Diabetes mellitus: a potential target for stem cell therapy

Type 1 diabetes mellitus has received much attention recently as a potential target for the emerging science of stem cell medicine. In this autoimmune disease, the insulin-secreting beta-cells of the pancreas are selectively and irreversibly destroyed by autoimmune assault. Advances in islet transplantation procedures now mean that patients with the disease can be cured by transplantation of primary human islets of Langerhans. A major drawback in this therapy is the availability of donor islets, and the search for substitute transplant tissues has intensified in the last few years. This review will describe the essential requirements of a material designed as a replacement beta-cell and will look at the potential sources of such replacements. These include embryonic stem (ES) cells and multipotent adult stem/progenitor cells from a range of tissues including the pancreas, intestine, liver, bone marrow and brain. These stem cell populations will be evaluated and the different experimental approaches that have been employed to derive functional insulin-expressing cells will be discussed. The review will also look at the capability of human ES (hES) cells generated by somatic cell nuclear transfer and some adult stem cell populations such as bone marrow-derived stem cells, to offer autologous transplant material that would remove the need for immunosuppression. In patients with Type 1 diabetes, auto-reactive T-cells are programmed to recognise the insulin-producing beta-cells. As a result, for therapeutic replacement tissues, it may be more sensible to derive cells that behave like beta-cells but are immunologically distinct. Thus, the potential of cells derived from non-beta-cell origin to avoid the autoimmune response will also be discussed. Finally, the review will summarise the future prospects for stem cell therapies for diabetes and will highlight some of the problems that may be faced by researchers working in this area, such as malignancy, irreproducible differentiation strategies, immune-system rejection and social and ethical concerns over the use of hES cells.     

Growth factors and beta cell replication

Recent studies have demonstrated that human islet allograft transplantation can be a successful therapeutic option in the treatment of patients with Type I diabetes. However, this impressive recent advance is accompanied by a very important constraint. There is a critical paucity of pancreatic islets or pancreatic beta cells for islet transplantation to become a large-scale therapeutic option in patients with diabetes. This has prompted many laboratories around the world to invigorate their efforts in finding ways for increasing the availability of beta cells or beta cell surrogates that potentially could be transplanted into patients with diabetes. The number of studies analyzing the mechanisms that govern beta cell proliferation and growth in physiological and pathological conditions has increased exponentially during the last decade. These studies exploring the role of growth factors, intracellular signaling molecules and cell cycle regulators constitute the substrate for future strategies aimed at expanding human beta cells in vitro and/or in vivo after transplantation. In this review, we describe the current knowledge on the effects of several beta cell growth factors that have been shown to increase beta cell proliferation and expand beta cell mass in vitro and/or in vivo and that they could be potentially deployed in an effort to increase the number of patients transplanted with islets. Furthermore, we also analyze in this review recent studies deciphering the relevance of these specific islet growth factors as physiological and pathophysiological regulators of beta cell proliferation and islet growth.     

The umbilical cord: a rich and ethical stem cell source to advance regenerative medicine

Science and medicine place a lot of hope in the development of stem cell research and regenerative medicine. This review will define the concept of regenerative medicine and focus on an abundant stem cell source - neonatal tissues such as the umbilical cord. Umbilical cord blood has been used clinically for over 20 years as a cell source for haematopoietic stem cell transplantation. Beyond this, cord blood and umbilical cord-derived stem cells have demonstrated potential for pluripotent lineage differentiation (liver, pancreatic, neural tissues and more) in vitro and in vivo. This promising research has opened up a new era for utilization of neonatal stem cells, now used beyond haematology in clinical trials for autoimmune disorders, cerebral palsy or type I diabetes.     

In vitro reconstitution of pancreatic islets

The lack of transplantable pancreatic islets is a serious problem that affects the treatment of patients with type 1 diabetes mellitus. Beta cells can be induced from various sources of stem or progenitor cells, including induced pluripotent stem cells in the near future; however, the reconstitution of islets from β cells in culture dishes is challenging. The generation of highly functional islets may require three-dimensional spherical cultures that resemble intact islets. This review discusses recent advances in the reconstitution of islets. Several factors affect the reconstitution of pseudoislets with higher functions, such as architectural similarity, cell-to-cell contact, and the production method. The actual transplantation of naked or encapsulated pseudoislets and islet-like cell clusters from various stem cell sources is also discussed. Advancing our understanding of the methods used to reconstitute pseudoislets should expand the range of potential strategies available for developing de novo islets for therapeutic applications.     

