Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia

Objective： To study the efficacy and safety of autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia. Methods： Fifty Type 2 diabetic patients with lower limb ischemia were enrolled and randomized to either transplanted group or control group. Patients in both group received the same conventional treatment. Meanwhile, 20 ml bone marrow from each transplanted patient were collected, and the mesenchymal stem cells were separated by density gradient centrifugation and cultured in the medium with autologous serum. After three-weeks adherent culture in vitro, 7.32×10^8-5.61×10^9 mesenchymal stem cells were harvested and transplanted by multiple intramuscular and hypodermic injections into the impaired lower limbs. Results： At the end of 12-week follow-up, 5 patients were excluded from this study because of clinical worsening or failure of cell culture. Main ischemic symptoms, including rest pain and intermittent claudication, were improved significantly in transplanted patients. The ulcer healing rate of the transplanted group （1 5 of 18, 83.33%） was significantly higher than that of the control group （9 of 20, 45.00%, P=0.012）.The mean of resting ankle-brachial index （ABI） in transplanted group significantly was increased from 0.61±0.09 to 0.74±0.11 （P〈0.001）. Magnetic resonance angiography （MRA） demonstrated that there were more patients whose score of new vessels exceeded or equaled to 2 in the transplant patients （11 of 15） than in control patients （2 of 14, P=0.001）. Lower limb amputation rate was significantly lower in transplanted group than in the control group （P=0.040）. No adverse effects was observed in transplanted group. Conclusion： These results indicate that the autologous transplantation of bone marrow mesenchymal stem cells relieves critical lower limb ischemia and promotes ulcers healing in Type 2 diabetic patients.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes

Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach forβcell replacement,but long-term blood control is still largely unachievable.This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia.Moreover,graft failures continue to occur because of immunological rejection,despite the use of potent immunosuppressive agents.Mesenchymal stem cells(MSCs)have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection.In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.

Autologous hematopoietic stem cell transplantation for diabetic foot:A meta-analysis

Objective:To systematically evaluate the efficacy and safety of autologous hematopoietic stem cell(AHSCs)transplantation for diabetic foot(DF).Methods:A systematic search of literatures in PubMed,Embase,the Cochrane Library,CNKI,WanFang and VIP from inception to March 2020 was conducted.Clinical randomized controlled trials of AHSCs transplantation for DF were screened according to inclusion and exclusion criteria,and meta-analysis was performed using RevMan 5.3 software.Results:A total of 13 articles were included,including 582 patients within 292 received conventional treatment in the control group and 290 additionally received AHSCs in the transplantation group.Meta-analysis results showed that compared with the control group,the transplantation group improved ulcer healing rate[RR=2.38,95%CI(1.91,2.98),P<0.00001],ankle brachial index[MD=0.14,95%CI(0.11,0.16),P<0.00001]and skin temperature of injured limb[MD=1.39,95%CI(0.93,1.86),P<0.00001].And lowered mutation rate[RR=0.10,95%CI(0.04,0.26),P<0.00001],pain scores[MD=-1.37,95%CI(-1.62,-1.12),P<0.00001]and indirect claudication scores[MD=-0.89,95%CI(-1.04,-0.75),P<0.00001].The above differences were all statistically significant(P<0.05).Conclusion:Existing evidence shows that AHSCs transplantation for DF has certain clinical effects and safety.However,more high-quality research are needed to further demonstrate the above results.

Understanding host-graft crosstalk for predicting the outcome of stem cell transplantation

Mesenchymal stromal cells(MSCs)hold great promise for tissue regeneration in debilitating disorders.Despite reported improvements,the short-term outcomes of MSC transplantation,which is possibly linked to poor cell survival,demand extensive investigation.Disease-associated stress microenvironments further complicate outcomes.This debate underscores the need for a deeper understanding of the phenotypes of transplanted MSCs and their environment-induced fluctuations.Additionally,questions arise about how to predict,track,and comprehend cell fate post-transplantation.In vivo cellular imaging has emerged as a critical requirement for both short-and long-term safety and efficacy studies.However,translating preclinical imaging methods to clinical settings remains challenging.The fate and function of transplanted cells within the host environment present intricate challenges,including MSC engraftment,variability,and inconsistencies between preclinical and clinical data.The study explored the impact of high glucose concentrations on MSC survival in diabetic environments,emphasizing mitochondrial factors.Preserving these factors may enhance MSC survival,suggesting potential strategies involving genetic modification,biomaterials,and nanoparticles.Understanding stressors in diabetic patients is crucial for predicting the effects of MSC-based therapies.These multifaceted challenges call for a holistic approach involving the incorporation of large-scale data,computational disease modeling,and possibly artificial intelligence to enable deterministic insights.

