A preliminary study of the use of human adipose tissue-derived stem cells for the treatment of streptozotocin-induced diabetes mellitus in a rat model (original) (raw)
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Egyptian Journal of Histology
Background: Diabetes Mellitus (D.M.) is a major health problem affecting more than 200 million worldwide. The ideal treatment for autoimmune type I diabetes is regeneration of endogenous β-cells which could be achieved by mesenchymal stem cells transplantation. Aim of the work: This work aimed to compare the effect of intravenous bone marrow derived mesenchymal stem cells (BMSCs) and adipose tissue derived mesenchymal stem cells (AMSCs) on Streptozotocin (STZ)-induced type I diabetes in albino rats. Material and Methods: Fifty albino male rats were divided into 4 groups; control, diabetic, BMSCs treated and AMSCs treated. Treated groups were intravenously given 1 ml PKH26 labeled allogenic BMSCs or AMSCs suspended in phosphate buffered saline, respectively. Animals of all groups were sacrificed 2 weeks after stem cells administration. Sections from control and treated groups were examined by fluorescence microscope. Sections from all groups were immunohistochemically stained to detect insulin and proliferating cell nuclear antigen (PCNA). Mean area percent of insulin and number of PCNA positive reactions were measured and statistically analyzed. Results: Diabetic rats showed cell death and congested blood vessels in both exocrine and endocrine pancreas. Treated groups revealed homing of stem cells in pancreas after their transplantation. Moreover, nearly normal histological features were seen in AMSCs treated group. Studying the treated groups immunohistochemically, revealed increase in insulin and PCNA positive reactions when compared to diabetic group with more increase in AMSCs treated group than BMSCs treated group. Conclusion: Intravenous AMSCs could be more effective than BMSCs in treatment of STZ-induced type I diabetes.
Al-Azhar Medical Journal, 2015
Background: Diabetes mellitus (DM) is one of the most recognizable endocrine metabolic disorders characterized by chronic hyperglycemia. Mesenchymal stem cells (MSCs) are promising tool to treat DM type I (DM 1). They can be isolated from many sources including adipose tissue because of its easy availability. Objective: Evaluation of the effect of adipose derived MSCs (ADMSCs) on streptozotocin (STZ)-induced DM in rats. Materials and Methods: Forty eight adult male albino rats were included and divided into 4 equal groups. Group I: control untreated, group II: diabetic group, group III: insulintreated group, and group IV: ADMSCs-treated group. After 21 days from treatment, animals were sacrificed and pancreas was obtained for histological assessments. Stem cell homing was detected by polymerase chain reaction for human specific Alu gene. Results: ADMSCs caused lowering of blood glucose levels starting at the 14th day of treatment and increased blood insulin levels accompanied by reversal of the histopathological changes that were found in the diabetic group and increase insulin secreting cells. Conclusion: ADMSCs improved blood glucose levels and reversed the histopathological changes of the pancreas in experimentally induced DM I.