胚胎干细胞移植治疗糖尿病的研究进展

糖尿病是一种严重的免疫缺陷性疾病,目前的治疗方法很难从根本上治愈。近年来的研究表明,通过诱导胚胎干细胞定向分化为胰岛β细胞,并进行移植治疗糖尿病,是一种有希望的根治方案。本文就利用胚胎干细胞移植治疗糖尿病的最新进展作一综述。     

Stem cell-based approaches to solving the problem of tissue supply for islet transplantation in type 1 diabetes

Type 1 diabetes is a debilitating condition, affecting millions worldwide, that is characterized by the autoimmune destruction of insulin-producing pancreatic islets of Langerhans. Although exogenous insulin administration has traditionally been the mode of treatment for this disease, recent advancements in the transplantation of donor-derived insulin-producing cells have provided new hope for a cure. However, in order for islet transplantation to become a widely used technique, an alternative source of cells must be identified to supplement the limited supply currently available from cadaveric donor organs. Stem cells represent a promising solution to this problem, and current research is being aimed at the creation of islet-endocrine tissue from these undifferentiated cells. This review presents a summary of the research to date involving stem cells and cell replacement therapy for type 1 diabetes. The potential for the differentiation of embryonic stem (ES) cells to islet phenotype is discussed, as well as the possibility of identifying and exploiting a pancreatic progenitor/stem cell from the adult pancreas. The possibility of creating new islets from adult stem cells derived from other tissues, or directly form other terminally differentiated cell types is also addressed. Finally, a model for the isolation and maturation of islets from the neonatal porcine pancreas is discussed as evidence for the existence of an islet precursor cell in the pancreas.     

成体干细胞在1型糖尿病中的应用研究及展望

成体干细胞存在于机体已分化的组织中,可在一定条件下分化为特定类型的细胞。成体干细胞来源广,移植后不存在免疫排斥反应,在1型糖尿病治疗领域有广阔的应用前景,可以作为受损伤或无功能的β细胞的替代细胞。该文主要概述了近年来成体干细胞在1型糖尿病中的应用研究及面临的问题。     

Animal models to study adult stem cell-derived, in vitro-generated islet implantation

Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia following the destruction of the insulin-producing beta cells of the pancreatic islets of Langerhans by the body's own immune system. Although routine insulin injections can provide diabetic patients with their daily insulin requirements, this treatment is not always effective in maintaining normal glucose levels. A true "cure" is considered possible only through replacement of the beta cell mass, by pancreas transplantation, islet implantation, or implantation of nonendocrine cells modified to secrete insulin. With the recent success of islet implantation to reverse T1D, this procedure has become a welcome therapy for T1D patients. Unfortunately, this procedure is hampered by the limited number of transplantation quality pancreata available for the harvesting of islets. This shortage has sparked great interest in finding a replacement for organ donation, primarily the possible use of stem cell-derived islets starting with stem cells, or alternatively the harvesting of nonhuman islets. This review focuses on progress with growing islets in the laboratory from stem cells and a comparison between this developing technology and the current use of islets harvested from nonhuman sources.     

In vitro reconstitution of pancreatic islets

The lack of transplantable pancreatic islets is a serious problem that affects the treatment of patients with type 1 diabetes mellitus. Beta cells can be induced from various sources of stem or progenitor cells, including induced pluripotent stem cells in the near future; however, the reconstitution of islets from β cells in culture dishes is challenging. The generation of highly functional islets may require three-dimensional spherical cultures that resemble intact islets. This review discusses recent advances in the reconstitution of islets. Several factors affect the reconstitution of pseudoislets with higher functions, such as architectural similarity, cell-to-cell contact, and the production method. The actual transplantation of naked or encapsulated pseudoislets and islet-like cell clusters from various stem cell sources is also discussed. Advancing our understanding of the methods used to reconstitute pseudoislets should expand the range of potential strategies available for developing de novo islets for therapeutic applications.     