Transfection with CXCR4 potentiates homing of mesenchymal stem cells in vitro and therapy of diabetic retinopathy in vivo

AIM：To investigate the effect of the overexpression of C-X-C chemokine receptor type 4（CXCR4） on homing of mesenchymal stem cells（MSCs） in vitro and therapeutic effects of diabetic retinopathy（DR） in vivo.METHODS：MSCs were infected by lentivirus constructed with CXCR4.The expression of CXCR4 was examined by immunofluorescence,Western blot,and quantitative polymerase chain reaction.CXCR4-overexpressing MSCs were cultured in vitro to evaluate their chemotaxis,migration,and apoptotic activities.CXCR4-overexpressing MSCs were intravitreally injected to observe and compare their effects in a mouse model of DR.The histological structure of DR in rats was inspected by hematoxylin and eosin staining.The expression of rhodopsin,neuron-specific enolase（NSE）,and inflammatory cytokines interleukin（IL）-6 and tumor necrosis factor（TNF）-α was examined by Western blot and immunohistochemical analyses.RESULTS：The transduction of MSCs by lentivirus was effective,and the transduced MSCs had high expression levels of CXCR4 gene and protein.Improved migration activities were observed in CXCR4-overexpressing MSCs.Further,reduced retinal damage,upregulation of rhodopsin and NSE protein,and downregulation of inflammatory cytokines IL-6 and TNF-α were observed in CXCR4-overexpressing MSCs in vivo.CONCLUSION：The homing of MSCs can be enhanced by upregulating CXCR4 levels,possibly improving histological structures of DR.CXCR4-overexpressing MSCs can be a novel strategy for treating DR.

Salidroside Pretreatment to Mesenchymal Stem Cells Improves Cell Survival and Migration to Promote Diabetic Wound Healing

Objective Diabetic patients pose a greater challenge in managing chronic wound healing,leading to a higher amputation risk compared to non-diabetic patients.Due to their paracrine function by secreting various cytokines and angiogenic factors,mesenchymal stem cells(MSCs)have been acknowledged to be a potential agent in modulating wound healing process.However,post-transplanted MSCs are vulnerable to death,indicating poor survival and migration ability in the wound site of the host,especially under hyperglycemia.As hyperglycemia induces reactive oxygen species(ROS)generation and cellular apoptosis,improvement of MSCs survival and migration potentials under hyperglycemia could contribute to a more efficient MSCs-based wound healing therapy.Salidroside(Sa),a small-molecule drug derived from Rhodiola plant,has been proved to enhance the paracrine function of skeletal muscle cells,as well as their migration even under hypoxichyperglycemia.Herein,we investigated whether Sa could improve the survival and migration potentials of MSCs,subsequently enhance the wound healing process under hyperglycemia.Methods MSCs were cultured under three conditions:low glucose,high glucose,and high glucose+Sa.qPCR analysis and western blotting were done to examine the mRNA and protein expression level of several factors which are important in upregulating the wound healing process.MTT colorimetric assay,intracellular ROS detection,and flow cytometry assay were employed to examine the effect of Sa in MSCs survival.Transwell chamber assay,scratch assay,and phalloidin staining were done to elucidate the role of Sa in regulating MSCs migration potential.For in vivo experiment,diabetic wound healing mice model was generated to elucidate the effect of Sa-pretreated MSCs transplantation in wound closure rate,as well as re-epithelization status,observed with hematoxylin and eosin staining.The diabetic wound healing mice model were divided into three groups:1)mice injected with PBS,2)mice transplanted with PBS-pretreated MSCs,and 3)mice transplanted with Sa-pretreated MSCs.Results(1)Hyperglycemic condition induced the generation of ROS and suppressed total cell number of MSCs,while Sa treatment into MSCs restored these hyperglycemia-induced alterations.In line with this,total apoptotic cells were also suppressed by treating MSCs with Sa.The expression level of cell survival factor,heme-oxygenase 1(HO-1),was enhanced in Sa-pretreated MSCs.Further treatment of HO-1 inhibitor into Sa-pretreated MSCs nullified the ROS level and total apoptotic cells,indica-ting the importance of HO-1 in mediating the Sa-induced survival of MSCs under hyperglycemia.(2)Transwell chamber and scratch assay results showed that Sa-pretreated MSCs have a higher migration potential under hyperglycemia,supported by higher F-actin polymerization fractal dimension.Fibroblast growth factor 2(FGF2)and hepatocyte growth factor(HGF)expression level,which are essential factors for cell migration,were also improved in Sa-pretreated MSCs under hyperglycemia.(3)In diabetic wound healing mice model,transplantation of Sa-pretreated MSCs resulted in significantly improved wound closure rate and re-epithelization.The protein levels of HO-1,FGF2,and HGF were also enhanced in the tissues obtained from the wound site of diabetic wound healing mice model which were transplanted with Sa-pretreated MSCs.Conclusions Salidroside pretreatment on MSCs could improve their survival and migration potentials,subsequently promoting wound healing process under hyperglycemia.This prospective MSC-based therapy could serve as a novel strategy to improve diabetic wound healing.

