Stem Cell Therapy For Diabetes Research Articles

The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges.

In recent years, the potential of stem cells (SCs) to differentiate into various types of cells, including β-cells, has led to a significant boost in development. The efficiency of this differentiation process and the functionality of the cells post-transplantation are crucial factors for the success of stem cell therapy in diabetes. Herein, this article reviews the current advances and challenges faced by stem cell differentiation into functional β-cells for diabetes treatment. In vitro, researchers have sought to enhance the differentiation efficiency of functional β-cells by mimicking the normal pancreatic development process, using gene manipulation, pharmacological and culture conditions stimulation, three-dimensional (3D) and organoid culture, or sorting for functional β-cells based on mature islet cell markers. Furthermore, in vivo studies have also looked at suitable transplantation sites, the enhancement of the transplantation microenvironment, immune modulation, and vascular function reconstruction to improve the survival rate of functional β-cells, thereby enhancing the treatment of diabetes. Despite these advancements, developing stem cells to produce functional β-cells for efficacious diabetes treatment is a continuous research endeavor requiring significant multidisciplinary collaboration, for the stem-cell-derived beta cells to evolve into an effective cellular therapy.

Stem cell therapy in diabetes: a promising future

Stem cell therapy in diabetes: a promising future

Awareness of Stem Cell Therapy for Diabetes Among Type II Diabetic Patients in Makkah: A Cross-Sectional Study.

Background Diabetes mellitus is a chronic disease that affects millions of people worldwide. Several studies have suggested using stem cells for diabetes treatment. However, there is a lack of research assessing the population's awareness of stem cells. This study aimed to evaluate the level of awareness regarding the use of stem cell therapy for type 2 diabetes mellitus (T2DM). Methodology This study was conducted from December 2021 to April 2022 through an online survey that was distributed electronically via social media platforms. T2DM patients or their care providers who lived in Makkah were included. Patients aged less than 18 years and those with mental disabilities were excluded. Results Of the 316 participants included in the study, 56% were males, 33% had an age range of 46-55 years, and 76% were married. T2DM patients and their caregivers had a moderate level of awareness about stem cell therapy, with caregivers having higher awareness than diabetic patients. A non-significant relationship was found between educational level, income, diabetes control, time of diagnosis, and patients' awareness. However, regarding the decision of treatment, participants aged less than 35 years were highly likely to decide to undergo stem cell treatment compared to other age groups. Conclusions There is a moderate level of awareness about stem cell therapy as a treatment option for T2DM among T2DM patients and caregivers in Makkah. Hence, there is a need to raise awareness by using online and in-person well-organized education programs in Makkah.

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

In insulin-dependent diabetes, the islet β cells 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 functional β cells 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-secreting β cells 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.

Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases.

Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.

Towards a stem-cell therapy for diabetes

Towards a stem-cell therapy for diabetes

Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.

Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the most widely practiced treatment. However, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to a high blood glucose level. However, the determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for the treatment of diabetes is still debated. While hPSC-derived beta cells are perceived as the ultimate candidate, their efficiency needs further improvement in order to obtain a sufficient number of glucose responsive beta cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address the co-generation of functionally relevant islet cell subpopulations and structural properties contributing to the glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.

Stem cell therapy for diabetes

Stem cell therapy for diabetes

Cell therapies for pancreatic beta-cell replenishment.

The current treatment approach for type 1 diabetes is based on daily insulin injections, combined with blood glucose monitoring. However, administration of exogenous insulin fails to mimic the physiological activity of the islet, therefore diabetes often progresses with the development of serious complications such as kidney failure, retinopathy and vascular disease. Whole pancreas transplantation is associated with risks of major invasive surgery along with side effects of immunosuppressive therapy to avoid organ rejection. Replacement of pancreatic beta-cells would represent an ideal treatment that could overcome the above mentioned therapeutic hurdles. In this context, transplantation of islets of Langerhans is considered a less invasive procedure although long-term outcomes showed that only 10 % of the patients remained insulin independent five years after the transplant. Moreover, due to shortage of organs and the inability of islet to be expanded ex vivo, this therapy can be offered to a very limited number of patients. Over the past decade, cellular therapies have emerged as the new frontier of treatment of several diseases. Furthermore the advent of stem cells as renewable source of cell-substitutes to replenish the beta cell population, has blurred the hype on islet transplantation. Breakthrough cellular approaches aim to generate stem-cell-derived insulin producing cells, which could make diabetes cellular therapy available to millions. However, to date, stem cell therapy for diabetes is still in its early experimental stages. This review describes the most reliable sources of stem cells that have been developed to produce insulin and their most relevant experimental applications for the cure of diabetes.

Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration.

Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgene-free cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo. Pluripotent stem cell therapy for diabetes relies on the safety as well as the quality of derived insulin-producing cells. Data from this study highlight prominent tumorigenic risks of induced pluripotent stem cell (iPSC) products, especially when reprogrammed with integrating vectors. Two major underlying mechanisms in iPSC tumorigenicity are residual pluripotent cells and cMYC overload by vector integration. This study also demonstrated that combined transgene-free reprogramming and enzymatic dissociation allows teratoma-free transplantation of iPSC progeny in the mouse model in testing the tumorigenicity of iPSC products. Further safety assessment and improvement in iPSC specification into a mature β cell phenotype would lead to safe islet replacement therapy for diabetes.

Mechanism study for hypoxia induced differentiation of insulin-producing cells from umbilical cord blood-derived mesenchymal stem cells

Recently, we have successfully obtained functional IPCs efficiently from umbilical cord blood-derived mesenchymal stem cells by using hypoxia treatment. In this study, we further elaborated that the improved function and viability of IPCs are the result of the interaction β cell development pathway and c-Met/HGF axis induced by hypoxia. We found that hypoxia induced c-MET elevation is efficiently initiated the early stage differentiation IPCs from MSCs, and HGF improved the fully differentiation of IPCs by inducing the expression of NGN3. This finding may contribute to understanding β cell development and the development of stem cell therapy for diabetes.

Transplantation of islet-like cell clusters derived from human dental pulp stem cells restores normoglycemia in diabetic mice

Background aimsThe success of islet transplantation for diabetes depends on the availability of an adequate number of allogeneic or autologous islets. Postnatal stem cells are now considered for the generation of physiologically competent, insulin-producing cells. Our group showed earlier that it is possible to generate functional islets from human dental pulp stem cells by using a serum-free cocktail in a three-step protocol. MethodsWe compared the yield of generated islet-like cell clusters (ICCs) from stem cells from pulps of human exfoliated deciduous teeth (SHED) and dental pulp stem cells from permanent teeth (DPSCs). ICCs derived from SHED were packed in immuno-isolatory biocompatible macro-capsules and transplanted into streptozotocin (STZ)-induced diabetic mice. Non-diabetic and diabetic controls were transplanted with macro-capsules with or without islets. ResultsSHED were superior to DPSCs. STZ diabetic mice alone and mice transplanted with empty macro-capsules exhibited hyperglycemia throughout the experiment, whereas mice transplanted with macro-capsules containing ICCs were restored to normoglycemia within 3–4 weeks, which persisted for >60 days. ConclusionsOur results demonstrate for the first time that ICCs derived from SHED reverse STZ diabetes in mice without immunosuppression and offer an autologous and non-controversial source of human tissue that could be used for stem cell therapy in diabetes.

Generation of Insulin Producing Cells using Mesenchymal Stem Cells Derived from Bone Marrow of New-Zealand White Rabbits

Background: The utilization of stem cell trans-differentiation into insulin-producing cells (IPCs) would provide potential promising therapy for diabetes mellitus (DM). Objective: The study was aimed to investigate the differentiation potential of rabbit’s bone marrowderived cells into insulin producing cells. Methods: Bone marrow-derived mesenchymal stem cells (MSCs) were obtained from three New-Zealand male white rabbits and propagated in a primary culture for 14 days in low glucose Dulbecco's Modified Eagle's Medium (DMEM), harvested and subjected to another three passages encompassing 21 days. After that, MSCs were functionally defined by their ability to differentiate into osteoblasts. This was achieved by incubation with the DMEM containing 10 -7 M dexamethasone, 10 mM βglycerophosphate and 50 μl/ml of ascorbic acid. Osteogenic differentiation was followed up at days 2, 4, 7 and 9 by staining cells with alizarin red S and vonKossa. Results: It was found that the onset of differentiation was at day 7 and continued at day 9. On the other hand, another patch of MSCs were induced into insulin-producing cells by two step incubation. The first with high glucose serum-free DMEM containing 0.5 mmol/L β-mercaptoethanol for three days and the second follows by incubation with the same medium containing 10 mmol/L nicotinamideinstead of β-mercaptoethanolfor 18 days. Trans-differentiation was followed up at days 4, 9, 14 and 21. It was found that the cells have trans-differentiated into insulin-producing cells starting from day 14 and continued in the subsequent days as judged by their affinity to stain with diphenylthiocarbazone (dithizone or DTZ) at days 14 and 21. Conclusion: The results would provide some insights of using rabbit's bone marrow as a source of MSCs with their differentiation potentials. This might help for the development of a future stem cell therapy for diabetes as well as several other human diseases.