Effects of shear stress on differentiation of stem cells into endothelial cells

Stem cell transplantation is an appealing potential therapy for vascular diseases and an indispensable key step in vascular tissue engineering. Substantial effort has been made to differentiate stem cells toward vascular cell phenotypes, including endothelial cells (ECs) and smooth muscle cells. The microenvironment of vascular cells not only contains biochemical factors that influence differentiation but also exerts hemodynamic forces, such as shear stress and cyclic strain. More recently, studies have shown that shear stress can influence the differentiation of stem cells toward ECs. A deep understanding of the responses and underlying mechanisms involved in this process is essential for clinical translation. This review highlights current data supporting the role of shear stress in stem cell differentiation into ECs. Potential mechanisms and signaling cascades for transducing shear stress into a biological signal are proposed. Further study of stem cell responses to shear stress will be necessary to apply stem cells for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.     

How to make pancreatic beta cells--prospects for cell therapy in diabetes

One promising approach for the cure of diabetes is the replacement of lost insulin-expressing beta cells by cell or regenerative therapy. The recent development of an effective islet transplantation procedure has focused attention on the limiting supply of beta cells. Various sources for new beta cells are therefore being considered, including embryonic stem cells, adult stem cells and transdifferentiation of certain types of differentiated cells, so far with limited success. The major physiological mechanism for adult beta cell formation was recently shown to be beta cell proliferation. This finding underscores the potential use of terminally differentiated beta cells as a starting material for enhancement of beta cell mass.     

糖尿病的细胞治疗

胰岛素产生细胞的缺陷或缺乏导致的Ⅰ型糖尿病是影响人类健康的重大疾病之一。最近细胞移植和组织工程的研究进展,使得糖尿病的细胞替代治疗成为可能,即通过胰岛素产生细胞的移植治疗Ⅰ型糖尿病和某些Ⅱ型糖尿病。但是由于供体细胞缺乏的限制,使得糖尿病的细胞治疗难以广泛开展。胰腺干细胞将成为胰岛素产生细胞的潜在来源。就Ⅰ型糖尿病的发病机制和治疗中存在的问题、胰腺干细胞的分离和分化、胰岛移植治疗糖尿病的局限性和干细胞治疗的必要性、糖尿病细胞治疗的探讨作如下介绍。     

胰高血糖素样肽1与干细胞定向分化

糖尿病已经成为21世纪严重威胁人类健康的疾病之一。胰岛移植被认为是治疗Ⅰ型和部分Ⅱ型糖尿病的最有效方法。然而,供体组织来源的匮乏限制了其应用。随着细胞移植和组织工程的日益发展,干细胞研究为新型胰岛的来源开辟了新的途径。干细胞定向诱导分化的关键是筛选合适的诱导剂以及优化诱导微环境,使干细胞培养微环境尽可能接近体内正常细胞发育分化的微环境,从而有利于干细胞适宜生长及定向分化。最近研究证实,胰高血糖素样肽1（Glucagon- Like PeptideⅠ,GLP-1）在干细胞向胰岛样细胞诱导分化中具有显著作用。因此,为了更好地应用GLP-1在干细胞定向分化中的潜能、促进应用干细胞治疗糖尿病新疗法研究的进程及干细胞定向分化技术逐渐成熟,本文就胰高血糖素样肽-1及它诱导干细胞定向分化胰岛样细胞的研究进展作一阐述。     

Isolation and in vitro characterization of pancreatic progenitor cells from the islets of diabetic monkey models

Recent studies on the identification of stem/progenitor cells within adult mouse and human pancreatic islets have raised the possibility that autologous transplantation might be used in treating type 1 diabetes. However, it is not yet known whether such stem/progenitor cells are impaired in type 1 diabetic patients or diabetic animal models. The latter would also allow us to test the efficacy of autologous transplantation in large animal models prior to clinical applications. The present study aims to determine the existence of stem/progenitor cells in the islets of diabetic monkey models and to assess the proliferation and differentiation potential of such cells in vitro. Our results indicate that there are pancreatic progenitor cells in the adult pancreatic islets in both normal and type 1 diabetic monkeys. The isolated pancreatic progenitor cells can be greatly expanded in culture. Upon the removal of growth medium, these cells spontaneously form islet-like cell clusters, which could be further induced to secrete insulin by inductive factors. Furthermore, the secretion of insulin and C-peptide from the islet-like cell clusters responds to glucose and other stimuli, indicating that the differentiated cells not only resemble beta-cells but also possess the unique biological function of beta-cells. This study provides a foundation for further characterization of adult pancreatic progenitor cells and autologous transplantation using pancreatic progenitor cells in treating diabetic monkeys.     