Bioengineered stem cells as an alternative for islet cell transplantation

Type 1 diabetes is an autoimmune and increasingly prevalent condition caused by immunological destruction of beta cells. Insulin remains the mainstay of therapy. Endeavours in islet transplantation have clearly demonstrated that type 1 diabetes is treatable by cellular replacement. Many challenges remain with this approach. The opportunity to use bioengineered embryonic or adult pluripotential stem cells, or islets derived from porcine xenograft sources could address future demands, but are still associated with considerable challenges. This detailed review outlines current progress in clinical islet transplantation, and places this in perspective for the remarkable scientific advances now occurring in stem cell and regenerative medicine approaches in the treatment of future curative treatment of diabetes.

Molecular Analysis of Clerodendrum formicarum Effects in Painful Diabetic Neuropathy in Rat

The pathophysiology of diabetic neuropathic pain is due to primarily metabolic and vascular factors. There is an increase in sorbitol and fructose, glycated end products, reactive oxygen species and activation of protein kinase C in the diabetic state. All these factors lead to direct damage to the nerves. Taking effective clinical management of neuropathic pain is based on a pharmacological treatment that has shown their limits and many side effects. The hypothesis of central sensitization inhibited by Clerodendrum formicarum, an African pharmacopoeia plant used to treat headaches, arthritis, epilepsy and chronic pain could act on astrocytes and microglial cells. The objective of this work is to study the effect of Clerodendrum formicarum (100, 150 and 200 mg/kg body weight) on astrocytes and microglial cells in a model of diabetic neuropathic pain induced by alloxan monohydrate (150 mg/kg). We noted a suppression of mechanical allodynia and mechanical hyperalgesia respectively by the Von Frey filaments test and the pressure test on the paw by the Clerodendrum formicarumextracts (ECF) at different doses from 2 h at the first injection of the ECF. After 5 days of treatment, we expressed by Western Blot bands of different proteins and by quantitative RT-PCR, we determined inhibition of the expression of GFAP, CD11b and isoforms 1 and 2 of cyclooxygenase. These results suggest that ECF inhibits the activation of astrocytes, microglial cells and cyclooxygenase signaling pathway.