Can Stem Cells Ameliorate the Pancreatic Damage Induced by Streptozotocin in Rats? ARTICLE IN PRESS
2018
Background: Stem cell therapy holds great promise for the repair of injured tissues and organs, and it is one of the most promising therapies for diabetes mellitus. Therefore, the present study was undertaken to elucidate the antidiabetic effect of both mesenchymal stem cells (MSCs) and insulin-producing cells (IPCs) on streptozotocin (STZ)–induced diabetes in rats. Materials and methods: MSCs were derived from bone marrow of male albino rats. MSCs were characterized morphologically and by Cluster of differentiation (CD-ve34) and (CD +ve105). They were then differentiated into IPCs, and both MSCs and IPCs were infused independently into tail veins of rats with STZ-induced diabetes. Results: MSC and IPC therapy significantly improved the body weight and serum insulin, alpha-amylase, adiponectin, creatinine, total cholesterol, triacylglycerol, interleukin-6, tumour necrosis factor-alpha, liver L-malonaldehyde and glycogen levels in the STZ-induced diabetes model. Conclusions: Bone marrow–derived MSCs have the capacity to differentiate into IPCs capable of controlling the blood glucose level in rats with STZ-induced diabetes. Furthermore, treatment with MSCs and IPCs can improve aberrant biochemical parameters in an STZ-induced diabetes model. Mots clés : diabète différenciation cellules souches mésenchymateuses thérapie par les cellules souches r é s u m é Introduction : Riche de promesses dans la réparation des tissus et des organes lésés, la thérapie par les cellules souches est l'une des thérapies les plus prometteuses dans le traitement du diabète sucré. Par conséquent, la présente étude était entreprise pour élucider les effets antidiabétiques des cellules souches mésenchymateuses (CSM) et des cellules productrices d'insuline (CPI) sur le diabète induit par la streptozotocine (STZ) chez les rats. Matériaux et méthodes : Les CSM ont été dérivés de la moelle osseuse de rats mâles albinos. Les CSM ont été caractérisées de manière morphologique et par groupe de différenciation (CD −ve34 et CD +ve105). Elles se sont ensuite différenciées en CPI, puis les CSM et les CPI ont été infusées de façon indépendante dans les veines de la queue des rats ayant un diabète induit par la STZ. Résultats : La thérapie par les CSM et les CPI a amélioré de manière significative le poids corporel et les concentrations sériques de l'insuline, de l'alpha-amylase, de l'adiponectine, de la créatinine, du cholestérol total, du triacylglycérol, de l'interleukine-6, du facteur de nécrose tumorale alpha, du L-malonaldéhyde hépatique et du glycogène dans le modèle de diabète induit par la STZ. Conclusions : Les CSM dérivées de la moelle osseuse ont la capacité de se différencier en CPI capables de maîtriser la concentration de la glycémie chez les rats ayant un diabète induit par la STZ. De plus, la thérapie par les CSM et les CPI peut améliorer les valeurs aberrantes des paramètres biochimiques dans un modèle de diabète induit par la STZ. j o u r n a l h o m e p a g e : w w w. c a n a d i a n j o u r n a l o f d i a b e t e s .
Effective Dose Regimen of Streptozotocin for Inducing Diabetes in a Rat Model
Iranian Journal of Veterinary Medicine, 2024
Background: Diabetes mellitus (DM) is a metabolic disorder characterized by an elevated blood sugar level due to problems with insulin synthesis, effect, or both. Various clinical signs follow DM: Hyperglycemia, polydipsia, polyuria, and polyphagia. Worldwide prevalence is high and predicted to be 592 million by 2035. Animal models are used in the study of diabetes due to ethical issues. Although the streptozotocin (STZ) model is frequently used, it is unreliable due to unexplained acute toxicity and effective dose variability. Objectives: This research was conducted to determine the effective dose regimen of STZ for inducing diabetes in Wister rats. Methods: A total of 28 male Wistar rats (160-190 g) were randomly divided into 4 groups (each 7 rats) and monitored for 21 days after diabetes induction with STZ: Control (CTR), diabetics (DIA)1 (60 mg/kg STZ), DIA2 (60 mg/kg STZ twice at 0 and 24 hours), and DIA3 (60 mg/ kg STZ thrice at 0, 24 and 48 hours). Plasma glucose was determined with a glucometer. Body weights, feed intake, and fecal output were weighed with a digital balance, while water intake and urine output were measured with a measuring cylinder. Analyses of data obtained were performed using a one-way ANOVA and Tukey's test at a significance level of P≤0.05. Results: There was a significant (P<0.05) decrease in body weight of the diabetic groups (-15.53%±1.2%,-26.8%±1.2%,-28.5%±1.9%) compared to the CTR (10.5%±2.5%). There was a significant (P<0.05) increase in fasting blood glucose concentrations (135.2±9.0, 273.2±6.5, 257.0±5.3 mg/dL) in the people with diabetes compared to the CTR (79.3±1.1 mg/dL). Water intake (56.9±0.9, 72.1±1.7, 77.8±5.5 mL), feed intake (19.4±0.6, 23.3±1.9, 42.1±2.1 g), voided urine (6.34±0.1, 8.39±0.88, 9.8±0.50 mL) and voided feces (10.4±0.26, 11.7±0.43, 8.5±0.17 g) in the diabetic groups increased significantly (P<0.05) compared to the CTR (26.5±0.8 mL, 13.4±0.3 g, 1.84±0.08 mL, and 6.5±0.33 g, respectively). Conclusion: The dose regimen of 60 mg/kg STZ administered intraperitoneally twice (24 hours apart) sustained diabetes for 21 days. We recommend adopting this dose regimen in STZ-induced diabetic studies in male Wistar rats.