Stem Cell Therapy for Diabetes: A Call for Efficient Differentiation of Pancreatic Progenitors

Stem Cell Therapy for Diabetes: A Call for Efficient Differentiation of Pancreatic Progenitors Given the capacity of differentiating into functional beta cells in vivo, transplantation of pancreatic progenitors derived from human embryonic stem cells (hESCs) has been considered as a promising avenue in beta cell replacement therapy . Besides the concerns of preventing teratoma formation, reducing host immune system rejection and other related safety issues , generating sufficient number of pancreatic progenitors is one of the priorities before any consideration of clinical application.

Esicon 2012,Kolkata: The best of Indian Endocrinology

It has been 42 years since the first ESICON was held. Over the years, ESICON has grown from strength to strength in becoming the largest national forum for endocrinologists in India. Amongst all the sub-specialties of medicine, endocrinology has the strongest association with global health, be it diabetes, thyroid disorders or osteoporosis. It covers the entire gamut of medical science and is one of the fastest developing fields in medical research, worldwide. This annual program is designed to update endocrinologists on recent advances and practices in the field of endocrinology, as well as encourage research in endocrinology. ESICON 2012 has invited eminent national speakers and speakers from across the globe, in order to create a platform for academic interaction between researchers, clinicians and trainees. To establish ESICON as one of the premier endocrine meetings we need to collaborate and exchange ideas with other renowned societies across the world. Thyroid ultrasonography is a well established diagnostic tool in the hands of practicing clinical endocrinologists in the west especially USA. For the first time in an ESICON meeting, we have arranged for a hands-on thyroid ultrasound training mainly focusing on trainees. The Endocrine Society has agreed to conduct this program. Moreover, we have also arranged for a short training in medical statistics, which will enable young researchers to develop their analytical skills and facilitate international publications. Workshops on clinical genetics and insulin pumps are also been organized. Another key feature of ESICON is the oral communications and poster presentations by researchers in the field of endocrinology. This year, more than hundred abstracts will be presented in the meeting. The topics of research papers cover the entire spectrum of endocrinology from diabetes, thyroid, adrenal, pituitary, bone to reproductive and pediatric endocrinology. For the first time since its inception, we are publishing a special conference edition of Indian Journal of Endocrinology and Metabolism. The main focus of this edition is the brief communications of the papers to be presented as abstracts in the meeting. The objective of this supplement is to give a fillip to research activity in India. We have received brief communications from all over India that gives a perspective on varied endocrine researches covering all fields of endocrinology. We have epidemiological research papers ranging from dyshormonogenetic goiter, hypothyroidism after external beam radiation, empty sella syndrome to hyperparathyroidism, cardiovascular risk (CV) risk in PCOS. We have basic research papers like association of severity of diabetic neuropathy with serum sFasL level, characterization of GH1 gene in isolated growth hormone deficiency (GHD) and use of urinary cortisol creatinine ratio as a novel diagnostic tool in Cushing's syndrome. In the area of intervention, we have a huge variety from effect of vitamin D fortification in school children, selenium substitution in autoimmune thyroid disease and also effect of ileal interposition and sleeve gastrectomy in diabetes treatment, to name a few. Numerous interesting case reports with learning issues like De Morseir syndrome, gigantism and pachydermoperiostosis have also been illustrated. Endocrinology cuts across different disciplines of medicine and requires integrated inputs from fields like genetics, biochemistry, physiology, immunology, molecular biology just like the hormones that act like chemical messengers influencing the whole of our systems biology. This supplement aims to provide the most up-to-date information in various aspects of endocrinology to practicing endocrinologists, trainees and researchers alike. Basic science topics like calcium sensing receptors, molecular pathology of pituitary tumors have been given due importance as has diagnostic issues like FRAX, vitamin D assay, clinical management concerns like management of diabetes insipidus, osteoporosis, neonatal hypoglycemia and futuristic topics like stem cell therapy in diabetes, thyromimetics. It is a great honor for the organizing committee to have eminent experts in the field of endocrinology from India and across the world to deliver lectures in ESICON 2012. The recent advances and clinical practice guidelines from experts in different fields of endocrinology have been incorporated as mini reviews in this edition. We wish to thank all authors including the young researchers and eminent speakers for their time and effort in providing up to date information and concise review relating to all fields of endocrinology. Without their valuable inputs, this edition would not have seen the light of the day. We would like to express our sincere gratitude to the editor of the journal who has given us this opportunity.