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

Safety evaluation of human umbilical cord-mesenchymal stem cells in type 2 diabetes mellitus treatment:A phase 2 clinical trial

BACKGROUND Progressive pancreaticβcell dysfunction is a fundamental aspect of the pathology underlying type 2 diabetes mellitus(T2DM).Recently,mesenchymal stem cell(MSC)transplantation has emerged as a new therapeutic method due to its ability to promote the regeneration of pancreaticβcells.However,current studies have focused on its efficacy,and there are few clinical studies on its safety.AIM To evaluate the safety of human umbilical cord(hUC)-MSC infusion in T2DM treatment.METHODS An open-label and randomized phase 2 clinical trial was designed to evaluate the safety of hUC-MSC transplantation in T2DM in a Class A hospital.Ten patients in the placebo group received acellular saline intravenously once per week for 3 wk.Twenty-four patients in the hUC-MSC group received hUC-MSCs(1×106 cells/kg)intravenously once per week for 3 wk.Diabetic clinical symptoms and signs,laboratory findings,and imaging findings were evaluated weekly for the 1st mo and then at weeks 12 and 24 post-treatment.RESULTS No serious adverse events were observed during the 24-wk follow-up.Four patients(16.7%)in the hUC-MSC group experienced transient fever,which occurred within 24 h after the second or third infusion;this did not occur in any patients in the placebo group.One patient from the hUC-MSC group experienced hypoglycemic attacks within 1 mo after transplantation.Significantly lower lymphocyte levels(weeks 2 and 3)and thrombin coagulation time(week 2)were observed in the hUC-MSC group compared to those in the placebo group(all P<0.05).Significantly higher platelet levels(week 3),immunoglobulin levels(weeks 1,2,3,and 4),fibrinogen levels(weeks 2 and 3),D-dimer levels(weeks 1,2,3,4,12,and 24),and neutrophil-to-lymphocyte ratios(weeks 2 and 3)were observed in the hUC-MSC group compared to those in the placebo group(all P<0.05).There were no significant differences between the two groups for tumor markers(alpha-fetoprotein,carcinoembryonic antigen,and carbohydrate antigen 199)or blood fat.No liver damage or other side effects were observed on chest X-ray.CONCLUSION Our study suggested that hUC-MSC transplantation has good tolerance and high safety in the treatment of T2DM.It can improve human immunity and inhibit lymphocytes.Coagulation function should be monitored vigilantly for abnormalities.

Stem cells and pain

ain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience.For years,science has sought to find treatment alternatives,with minimal side effects,to relieve pain.However,the currently available pharmacological options on the market show significant adverse events.Therefore,the search for a safer and highly efficient analgesic treatment has become a priority.Stem cells(SCs)are non-specialized cells with a high capacity for replication,self-renewal,and a wide range of differentiation possibilities.In this review,we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain.With the advantage of multiple administration routes and dosages,therapies based on SCs for pain relief have demonstrated meaningful results with few downsides.Nonetheless,there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs.Thus,this is an evolving field that merits further investigation towards the development of SCbased analgesic therapies,and this review will approach all of these aspects.

Transplantation of mobilized peripheral blood mononuclear cells for peripheral arterial occlusive disease of the lower extremity

Objectives To assess the clinical efficacy,safety,and feasibility of autologous transplantation of mobilized peripheral blood mononuclear cells(PBMNCs)for patients with peripheral arterial occlusive disease(PAOD)of the lower extremity.Methods A total of 152 patients with PAOD of the lower extremity were enrolled into this non-controlled observational study from November 2003 to March 2006.All patients received subcutaneous injections of recombinant human granulocyte colony-stimulating factor(G-CSF,450-600μg/day)for 5 days in order to mobilize stem/progenitor cells;their PBMNCs were collected and transplanted by multiple intramuscular injections into ischemic limbs.Patients were followed up for at least 12 weeks.Results At 12 weeks,primary manifestations,including lower limb pain and coldness,were significantly improved in 137(90.1%)of the patients;limb ulcers improved or healed in 46(86.8%)of the 53 patients,while 25 of the 48(47.9%)patients with limb gangrene remained steady or improved.Ankle-brachial index(ABI)improved in 33(22%)of the cases,and TcPO_(2) increased in 45(30%)of the cases.Angiography before treatment,and at 12 weeks after treatment,was performed in 10 of the patients and showed formation of new collateral vessels.No severe adverse effects or complications specifically related to cell transplantation were observed.Conclusion Autologous transplantation of G-CSF-mobilized PBMNCs might be a safe and effective treatment for lower limb ischemic disorder.