Four-week induction of type 2 diabetes mellitus in rats by streptozotocin and high-fat diet
2021
Background: Current rodent models for diabetes mellitus type 2 could be divided into genetic-engineered and environmental-induced. Since genetic-modified rodents are difficult to acquire and costly for Thai researchers, we tried to develop a protocol for food-induced diabetic rats. Objectives: To develop a convenient and economical type 2 diabetic mellitus rats with a short course (4-week) of induction for research purpose. Methods: Eight-week-old male Wistar rats were divided into two groups: control group and streptozotocin with high-fat diet (STZ-HFD) group (n = 4 each). The control group received normal chow (c.p.082 diet with 20.0% energy from fat). For the STZ-HFD group, STZ (30 mg/kg) was intraperitoneal injected at week 0 of experiment with HFD feeding (58.0% energy from fat). Rats were fed ad libitum. Blood samples were collected for diabetic evaluation weekly for 4 weeks. Results: The body weight of the STZ-HFD group was significantly higher than that of the control group. Blood glucose, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index and HbA1C were increased in the STZ-HFD group. Moreover, STZ-HFD rats suffered with a non-alcoholic fatty liver disease. Conclusion: Low dose STZ injection (30 mg/kg) with HFD feeding (58.0% energy from fat) could be used to induced type 2 diabetes in rats within 4 weeks.
Mesenchymal Stem Cells Ameliorate Hyperglycemia in Type I Diabetic Developing Male Rats
Stem Cells International, 2022
One of the most promising treatments for diabetes mellitus (DM) is stem cell therapy. This study is aimed at elucidating the antidiabetic effect of mesenchymal stem cells (MSCs) on streptozotocin-(STZ-) induced DM in developing male rats. Twentyfour male albino rats (4 weeks old) were divided into control, diabetic, diabetic+MSCs1 (received MSCs one week after STZ treatment), and diabetic+MSCs2 (received MSCs 4 weeks after STZ treatment). Diabetic rats showed marked impairment (p < 0:05) in serum levels of glucose, insulin, C-peptide, glycosylated hemoglobin (HbA1c), malondialdehyde (MDA), total antioxidant status (TAS), and total oxidant status (TOS) in addition to disruption of the calculated values of homeostatic model assessment of insulin resistance (HOMA-IR), pancreatic β cell function (HOMA-β), and oxidative stress index (OSI). These biochemical alterations were confirmed by the histopathological and ultrastructural assessments which showed marked destructive effect on pancreatic islet cells. MSC therapy in an early stage reversed most of the biochemical, histological, and ultrastructural alterations in the STZ-induced diabetic model and restored the normal cellular population of most acinar cells and islet of Langerhans. These results indicate that MSC therapy of STZ-induced diabetic developing rats during an early stage has the capacity of β cell restoration and the control of blood glycemic homeostasis.
