Stem Cell-Based Therapies: A New Ray of Hope for Diabetic Patients

Diabetes and its complications are a significant health concern throughout the globe. There are physiological differences in the mechanism of type-I and type-II diabetes and the conventional drug therapy as well as insulin administration seem to be insufficient to address the problem at large successfully. Hypoglycemic swings, frequent dose adjustments and resistance to the drug are major problems associated with drug therapy. Cellular approaches through stem cell based therapeutic interventions offer a promising solution to the problem. The need for pancreatic transplants in case of Type- I diabetes can also be by-passed/reduced due to the formation of insulin producing β cells via stem cells. Embryonic Stem Cells (ESCs) and induced Pluripotent Stem Cells (iPSCs), successfully used for generating insulin producing β cells. Although many experiments have shown promising results with stem cells in vitro, their clinical testing still needs more exploration. The review attempts to bring into light the clinical studies favoring the transplantation of stem cells in diabetic patients with an objective of improving insulin secretion and improving degeneration of different tissues in response to diabetes. It also focuses on the problems associated with successful implementation of the technique and possible directions for future research.

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Human stem cells – sources, sourcing and in vitro methods

Medical Journal of Cell Biology ◽

10.2478/acb-2021-0011 ◽

2021 ◽

Vol 9 (2) ◽

pp. 73-85

Author(s):

Alicja Szubarga ◽

Marta Kamińska ◽

Wiktoria Kotlarz ◽

Stefan Malewski ◽

Wiktoria Zawada ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Type I Diabetes ◽

Embryonic Stem ◽

The Body ◽

Type I ◽

Human Stem Cells ◽

Hematopoietic Stem

Abstract Stem cells are an important subject of research, and are increasingly used in the treatment of various diseases. Due to the development of advanced in vitro techniques, they have become an integral part of modern medicine. The sources of human stem cells are primarily bone marrow and adipose tissue, although non – embryonic stem cells are also scattered throughout the body. Notably, recent research has focused on stem cells found in the oral cavity, both in the dental pulp and oral mucosa. Furthermore, isolation of stem cells from umbilical cord blood is also becoming increasingly popular, while wharton’s jelly and amniotic fluid also seem to be an interesting source of stem cells. The safety and efficacy of stem cells use can be established by animal studies, which are a key element of preclinical research. Mouse, rat and pig models allow for testing of stem cell therapies. Recent studies primarily use mesenchymal stem cells such as mouse – adipose derived mesenchymal stem cells and mouse and rat hematopoietic stem cells. Great hope for future therapies is the use of bioengineering to program cells into induced stem cells, which have the biggest ability for differentiation and transdifferentiation, which carries no risk of teratogenesis. Stem cells are used in many areas of medicine, especially in regenerative medicine, with a growing interest in orthopedics and in the treatment of heart failure. Mesenchymal stem cells are the most used stem cell type, which despite their limited ability to differentiate, give great therapeutic results, mainly due to their immunomodulating effect. Recent studies have even shown that the use of mesenchymal stem cells may be useful in the treatment of COVID-19. Moreover, Research on the use of mesenchymal stem cells in the treatment of Crohn’s disease, acute-graft-versus-host disease and type I diabetes are also promising. The aim of the current review is to present and systematize current knowledge about stem cells, their use and related in vitro research. Running title: Research and use of human stem cells

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Accelerated Wound Healing by Fibroblasts Differentiated from Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells in a Pressure Ulcer Animal Model

Stem Cells International ◽

10.1155/2018/4789568 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Dajeong Yoon ◽

Dogeon Yoon ◽

Heejoong Sim ◽

Inseok Hwang ◽

Ji-Seon Lee ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Embryonic Stem Cell ◽

