Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db - /db- mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin-1 receptor antagonist (anakinra, 0.5 μg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db - /db- mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db - /db- mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind-limb in db - /db- mice were attenuated by TUDCA and anakinra treatment. Ischaemia-induced neovascularization and blood flow recovery were significantly reduced in db - /db- mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db - /db- mice treated with TUDCA or anakinra compared to non-treated db - /db- mice. TUDCA and anakinra enhanced eNOS-cGMP, VEGFR2, and reduced ERK1/2 MAP-kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia-induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia-induced vascular pathology in type II diabetes.     

Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor

MSCs have received attention for their therapeutic potential in a number of disease states, including bone formation, diabetes, stem cell engraftment after marrow transplantation, graft-versus-host disease, and heart failure. Despite this diverse interest, the molecular signals regulating MSC trafficking to sites of injury are unclear. MSCs are known to transiently home to the freshly infarcted myocardium. To identify MSC homing factors, we determined chemokine expression pattern as a function of time after myocardial infarction (MI). We merged these profiles with chemokine receptors expressed on MSCs but not cardiac fibroblasts, which do not home after MI. This analysis identified monocyte chemotactic protein-3 (MCP-3) as a potential MSC homing factor. Overexpression of MCP-3 1 month after MI restored MSC homing to the heart. After serial infusions of MSCs, cardiac function improved in MCP-3-expressing hearts (88.7%, p < .001) but not in control hearts (8.6%, p = .47). MSC engraftment was not associated with differentiation into cardiac myocytes. Rather, MSC engraftment appeared to result in recruitment of myofibroblasts and remodeling of the collagen matrix. These data indicate that MCP-3 is an MSC homing factor; local overexpression of MCP-3 recruits MSCs to sites of injured tissue and improves cardiac remodeling independent of cardiac myocyte regeneration.     

Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes : Selenoorganic Antioxidant Ebselen Restores Stem Cell Competence

There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress, improved acetylcholine-induced vasorelaxation, and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by Ebselen therapy.Transplantation of bone marrow-derived cells (BMDCs) has emerged as a promising tool in regenerative medicine. This heterogeneous cell population, consisting of hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitors, has the capacity to differentiate into cells of endothelial, epithelial, cardiomyocyte, and neuronal lineage.^1,2,3,4 In a model of hindlimb ischemia, implantation of autologous BMDCs resulted in therapeutic angiogenesis and improved vascularization of the affected limb in both non-diabetic and diabetic rats.⁵ In ApoE-deficient mice, transplantation of BMDCs resulted in the restoration of vascular functions.⁶ There are conflicting data on the effect of transplantation of BMDCs on the severity of diabetes^7,8,9,10 and on the renal pathology and dysfunction in the murine model of renal fibrosis and ischemia-reperfusion injury.^11,12 Furthermore, recent data indicate that BMDC may become incompetent with regard to their ability to regenerate various tissues and organs.^6,13 Taking into account multiple macro- and microvascular complications of diabetes, we inquired a) whether transplantation of BMDCs may affect some of these functional abnormalities, and b) whether the competence of BMDCs in diabetic mice is preserved. Here, we report a dramatic improvement of macrovascular dysfunction and insulin sensitivity in db/db mice recipients of syngeneic BMDC isolated from the non-diabetic mice (but not from their diabetic counterparts), and provide evidence for BMDC incompetence in diabetic animals.     