STEM CELLS, 2014
Adipose-derived stromal/stem cells (ASCs) ameliorate hyperglycemia in rodent models of islet transplantation and autoimmune diabetes, yet the precise human ASC (hASC)-derived factors responsible for these effects remain largely unexplored. Here, we show that systemic administration of hASCs improved glucose tolerance, preserved b cell mass, and increased b cell proliferation in streptozotocin-treated nonobese diabetic/severe combined immunodeficient mice. Coculture experiments combining mouse or human islets with hASCs demonstrated that islet viability and function were improved by hASCs following prolonged culture or treatment with proinflammatory cytokines. Analysis of hASC-derived factors revealed vascular endothelial growth factor and tissue inhibitor of metalloproteinase 1 (TIMP-1) to be highly abundant factors secreted by hASCs. Notably, TIMP-1 secretion increased in the presence of islet stress from cytokine treatment, while TIMP-1 blockade was able to abrogate in vitro prosurvival effects of hASCs. Following systemic administration by tail vein injection, hASCs were detected in the pancreas and human TIMP-1 was increased in the serum of injected mice, while recombinant TIMP-1 increased viability in INS-1 cells treated with interleukin-1beta, interferon-gamma, and tumor necrosis factor alpha. In aggregate, our data support a model whereby factors secreted by hASCs, such as TIMP-1, are able to mitigate against b cell death in rodent and in vitro models of type 1 diabetes through a combination of local paracrine as well as systemic effects. STEM
Scientific Reports, 2018
This study was designed to assess whether the protective effects of bone marrow-derived mesenchymal stem cells (MSCs) against diabetes could be enhanced by pioglitazone (PIO), a PPARγ agonist. Combined MSCs and PIO treatments markedly improved fasting blood glucose, body weight, lipid profile levels, insulin level, insulin resistance, β cell function. Those protective effects also attenuated both pancreatic lesions and fibrosis in diabetic rats and decreased the depletion of pancreatic mediators of glycemic and lipid metabolism including peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, GLP-1 and IRS-2. Cardiac biogenesis of diabetic groups was also improved with MSCs and/or PIO treatments as reflected by the enhanced up-regulation of the expressions of cardiac IRS1, Glucose transporter 4, PGC-1, PPARα and CPT-1 genes and the down-regulated expression of lipogenic gene SREBP. The combination of MSCs and PIO also potentiated the decrease of abnormal myocardial pathological lesions in diabetic rats. Similarly, the inhibitory effects of MSCs on diabetic cardiac fibrosis and on the up regulations of TGF-β, collagen I and III gene expressions were partial but additive when combined with PIO. Therefore, combined therapy with PIO and BMCs transplantation could further potentiate the protective benefit of MSCs against diabetes and cardiac damage compared to MSCs monotherapy. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes representing over 90% of all current diabetic cases. Diabetic cardiomyopathy is a major complication and the main cause of mortality among diabetic patients 1. Patients with T2DM have a significantly higher risk of developing cardiovascular disease namely myocardial infarction, heart failure, and stroke 2. The principle etiologies of T2DM incorporate insulin resistance in target tissues, relatively insufficient secretion of insulin, and subsequent decline of pancreatic β-cell function 3,4. Multiple factors contribute to the development of cardiac dysfunction in diabetes including: alteration in lipid and glucose metabolism inside cardiomyocytes, induced oxidative stress, chronic inflammation, collagen deposition and apoptosis 5-7. Insulin resistance in myocardium contributes to the adverse left ventricular remodeling and mitochondrial dysfunction leading to repression of insulin signaling pathways or glucose transporters (GLUTs; such as GLUT1 and GLUT4) in myocardium-mediated glucose transport 8. Metabolic dysregulation occurring in the heart of diabetic patients involves derangements in the activity of peroxisome proliferator-activated receptors (PPARs), PPAR gamma coactivator 1-alpha (PGC-1α), AMP-activated protein kinase (AMPK) and nuclear factor-kB (NF-κB). Consequently, oxidative stress, chronic inflammation, fibrosis, and cell death can be induced and eventually contribute to and exacerbate diabetic