Stem cell therapy for diabetes

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Differentiation of Dental Pulp Stem Cells into Islet-like Aggregates

The post-natal dental pulp tissue contains a population of multipotent mesenchymal progenitor cells known as dental pulp stromal/stem cells (DPSCs), with high proliferative potential for self-renewal. In this investigation, we explored the potential of DPSCs to differentiate into pancreatic cell lineage resembling islet-like cell aggregates (ICAs). We isolated, propagated, and characterized DPSCs and demonstrated that these could be differentiated into adipogenic, chondrogenic, and osteogenic lineage upon exposure to an appropriate cocktail of differentiating agents. Using a three-step protocol reported previously by our group, we succeeded in obtaining ICAs from DPSCs. The identity of ICAs was confirmed as islets by dithiozone-positive staining, as well as by expression of C-peptide, Pdx-1, Pax4, Pax6, Ngn3, and Isl-1. There were several-fold up-regulations of these transcription factors proportional to days of differentiation as compared with undifferentiated DPSCs. Day 10 ICAs released insulin and C-peptide in a glucose-dependent manner, exhibiting in vitro functionality. Our results demonstrated for the first time that DPSCs could be differentiated into pancreatic cell lineage and offer an unconventional and non-controversial source of human tissue that could be used for autologous stem cell therapy in diabetes.

Induced pluripotent stem cell technology and stem cell therapy for diabetes

Although diabetes can be managed clinically with the use of insulin injections, it remains an incurable and inconvenient disorder. In the long-term, it is associated with a number of clinical complications, such as cardiovascular disease, resulting in a desire for the development of new methodologies to replace defective cells and provide a lasting normality without the need for drug treatment. Stem cells, including induced pluripotent stem cells, offer the possibility of generating cells suitable for transplantation due to their capacity to differentiate into all tissue lineages. However, many issues must be addressed before this type of treatment becomes a reality, including the need for a greater understanding of the underlying biology involved in the onset of diabetes.

Human Placenta-Derived Mesenchymal Stem Cells and Islet-Like Cell Clusters Generated From These Cells as a Novel Source for Stem Cell Therapy in Diabetes

Placental tissue holds great promise as a source of cells for regenerative medicine due to its plasticity, and easy availability. Human placenta-derived mesenchymal stem cells (hPDMSCs) have the potential to differentiate into insulin-producing cells. Upon transplantation, they can reverse experimental diabetes in mice. However, it is not known whether culture-expanded undifferentiated hPDMSCs are capable of restoring normoglycemia upon transplantation in streptozotocin (STZ)-induced diabetic mice. Hence we prepared long-term cultures of hPDMSCs from the chorionic villi of full-term human placenta. Flow cytometry analyses and immunocytochemistry study revealed bonafide mesenchymal nature of the isolated hPDMSCs. These cultures could differentiate into adipogenic, oesteogenic, chondrogenic, and neuronal lineages on exposure to lineage-specific cocktails. Furthermore, we showed that hPDMSCs can form islet-like cell clusters (ILCs) on stepwise exposure to serum-free defined media containing specific growth factors and differentiating agents. qRT-PCR showed the expression of insulin, glucagon, and somatostatin in undifferentiated hPDMSCs and in ILCs. Differentiated ILCs were found to express human insulin, glucagon, and somatostatin by immunocytochemistry. Additionally, ILCs also showed abundance of pancreatic transcription factors ngn3 and isl1. Both undifferentiated hPDMSCs and ILCs exihibited insulin secretion in response to glucose. Transplantation of hPDMSCs or ILCs derived from hPDMSCs in STZ-induced diabetic mice led to restoration of normoglycemia. Our results demonstrate, for the first time, reversal of hyperglycemia by undifferentiated hPDMSCs and ILCs derived from hPDMSCs. These results suggest human placenta-derived MSCs as an alternative source for cell replacement therapy in diabetes.