Defects in Innate Immunity Predispose C57BL/6J-Leprdb/Leprdb Mice to Infection by Staphylococcus aureus

Foot and ankle infections are the most common cause of hospitalization among diabetic patients, and Staphylococcus aureus is a major pathogen implicated in these infections. Patients with insulin-resistant (type 2) diabetes are more susceptible to bacterial infections than nondiabetic subjects, but the pathogenesis of these infections is poorly understood. C57BL/6J-Lepr^db/Lepr^db (hereafter, db/db) mice develop type 2 diabetes due to a recessive, autosomal mutation in the leptin receptor. We established a S. aureus hind paw infection in diabetic db/db and nondiabetic Lepr^+/+ (+/+) mice to investigate host factors that predispose diabetic mice to infection. Nondiabetic +/+ mice resolved the S. aureus hind paw infection within 10 days, whereas db/db mice with persistent hyperglycemia developed a chronic infection associated with a high bacterial burden. Diabetic db/db mice showed a more robust neutrophil infiltration to the infection site and higher levels of chemokines in the infected tissue than +/+ mice. Blood from +/+ mice killed S. aureus in vitro, whereas db/db blood was defective in bacterial killing. Compared with peripheral blood neutrophils from +/+ mice, db/db neutrophils demonstrated a diminished respiratory burst when stimulated with S. aureus. However, bone marrow-derived neutrophils from +/+ and db/db mice showed comparable phagocytosis and bactericidal activity. Our results indicate that diabetic db/db mice are more susceptible to staphylococcal infection than their nondiabetic littermates and that persistent hyperglycemia modulates innate immunity in the diabetic host.Approximately 2 million of the estimated 16 million individuals with diabetes in the United States will develop chronic foot ulcers or infections during the course of their disease (38). An infection is initiated when the skin barrier is breached and bacteria, mostly skin commensals, gain access to the underlying tissues. Although limb-threatening infections are usually polymicrobial, Staphylococcus aureus is a major determinant of these infections (21). S. aureus is the predominant pathogen in non-limb-threatening infections, particularly in patients who have not received antimicrobial therapy (5, 26, 27). The emergence of S. aureus strains resistant to multiple antibiotics has made treatment of staphylococcal infections especially problematic. Methicillin-resistant S. aureus strains have become increasingly prevalent among both nosocomial and community-acquired infections within the United States (22, 36, 43). The prevalence of methicillin-resistant S. aureus is higher among diabetic patients than in the general population (11, 44, 45). Seven S. aureus strains resistant to vancomycin have been isolated in the United States, and four of these strains were isolated from patients with diabetes (42, 50). Complications of type 2 diabetes such as peripheral neuropathy and vasculopathy contribute to delayed wound healing. Although the increased susceptibility of the diabetic host to bacterial infections is well established, the chronicity of these infections is poorly understood. A consistent defect in the humoral or cell-mediated host immune system of diabetic patients has not been demonstrated. However, deficiencies in the host innate immune response are apparent since clinical investigations have indicated that phagocytes from type 2 diabetic patients are in a heightened state of oxidative stress and have impaired bactericidal activity and chemotaxis (6, 15, 41, 48). Clearly, numerous pathophysiologic perturbations contribute to the recurrence of soft tissue and bone infections in the lower extremity of patients with diabetes.C57BL/6J-Lepr^db/Lepr^db (hereafter, db/db) mice are a valuable model of type 2 diabetes since they are hyperglycemic and resistant to insulin, and they experience peripheral neuropathy, delayed wound healing, and myocardial disease. In this study we inoculated the hind paws of wild-type Lepr^+/+ (+/+) and diabetic db/db mice with S. aureus and evaluated the course of the ensuing infection in each host type, as well as the resultant host innate immune response to infection. Diabetic mice that were ≥4 months of age were more susceptible to staphylococcal infection than age-matched nondiabetic control animals. The db/db mice showed a heightened inflammatory response that was characterized by defects in phagocyte function.     

Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases

Transplantation of mesenchymal stem cells (MSCs) has been recently studied in animal models, and in clinical trials of patients with fulminant hepatic failure, end-stage liver diseases and inherited metabolic disorders. Modulatory cytokines produced by MSCs can inhibit immunocyte proliferation and migration to the liver, thereby attenuating inflammatory injury and reducing hepatocyte apoptosis. In addition, MSCs play an important role in regressing liver fibrosis and in supporting the function, proliferation and differentiation of endogenous hepatocytes under appropriate conditions. Although remarkable progress has been achieved in basic and clinical MSC studies, optimal therapeutic regimens for the clinical application of MSCs, such as optimal doses, transplantation routine and interval period for transplantation, need to be elucidated in detail. Furthermore, the long-term safety and therapeutic efficacy of MSC transplantation should be evaluated in future clinical trials. This review summarizes our current understanding of the immunomodulatory effects of MSC therapies on human liver diseases.     

Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs) expressing human basic fibroblast growth factor (hbFGF). After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS) controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF) expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001); however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.     

Chronic inhibition of epidermal growth factor receptor tyrosine kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2) augments vascular response to limb ischemia in type 2 diabetic mice

Type 2 diabetes is a key risk factor for ischemia-dependent pathology; therefore, a significant medical need exists to develop novel therapies that increase the formation of new vessels. We explored the therapeutic potential of epidermal growth factor receptor tyrosine kinase (EGFRtk) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibition in impaired ischemia-induced neovascularization in type 2 diabetes. Unilateral femoral artery ligation was performed in diabetic (db(-)/db(-)) and their control (db(-)/db(+)) mice for 4 weeks, followed by treatments with EGFRtk and ERK1/2 inhibitors (AG1478, 10 mg/kg/day and U0126, 400 μg/kg/day, respectively) for 3 weeks. Neovascularization, blood flow recovery, vascular and capillary density, and endothelial nitric oxide synthase activity were significantly impaired and were associated with enhanced EGFRtk and ERK1/2 activity in db(-)/db(-) mice. EGFRtk and ERK1/2 inhibitors did not have any effect in control mice, while in db(-)/db(-) mice there was a significant increase in neovascularization, blood flow recovery, vascular and capillary density, endothelial nitric oxide synthase activity, and were associated with a decrease in EGFRtk and ERK1/2 activity. Our data demonstrated that the inhibition of EGFRtk and ERK1/2 restored ischemia-induced neovascularization and blood flow recovery in type 2 diabetic mice. Thus, EGFRtk and ERK1/2 could be possible targets to protect from ischemia-induced vascular pathology in type 2 diabetes.     

Neurobehavioral deficits in db/db diabetic mice

Recent clinical studies indicate neurobehavioral disturbances in type-2 diabetics. However, there is paucity of preclinical research to support this concept. The validity of db/db mouse as an animal model to study type-2 diabetes and related complications is known. The present study was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. We tested juvenile (5-6 weeks) and adult (10-11 weeks) db/db mice for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypo-locomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. This is the first report of depression, psychosis-like symptoms and anxiolytic behavior of db/db mouse strain. It is tempting to speculate that this mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications.     

Local renin-angiotensin system regulates hypoxia-induced vascular endothelial growth factor synthesis in mesenchymal stem cells

The use of mesenchymal stem cell (MSC) transplantation for ischemic heart disease has been reported for several years. The main mechanisms responsible for the efficacy of this technique include the differentiation of MSCs into cardiomyocytes and endothelial cells, as well as paracrine effects. However, the differentiation rates of MSCs are very low, and the differentiated cells are not mature. In addition, MSCs undergo massive cell death within a few days after transplantation to the ischemic myocardium. Paracrine effects may thus play a major role in MSCs transplantation. Angiotensin II (Ang II) is known to be produced locally in the ischemic myocardium, but the effects of hypoxia on the local renin-angiotensin system (RAS) in MSCs, and the role of the RAS in hypoxia-induced vascular endothelial growth factor (VEGF) secretion remain unknown. In this study, we demonstrated that hypoxia stimulated the local RAS in MSCs, while pretreatment with the Ang II type 1 (AT1) receptor antagonist losartan reduced hypoxia-induced hypoxia-inducible factor 1α (HIF-1α) and VEGF production. The ERK1/2 inhibitor U0126 and the Akt inhibitor LY294002 also inhibited hypoxia-induced HIF-1α and VEGF production. Overall, these results indicate that the local RAS in MSCs regulates hypoxia-induced VEGF production through ERK1/2, Akt and HIF-1α pathways via the AT1 receptor.     