Pain inhibition through transplantation of fetal neuronal progenitors into the injured spinal cord in rats

Neuropathic pain after spinal cord injury(SCI) is a complex condition that responds poorly to usual treatments. Cell transplantation represents a promising therapy;nevertheless, the ideal cell type in terms of neurogenic potential and effectiveness against pain remains largely controversial. Here, we evaluated the ability of fetal neural stem cells(fNSC) to relieve chronic pain and, secondarily, their effects on motor recovery. Adult Wistar rats with traumatic SCI were treated, 10 days after injury, with intra-spinal injections of culture medium(sham) or fNSCs extracted from telencephalic vesicles(TV group) or the ventral medulla(VM group) of E/14 embryos. Sensory(von Frey filaments and hot plate) and motor(the Basso, Beattie,Bresnahan locomotor rating scale and inclined plane test) assessments were performed during 8 weeks. Thereafter, spinal cords were processed for immunofluorescence and transplanted cells were quantified by stereology. The results showed improvement of thermal hyperalgesia in the TV and VM groups at 4 and 5 weeks after transplantation, respectively. Moreover, mechanical allodynia improved in both the TV and VM groups at 8 weeks. No significant motor recovery was observed in the TV or VM groups compared with sham. Stereological analyses showed that ~70% of TV and VM cells differentiated into NeuN+ neurons,with a high proportion of enkephalinergic and GABAergic cells in the TV group and enkephalinergic and serotoninergic cells in the VM group. Our study suggests that neuronal precursors from TV and VM, once implanted into the injured spinal cord, maturate into different neuronal subtypes, mainly GABAergic, serotoninergic, and enkephalinergic, and all subtypes alleviate pain, despite no significant motor recovery. The study was approved by the Animal Ethics Committee of the Medical School of the University of S?o Paulo(protocol number 033/14) on March 4, 2016.

Stem cell therapy for insulin-dependent diabetes:Are we still on the road?

In insulin-dependent diabetes,the isletβcells do not produce enough insulin and the patients must receive exogenous insulin to control blood sugar.However,there are still many deficiencies in exogenous insulin supplementation.Therefore,the replacement of destroyed functionalβcells with insulin-secreting cells derived from functional stem cells is a good idea as a new therapeutic idea.This review introduces the development schedule of mouse and human embryonic islets.The differences between mouse and human pancreas embryo development were also listed.Accordingly to the different sources of stem cells,the important research achievements on the differentiation of insulin-secretingβcells of stem cells and the current research status of stem cell therapy for diabetes were reviewed.Stem cell replacement therapy is a promising treatment for diabetes,caused by defective insulin secretion,but there are still many problems to be solved,such as the biosafety and reliability of treatment,the emergence of tumors during treatment,untargeted differentiation and autoimmunity,etc.Therefore,further understanding of stem cell therapy for insulin is needed.

Efficacy of autologous bone marrow mononuclear cell transplantation therapy in patients with refractory diabetic peripheral neuropathy

Background:Owing to the multifactorial nature of the pathogenesis of diabetic peripheral neuropathy (DPN),conventional drug therapies have not been effective.The application of stem cells transplantation may be useful for the treatment of DPN.This study was designed to assess the safety and therapeutic effects of autologous bone marrow mononuclear cells (BMMNCs) transplantation on the treatment of refractory DPN.Methods:One hundred and sixty-eight patients with refractory DPN were recruited and enrolled in the study.They received intramuscular injection of BMMNCs and followed at 1,3,6,12,18,24,and 36 months after the transplantation.Clinical data,Toronto Clinical Scoring System (TCSS),and nerve conduction studies (NCSs) were compared before and after the transplantation.Results:The signs and symptoms of neuropathy were significantly improved after BMMNCs transplantation.The values of the TCSS scores at 1 month (9.68 ± 2.49 vs.12.55 ± 2.19,P<0.001) and 3 months (8.47 ± 2.39 vs.12.55 ± 2.19,P<0.001) after the treatment reduced significantly compared with the baseline value.This decrement remained persistent until the end of the study.The conduction velocity and action potential and sensory nerves were significantly improved after transplantation (3 and 12 months after the treatment vs.the baseline:motor nerve conduction velocity,40.24 ± 2.80 and 41.00 ± 2.22 m/s vs.38.21 ± 2.28 m/s,P<0.001;sensory nerve conduction velocity,36.96 ± 2.26 and 39.15 ± 2.61 m/s vs.40.41 ± 2.22 m/s,P<0.001;compound muscle action potential,4.67 ± 1.05 and 5.50 ± 1.20 μV vs.5.68 ± 1.08 μV,P<0.001;sensory nerve action potential,4.29 ± 0.99 and 5.14 ± 1.26 μV vs.5.41 ± 1.14 μV,P<0.001).No adverse event associated with the treatment was observed during the follow-up period.Conclusions:Autologous transplantation of BMMNCs may be an effective and promising therapeutic strategy for the treatment of refractory DPN.