Pressure Ulcer ◽

Human Embryonic Stem Cell ◽

Embryonic Stem ◽

Type I ◽

Skin Ulcers

Fibroblasts synthesize and secrete dermal collagen, matrix proteins, growth factors, and cytokines. These characteristics of fibroblasts provide a potential way for fibroblast therapy to treat skin ulcers more effectively than conventional therapies such as cytokine therapy and negative pressure wound therapy. However, the obstacle to the commercialization of fibroblast therapy is the limited supply of cells with consistent quality. In this study, we tested whether human embryonic stem cell-derived mesenchymal stem cells (hESC-MSCs) could be differentiated into fibroblasts considering that they have characteristics of high differentiation rates, unlimited proliferation possibility from a single colony, and homogeneity. As a result, hESC-MSC-derived fibroblasts (hESC-MSC-Fbs) showed a significant increase in the expression of type I and III collagen, fibronectin, and fibroblast-specific protein-1 (FSP-1). Besides, vessel formation and wound healing were enhanced in hESC-MSC-Fb-treated skin tissues compared to PBS- or hESC-MSC-treated skin tissues, along with decreased IL-6 expression at 4 days after the formation of pressure ulcer wound in a mouse model. In view of the limited available cell sources for fibroblast therapy, hESC-MSC-Fbs show a promising potential as a commercial cell therapy source to treat skin ulcers.

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Patterns of failure in the treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2005.06.213 ◽

2005 ◽

Vol 201 (3) ◽

pp. S90-S91

Author(s):

Takahisa Fujikawa ◽

Seh-Hoon Oh ◽

Liya Pi ◽

Tom Shupe ◽

Bryon Petersen ◽

...

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Type I Diabetes ◽

Embryonic Stem ◽

Type I ◽

Patterns Of Failure ◽

Insulin Producing Cells

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Effect of Type I Diabetes on the Proteome of Mouse Oocytes

Cellular Physiology and Biochemistry ◽

10.1159/000447924 ◽

2016 ◽

Vol 39 (6) ◽

pp. 2320-2330 ◽

Cited By ~ 5

Author(s):

Guangjian Jiang ◽

Guangli Zhang ◽

Tian An ◽

Zhongchen He ◽

Lihua Kang ◽

...

Keyword(s):

Type I Diabetes ◽

Protein Profile ◽

Reproductive Age ◽

Reproductive Capacity ◽

Health Concern ◽

Diabetic Patients ◽

Type I ◽

Metabolic Processes ◽

Spindle Formation ◽

Mouse Oocytes

Background: Type I diabetes is a global public health concern that affects young people of reproductive age and can damage oocytes, reducing their maturation rate and blocking embryonic development. Understanding the effects of type I diabetes on oocytes is important to facilitate the maintenance of reproductive capacity in female diabetic patients. Methods: To analyze the effects of type I diabetes on mammalian oocytes, protein profile changes in mice with streptozotocin-induced type I diabetes were investigated using proteomic tools; non-diabetic mouse oocytes were used as controls. Immunofluorescence analysis for the spindle and mitochondria of oocytes. Results: We found that type I diabetes severely disturbed the metabolic processes of mouse oocytes. We also observed significant changes in levels of histone H1, H2A/B, and H3 variants in diabetic oocytes (fold change: > 0.4 or < -0.4), with the potential to block activation of the zygotic genome and affect early embryo development. Furthermore, diabetic oocytes exhibited higher abnormal spindle formation and spatial remodeling of mitochondria than observed in the controls. Conclusion: Our results indicate that type I diabetes disrupts metabolic processes, spindle formation, mitochondria distribution and modulates epigenetic code in oocytes. Such effects could have a major impact on the reproductive dynamics of female patients with type I diabetes.

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Are stem cells a cure for diabetes?