Lithium enhanced cell proliferation and differentiation of mesenchymal stem cells to neural cells in rat spinal cord

Lithium has been shown to inhibit apoptosis of neural progenitor cells (NPCs) and promote differentiation of NPCs. However, there was rare data to discuss the effects of lithium on neural differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential promotion of lithium to MSC proliferation and neural differentiation in vitro and after transplanted into the ventral horn of rat spinal cord in vivo. We found that lithium possesses the ability to promote proliferation of GFP-MSCs in a dose dependent manner as verified by growth curve and bromodeoxyuridine (BrdU) incorporation assays; While in neural induction medium, lithium (0.1 mM) promotes neural differentiation of GFP-MSCs as verified by immunostaining and quantitative analysis. After transplantation of GFP-MSCs into the rat spinal cord, lithium treatment enhanced cell survival and neural differentiation after transplantation as verified by immunohistochemistry. These data suggested that lithium could be a potential drug to augment the therapeutic efficiency of MSCs transplantation therapy in central nervous system (CNS) disorders.     

Stem cell therapy for the treatment of parasitic infections: is it far away?

Stem cell therapy is an interventional treatment that introduces new cells into damaged tissues, which help in treating many diseases and injuries. It has been proved that stem cell therapy is effective for the treatment of cancers, diabetes mellitus, Parkinson’s disease, Huntington’s disease, cardiovascular diseases, neurological disorders, and many other diseases. Recently, stem cell therapy has been introduced to treat parasitic infections. The culture supernatant of mesenchymal stem cells (MSCs) is found to inhibit activation and proliferation of macrophages induced by the soluble egg antigen of Schistosoma japonicum, and MSC treatment relieves S. japonicum-induced liver injury and fibrosis in mouse models. In addition, transplantation of MSCs into naïve mice is able to confer host resistance against malaria, and MSCs are reported to play an important role in host protective immune responses against malaria by modulating regulatory T cells. In mouse models of Chagas disease, bone marrow mononuclear cell has been shown effective in reducing inflammation and fibrosis in mice infected with Trypanosoma cruzi, and transplantation of the bone marrow mononuclear cells prevents and reverses the right ventricular dilatation induced by T. cruzi infection in mice. Preliminary clinical trials demonstrate that transplantation of bone marrow derived-cells may become an important therapeutic modality in the management of end-stage heart diseases associated with Chagas disease. Based on these exciting results, it is considered by stating that it is firmly believed that, within the next few years, we will be able to find the best animal models and the appropriate stem cell type, stem cell number, injection route, and disease state that will result in possible benefits for the patients with parasitic infections, and stem cell therapy, although at an initial stage currently, will become a real therapeutic option for parasitic diseases.     

Peripheral nerve tissue engineering: autologous Schwann cells vs. transdifferentiated mesenchymal stem cells

Mesenchymal stem cells (MSCs) were evaluated as an alternative source for tissue engineering of peripheral nerves. MSCs, transdifferentiated MSCs, or Schwann cells cultured from male rats were grafted into devitalized autologous muscle conduits bridging a 2-cm sciatic nerve gap in female rats. The differentiation potential of MSCs and transformed cultivated MSCs into Schwann cell-like cells was exploited using a cocktail of cytokines. Polymerase chain reaction of the SRY gene confirmed the presence of the implanted cells in the grafts. After 6 weeks, regeneration was monitored clinically, histologically, and morphometrically. Autologous nerves and cell-free muscle grafts were used as control. Revascularization studies suggested that transdifferentiated MSCs, in contrast to undifferentiated MSCs, facilitated neo-angiogenesis and did not influence macrophage recruitment. Autologous nerve grafts demonstrated the best results in all regenerative parameters. An appropriate regeneration was noted in the Schwann cell-groups and, albeit with restrictions, in the transdifferentiated MSC groups, whereas regeneration in the MSC group and in the cell-free group was impaired. The results indicate that transdifferentiated MSCs implanted into devitalized muscle grafts are able to support peripheral nerve regeneration to some extent, and offer a potential for new therapeutic strategies.     