A secretory function of human insulin-producing cells in vivo

BACKGROUND: Mesenchymal stem cells derived from human umbilical cord blood (UCB-MSCs) have good research and application prospects in the treatment of diabetes. We once induced UCB-MSCs to differentiate into insulin-producing cells (IPCs) in vitro, but we did not know the functions of these cells in vivo. The aim of this study was to assess the functional effects of IPCs on insulin secretion and their role in the treatment of diabetes in vivo. METHODS: UCB-MSCs were induced to IPCs by an inducing protocol with extracellular matrix gel. BALB/C nude mice were made hyperglycemic by intraperitoneal injection of streptozotocin. The diabetic mice were transplanted with 1x10(7) IPCs under the renal capsule or with phosphate-buffered saline as a control. After transplantation, the grafts were analyzed by immunocytochemistry for the expression of human insulin; the serum human insulin levels were measured; and blood glucose and body weight status were monitored. RESULTS: Immunofluorescence showed that numerous IPCs under the kidney capsule were insulin-positive. On day 14 after transplantation, the serum human insulin level of the treatment group (n=9) averaged 0.44 +/- 0.12 mU/L, which was higher than that of the control group (n=9) that did not express insulin (t=10.842, P<0.05). The diabetic mice remained hyperglycemic and kept losing body weight after IPC transplantation, and there was no significant difference in the control group. CONCLUSION: IPCs differentiated from UCB-MSCs generate human insulin in diabetic mice, but more research is needed to make further use of them to regulate hyperglycemia and body weight in vivo. (Hepatobiliary Pancreat Dis Int 2009; 8: 255-260)

Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives

Diabetes mellitus(DM) is the most prevailing disease with progressive incidence worldwide. Despite contemporary treatment type one DM and type two DM are frequently associated with long-term major microvascular and macrovascular complications. Currently restoration of failing β-cell function, regulation of metabolic processes with stem cell transplantation is discussed as complements to contemporary DM therapy regimens. The present review is considered paradigm of the regenerative care and the possibly effects of cell therapy in DM. Reprogramming stem cells, bone marrowderived mononuclear cells; lineage-specified progenitor cells are considered for regenerative strategy in DM. Finally, perspective component of stem cell replacement in DM is discussed.

Alternative therapeutic strategies in diabetes management

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and results in a non-sufficient production of insulin.To adjust blood glucose levels,diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity.With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities,different strategies have been investigated.The first approaches included enhancing endogenousβcell activity or transplanting new islets.The protocol for this kind of intervention has recently been optimized,leading to standardized procedures.It is indicated for diabetic patients with severe hypoglycemia,complicated by impaired hypoglycemia awareness or exacerbated glycemic lability.Transplantation has been associated with improvement in all comorbidities associated with diabetes,quality of life,and survival.However,different trials are ongoing to further improve the beneficial effects of transplantation.Furthermore,to overcome some limitations associated with the availability of islets/pancreas,alternative therapeutic strategies are under evaluation,such as the use of mesenchymal stem cells(MSCs)or induced pluripotent stem cells for transplantation.The cotransplantation of MSCs with islets has been successful,thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms,including exosome release.The use of induced pluripotent stem cells is recent and requires further investigation.The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities,such as wound healing.Despite the number of advantages of the direct injection of MSCs,new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results.In conclusion,this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.