Generation of new islets from stem cells

Spain ranks number one in organ donors (35 per million per yr). Although the prevalence of diabetes is low (100,000 type 1 diabetic patients and 2 million type 2 diabetic patients), the expected number of patients receiving islet transplants should be estimated at 200 per year. Islet replacement represents a promising cure for diabetes and has been successfully applied in a limited number of type 1 diabetic patients, resulting in insulin independence for periods longer than 3 yr. However, it has been difficult to obtain sufficient numbers of islets from cadaveric donors. Interesting alternatives include acquiring renewable sources of cells using either embryonic or adult stem cells to overcome the islet scarcity problem. Stem cells are capable of extensive proliferation rates and are capable of differentiating into other cell types of the body. In particular, totipotent stem cells are capable of differentiating into all cell types in the body, whereas pluripotent stem cells are limited to the development of a certain number of differentiated cell types. Insulin-producing cells have been obtained from both embryonic and adult stem cells using several approaches. In animal models of diabetes, the therapeutic application of bioengineered insulin-secreting cells derived from stem cells has delivered promising results. This review will summarize the different approaches that have been used to obtain insulin-producing cells from embryonic and adult stem cells and highlights the key points that will allow in vitro differentiation and subsequent transplantation in the future.     

Toward beta cell replacement for diabetes

The discovery of insulin more than 90 years ago introduced a life‐saving treatment for patients with type 1 diabetes, and since then, significant progress has been made in clinical care for all forms of diabetes. However, no method of insulin delivery matches the ability of the human pancreas to reliably and automatically maintain glucose levels within a tight range. Transplantation of human islets or of an intact pancreas can in principle cure diabetes, but this approach is generally reserved for cases with simultaneous transplantation of a kidney, where immunosuppression is already a requirement. Recent advances in cell reprogramming and beta cell differentiation now allow the generation of personalized stem cells, providing an unlimited source of beta cells for research and for developing autologous cell therapies. In this review, we will discuss the utility of stem cell‐derived beta cells to investigate the mechanisms of beta cell failure in diabetes, and the challenges to develop beta cell replacement therapies. These challenges include appropriate quality controls of the cells being used, the ability to generate beta cell grafts of stable cellular composition, and in the case of type 1 diabetes, protecting implanted cells from autoimmune destruction without compromising other aspects of the immune system or the functionality of the graft. Such novel treatments will need to match or exceed the relative safety and efficacy of available care for diabetes.     

WJSC 6th 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.     

Research status and prospect of stem cells in the treatment of diabetes mellitus

Beta cell mass and function are decreased to varying degrees in diabetes. Islet cell replacement or regenerative therapy may offer great therapeutic promise to people with diabetes. In addition to primary pancreatic β cells, recent studies on regeneration of functional insulin producing cells (IPCs) revealed that several alternative cell sources, including embryonic stem cells, induced pluripotent stem cells and adult stem cells, can generate IPCs by differentiation, reprogramming, and trans-differentiation. In this review, we discuss stem cells as a potential alternative cell source for the treatment of diabetes.     

Diabetes Mellitus after Hematopoietic Stem Cell Transplantation

ObjectiveTo review the current literature on posttransplant diabetes mellitus after hematopoietic stem cell transplantation, including its epidemiologic features, transplant-related risk factors, and treatment.MethodsA literature search was conducted in PubMed for articles on diabetes mellitus after hematopoietic stem cell transplantation and effects of immunosuppressants on glucose metabolism.ResultsWithin 2 years after hematopoietic stem cell transplantation, up to 30% of patients may have diabetes. Although some of these cases resolve, the rates of diabetes and metabolic syndrome remain elevated in comparison with those in the nontransplant patient population during long-term follow-up. Traditional risk factors for diabetes as well as features related to the transplantation process, including immunosuppressive medications, are associated with posttransplant diabetes. Cardiovascular risk also appears to be increased in this population. Limited data are available on hypoglycemic agents for posttransplant diabetes; thus, treatment decisions must be based on safety, efficacy, and tolerability, with consideration of each patient’s transplant-related medications and comorbidities.ConclusionTreatment of diabetes mellitus in patients who have undergone hematopoietic stem cell transplantation necessitates attention to the posttransplant medication regimen and clinical course. Although no guidelines specific to treatment of posttransplant diabetes in this patient population currently exist, treatment to goals similar to those for nontransplant patients with diabetes should be considered in an attempt to help reduce long-term morbidity and mortality. (Endocr Pract. 2010;16:699-706)