Leptin Signaling Protects NK Cells from Apoptosis During Development in Mouse Bone Marrow

Increasing evidence indicates a role of leptin in immune response, but it remains largely unclear whether leptin signaling is involved in regulating NK cell development in the bone marrow （BM）. In this study, we have characterized NK cell differentiation and maturation in the BM of leptin-receptor deficient db/db mice at a prediabetic stage. Although the BM cellularity was similar to the control value, the total number of NK cells was severely reduced in mutant mice. Flow cytometric analysis of db/db BM cells revealed significantly decreased frequencies of developing NK cells at various stages of differentiation. BM db/db NK cells displayed markedly increased apoptosis but maintained normal cell cycling status and proliferative capacity. Moreover, recombinant leptin could significantly enhance the survival of NK cells from wild-type mice in cultures. Further examination on NK cell functional activity showed that db/db NK cells exhibited normal intrinsic cytotoxicity with significantly increased IL-10 production. Taken together, our findings suggest that leptin signaling regulates NK cell development via enhancing the survival of immature NK cells in mouse BM.     

Effects of mesenchymal stromal cells on motor function and collagen in the skeletal muscles of rats with type I diabetes

The present study aimed to evaluate the effects of mesenchymal stromal cell (MSC) transplantation on motor function and collagen organization in the muscles of rats with type 1 diabetes mellitus. Male Wistar rats were randomly assigned to three groups: control (C), diabetic (DM) and diabetic treated with MSCs (DM‐MSCs). Diabetes was induced by streptozotocin (50 µg/kg). Bone marrow cells were isolated from the tibia and femur. After 10 weeks of DM induction, the DM‐MSC rats received four i.p. injections of MSCs (1 × 106). Ten weeks after MSC transplantation, motor performance was evaluated by the rotarod test and the anterior tibial (TA) muscles were collected for morphometric and quantification of collagen birefringence by polarizing microscopy analysis. Motor performance of the DM group was significantly reduced when compared to the C group and increased significantly in the DM + MSC group. The TA muscle mass was significantly reduced in the DM and DM + MSC groups compared to the C group. The connective tissue increased in the DM group compared to the C group and decreased in the DM + MSC group. The percentage collagen birefringence decreased significantly in the DM group when compared to the C group and increased in the DM + MSC group. Motor performance was positively correlated with collagen birefringence and negatively correlated with percentage of connective tissue. The results indicate that MSC transplantation improves both motor function and the collagen macromolecular organization in type 1 DM.     

Dysfunction of Mesenchymal Stem Cells Isolated from Metabolic Syndrome and Type 2 Diabetic Patients as Result of Oxidative Stress and Autophagy may Limit Their Potential Therapeutic Use

Mesenchymal stem cells (MSC) have become a promising tool for therapeutic intervention. Their unique features, including self-renewal, multipotency and immunomodulatory properties draw the worldwide attention of researchers and physicians with respect to their application in disease treatment. However, the environment (so-called niche) from which MSCs are isolated may determine their usefulness. Many studies indicated the involvement of MSCs in ageing and disease. In this review, we have focused on how type 2 diabetes (T2D) and metabolic syndrome (MS) affect MSC properties, and thus limit their therapeutic potential. Herein, we mainly focus on apoptosis, autophagy and mitochondria deterioration processes that indirectly affect MSC fate. Based on the data presented, special attention should be paid when considering autologous MSC therapy in T2D or MS treatments, as their therapeutic potential may be restricted.     