Clinical Science ◽

10.1042/cs20090072 ◽

2009 ◽

Vol 118 (2) ◽

pp. 87-97 ◽

Cited By ~ 35

Author(s):

Michael D. McCall ◽

Christian Toso ◽

Emmanuel E. Baetge ◽

A. M. James Shapiro

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Embryonic Stem Cells ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Adult Stem Cells ◽

Embryonic Stem ◽

Diabetic Patients ◽

Insulin Producing Cells ◽

Early Mouse

With the already heightened demand placed on organ donation, stem cell therapy has become a tantalizing idea to provide glucose-responsive insulin-producing cells to Type 1 diabetic patients as an alternative to islet transplantation. Multiple groups have developed varied approaches to create a population of cells with the appropriate characteristics. Both adult and embryonic stem cells have received an enormous amount of attention as possible sources of insulin-producing cells. Although adult stem cells lack the pluripotent nature of their embryonic counterparts, they appear to avoid the ethical debate that has centred around the latter. This may limit the eventual application of embryonic stem cells, which have already shown promise in early mouse models. One must also consider the potential of stem cells to form teratomas, a complication which would prove devastating in an immunologically compromised transplant recipient. The present review looks at the progress to date in both the adult and embryonic stem cells fields as potential treatments for diabetes. We also consider some of the limitations of stem cell therapy and the potential complications that may develop with their use.

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Concise review: current trends on applications of stem cells in diabetic nephropathy

Cell Death and Disease ◽

10.1038/s41419-020-03206-1 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Dongwei Liu ◽

Wen Zheng ◽

Shaokang Pan ◽

Zhangsuo Liu

Keyword(s):

Stem Cells ◽

Diabetic Nephropathy ◽

Stem Cell ◽

Embryonic Stem ◽

Kidney Injury ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Future Expectations ◽

Differentiation Potential ◽

Cell Based Therapy

AbstractDiabetic nephropathy, with high prevalence, is the main cause of renal failure in diabetic patients. The strategies for treating DN are limited with not only high cost but an unsatisfied effect. Therefore, the effective treatment of DN needs to be explored urgently. In recent years, due to their self-renewal ability and multi-directional differentiation potential, stem cells have exerted therapeutic effects in many diseases, such as graft-versus-host disease, autoimmune diseases, pancreatic diseases, and even acute kidney injury. With the development of stem cell technology, stem cell-based regenerative medicine has been tried to be applied to the treatment of DN. Related stem cells include embryonic stem cells, induced pluripotent stem cells, mesenchymal cells, and endothelial progenitor cells. Undoubtedly, stem cell transplantation has achieved certain results in the treatment of DN animal models. However, stem cell therapy still remains certain thorny issues during treatment. For instance, poor engraftment and limited differentiation of stem cells caused by the diabetic microenvironment, differentiation into unwanted cell lineages, and malignant transformation or genetic aberrations of stem cells. At present, various researches on the therapeutic effects of stem cells in DN with different opinions are reported and the specific mechanism of stem cells is still unclear. We review here the potential mechanism of stem cells as new therapeutic agents in the treatment of DN. Also, we review recent findings and updated information about not only the utilization of stem cells on DN in both preclinical and clinical trials but limitations and future expectations of stem cell-based therapy for DN.

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Stem Cell-Based Clinical Trials for Diabetes Mellitus

Frontiers in Endocrinology ◽

10.3389/fendo.2021.631463 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eleonora de Klerk ◽

Matthias Hebrok

Keyword(s):

Clinical Trials ◽

Stem Cell ◽

Islet Transplantation ◽

Type I Diabetes ◽

Embryonic Stem ◽

Insurance Companies ◽

Type I ◽

Β Cells ◽

The Impact

Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized insulin therapy. To improve C-peptide levels in patients with both T1 and T2 Diabetes, numerous clinical trials have explored the efficacy of mesenchymal stem cells (MSCs), both as supporting cells to protect existing β cells, and as source for newly generated β cells. Transplantation of MSCs is found to be effective for T2D patients, but its efficacy in T1D is controversial, as the ability of MSCs to differentiate into functional β cells in vitro is poor, and transdifferentiation in vivo does not seem to occur. Instead, to address limitations related to supply, human embryonic stem cell (hESC)-derived β cells are being explored as surrogates for cadaveric islets. Transplantation of allogeneic hESC-derived insulin-producing organoids has recently entered Phase I and Phase II clinical trials. Stem cell replacement therapies overcome the barrier of finite availability, but they still face immune rejection. Immune protective strategies, including coupling hESC-derived insulin-producing organoids with macroencapsulation devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.