Autologous bone marrow stem cell transplantation for the treatment of type 2 diabetes mellitus

Background Autologous peripheral stem cell transplantation was first reported in 2007 to treat type 1 diabetes mellitus （DM） and achieved encouraging effect, but whether similar outcome can be achieved in type 2 DM is not well demonstrated. The objective of this study was to determine the effect of combination of autologous bone marrow stem cell transplantation （BMT） and hyperbaric oxygen treatment on type 2 DM. Methods The study involved 31 patients with type 2 DM （aged 33 to 62 years） from January 2009 to January 2011 in the Central Hospital of Wuhan, China. Clinical variables （body mass index, duration of DM, insulin requirement, oral hypoglycemic drugs, time free from insulin, time free from oral drugs） and laboratory variables （hemoglobin Alc （HbAlc）） mononuclear cells infused, and C-peptide in four time points） were assessed. Purified bone marrow stem cells were infused into major pancreatic arteries. Follow-up was performed at the 30, 90, 180, 360, 540 and 720 days （mean 321 days） after BMT. Results Mean HbAlc values showed a significant reduction during follow-up in all patients after BMT. It decreased by more than 1.5% （from 8.7% to 7.1%） as quickly as at 30 days after BMT. Afterwards mean HbAlc fluctuated between plus or minus 0.5% until 24 months rather than declined continuously. At 90 days after the combined therapy C-peptide increased significahtly compared with baseline （P 〈0.0001）. But in other time points C-peptide was similar with baseline data （P〉0.3）. All patients had insulin and/or oral hypoglycemic drugs reduced to different levels. The dose of insulin of 7 patients （7/26, 27%） reduced for a period of time after BMT. Conclusions Combined therapy of intrapancreatic BMT and hyperbaric oxygen treatment can improve glucose control and reduce the dose of insulin and/or oral hypoglycemic drugs in type 2 DM patients, but it only improve pancreatic 13-cell function transiently. Further randomized controlled clinical trials involved more patients will be required to confirm these findings and the mechanism needs to be illustrated deeply.

Autologous hematopoietic stem cell transplantation and conventional insulin therapy in the treatment of children with newly diagnosed type I diabetes： long term follow-up

Background It has been indicated that autologous hematopoietic stem cell transplantation （AHST） is a promising treatment to adults with type 1 diabetes, however, the application of AHST therapy to children with type 1 diabetes still needs more data. The aim of this study was to assess the clinical effect of immune intervention combined with AHST and conventional insulin therapy in the treatment of children with newly diagnosed type 1 diabetes. Methods This 1：2 matched case-control study was comprised of 42 children who were newly diagnosed with type 1 diabetes in the Department of Endocrinology, Beijing Children＇s Hospital from 2009-2010. The case group included 14 patients, who were treated with AHST within the first 3 months after being diagnosed with diabetes at request of their parents during 2009-2010. The control group included 28 patients with newly diagnosed type 1 diabetes at the same period of hospitalization. We compared the baseline and follow-up data of them, including ketoacidosis onset, clinical variables （glycosylated hemoglobin （HbAlc）, insulin dosage and serum C-peptide）. Results The clinical characteristics of the patients was comparable between the case group and the control group. At 6-12 months （（10.7±4.2） months） after AHST treatment, we found 11 patients in the case group did not stop the insulin therapy, three cases stopped insulin treatment for 2, 3 and 11 months, respectively. No diabetic ketoacidosis （DKA） occurred after transplantation in all the patients in the case group. HbAlc in the control group was significant lower than that in the case group （P 〈0.01）, while the insulin dosage and serum C-peptide were not significant different between the two groups （P 〉0.05）. In order to eliminate the honeymoon effect, we performed final follow-up at the 3-5 years （（4.2±1.8） years） after AHST treatment, and found that HbAlc in the control group was still lower than that in the case group （P 〈0.01）; however, the insulin dosage and serum C-peptide were not significantly different between the two groups （P 〉0.05）. Moreover, the insulin dosage was not significant different from baseline to follow-up period in the case group. Conclusion AHST treatment showed no advantage in effectiveness in children with newly diagnosed type 1 diabetes, both in insulin dose and long term blood glucose control. Chin med J2014;（14）：2618-2622