Area % of caspase-3 immune reactivity: The AD-MSCs treated group showed a significant decrease when compared with GIIa, GIIb and GIIc and a significant increase (P< 0.05) when compared with the control, GIIe, and GIIf groups. While in (AD-MSCs+ Res.) treated group showed a significant decrease when compared with GIIa, GIIb, GIIc, and GIId and a significant increase (P< 0.05) when compared with the control and GIIf groups. The (AD-MSCs + Res.+ insulin) group has non-significant change compared with the control group. Mean Area % of PCNA immune reactivity: There is significant increase in AD-MSCs treated groups and significant decrease in non MSC- treated groups when compared to control groups. Mean values of FBG mg/dl: There is significant decrease in the AD-MSCs treated groups when compared with untreated diabetic groups. GIIf group has non-significant change when compared with the control group.