Lentiviral-transduced human mesenchymal stem cells persistently express therapeutic levels of enzyme in a xenotransplantation model of human disease

Bone marrow-derived mesenchymal stem cells (MSCs) are a promising platform for cell- and gene-based treatment of inherited and acquired disorders. We recently showed that human MSCs distribute widely in a murine xenotransplantation model. In the current study, we have determined the distribution, persistence, and ability of lentivirally transduced human MSCs to express therapeutic levels of enzyme in a xenotransplantation model of human disease (nonobese diabetic severe combined immunodeficient mucopolysaccharidosis type VII [NOD-SCID MPSVII]). Primary human bone marrow-derived MSCs were transduced ex vivo with a lentiviral vector expressing either enhanced green fluorescent protein or the lysosomal enzyme beta-glucuronidase (MSCs-GUSB). Lentiviral transduction did not affect any in vitro parameters of MSC function or potency. One million cells from each population were transplanted intraperitoneally into separate groups of neonatal NOD-SCID MPSVII mice. Transduced MSCs persisted in the animals that underwent transplantation, and comparable numbers of donor MSCs were detected at 2 and 4 months after transplantation in multiple organs. MSCs-GUSB expressed therapeutic levels of protein in the recipients, raising circulating serum levels of GUSB to nearly 40% of normal. This level of circulating enzyme was sufficient to normalize the secondary elevation of other lysosomal enzymes and reduce lysosomal distention in several tissues. In addition, at least one physiologic marker of disease, retinal function, was normalized following transplantation of MSCs-GUSB. These data provide evidence that transduced human MSCs retain their normal trafficking ability in vivo and persist for at least 4 months, delivering therapeutic levels of protein in an authentic xenotransplantation model of human disease.     

Apelin 13: A novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes

Recent studies have proposed cell therapy as an alternative therapeutic strategy for many disease states such as diabetes mellitus. Among different cell types mesenchymal stem cells (MSC) have attracted a significant attention based on their intriguing potentials. However MSC therapy is limited as a large portion of transplanted cells undergo apoptosis after transplantation. Therefore, proposing a strategy to overcome this obstacle may be of great value. Recent studies have shown that hypoxia preconditioning (HPC) may improve cell viability after transplantation. Both HPC and hyperglycemia are reported to exert effects by different levels of ROS overproduction. Overdose of ROS in this case would trigger the apoptosis and thereby decreased cell viability after transplantation. Apelin; the endogenous ligand for the previously orphaned G protein–coupled receptor APJ is shown to exert anti apoptotic effects On oxidative stress-induced apoptosis in MSCs via MAPK/ERK1/2 and PI3K/AKT signaling pathways. Accordingly it has been hypothesized that pretreatment of HPC-MSC_s with apelin 13 would be an effective approach to modify and possibly enhance the efficacy of MSCs in cell therapy of diabetes.     

Apelin 13: A novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes

Recent studies have proposed cell therapy as an alternative therapeutic strategy for many disease states such as diabetes mellitus. Among different cell types mesenchymal stem cells (MSC) have attracted a significant attention based on their intriguing potentials. However MSC therapy is limited as a large portion of transplanted cells undergo apoptosis after transplantation. Therefore, proposing a strategy to overcome this obstacle may be of great value. Recent studies have shown that hypoxia preconditioning (HPC) may improve cell viability after transplantation. Both HPC and hyperglycemia are reported to exert effects by different levels of ROS overproduction. Overdose of ROS in this case would trigger the apoptosis and thereby decreased cell viability after transplantation. Apelin; the endogenous ligand for the previously orphaned G protein–coupled receptor APJ is shown to exert anti apoptotic effects On oxidative stress-induced apoptosis in MSCs via MAPK/ERK1/2 and PI3K/AKT signaling pathways. Accordingly it has been hypothesized that pretreatment of HPC-MSC_s with apelin 13 would be an effective approach to modify and possibly enhance the efficacy of MSCs in cell therapy of diabetes.