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Differentiation protocol for generating functional pancreatic β cells from human pluripotent stem cells

10.21203/rs.3.pex-1413/v1 ◽

2021 ◽

Author(s):

Haisong Liu ◽

Ronghui Li ◽

Hsin-Kai Liao ◽

Juan Carlos Izpisua Belmonte

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Type I Diabetes ◽

Embryonic Stem ◽

Human Pluripotent Stem Cells ◽

Type I ◽

Β Cells ◽

Pancreatic Β Cells ◽

Differentiation Protocol ◽

Induced Pluripotent

Abstract The efficient generation of pancreatic β cells from human pluripotent stem cells may allow us to study their biological characteristics and use them for the treatment of type I diabetes. The protocol we present in the study provides an efficient method for producing β cells using either human embryonic stem cells or human induced pluripotent stem cells as the starting material.

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Embryonic Stem Cell Transplant (ESCT)-Derived Mixed Hematopoietic Chimerism Prevents Diabetes in NOD Mice.

Blood ◽

10.1182/blood.v104.11.2132.2132 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2132-2132

Author(s):

Richard K. Burt ◽

Larissa Verda ◽

Duck A. Kim ◽

Laisvyde Statkute ◽

Yu Oyama ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Embryonic Stem Cell ◽

Embryonic Stem ◽

Nod Mice ◽

Lymphocytic Infiltration ◽

Type I ◽

Allogeneic Bone ◽

Hematopoietic Chimerism

Abstract NOD mice are a widely used animal model for studying type I diabetes mellitus characterized by lymphocytic infiltration of pancreatic islets following by development of diabetes by age 3 to 4 months. It has been shown that allogeneic bone marrow transplantation can prevent insulitis and overt diabetes. We have recently demonstrated that embryonic stem cell-derived hematopoietic stem cells (ESC-derived HSC) can reconstitute bone marrow in lethally irradiated mice across MHC barriers without graft versus host disease (GVHD). Herein we report a new ESC-derived HSCT approach for the prevention of autoimmune diabetes in NOD mice. 6-weeks old female mice were sublethally irradiated (8.0 Gy) and transplanted with ESC-derived HSC. To induce differentiation toward HSC in vitro, ESC (R1) were cultured in methylcellulose-based medium supplemented with SCF, IL-3 and IL-6. An enriched c-kit+CD45+ ESC-derived suspension was delivered intra bone marrow (IBM) (mean 0.5 x 106/mouse) (N=8) or intravenously (mean 1 x 106/mouse) (N=6). Six NOD mice were held as control. Mice were followed by blood glucose measurements and chimerism analysis until onset of diabetes or until 32 weeks after transplantation. 7 out of 8 mice from IBM group and 4 out of 6 from IV group did not become hyperglycemic in contrast to control group where 5 out of 6 mice were euthanized because of diabetes. The level of chimerism achieved after transplantation was 8.2%±5.76 in IBM group and 3.2%±2.75 in IV group. Histological examination showed that most of islets were replaced by lymphocytic infiltration or fibrous tissue in controls (even in case of a mouse without clinical evidence of diabetes). In 78% (11/14) of animals from ESC-derived hematopoiesis, remission was confirmed by histology revealing absence of insulinitis and normal immunohistochemical staining of islet cells for insulin. Prevention of diabetes/insulinitis was predicted by the percentage ESC-derived hematopoietic chimerism. All mice with > 5% ESC-derived chimerism remained free of diabetes and insulinitis. These results suggest that allogeneic chimerism achieved with embryonic stem cells can prevent diabetes in NOD mice without evidence of GVHD or use of post transplant immune suppression.

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Stem Cells - biological update and cell therapy progress

Medicine and Pharmacy Reports ◽

10.15386/cjmed-483 ◽

2015 ◽

Vol 88 (3) ◽

pp. 265-271 ◽

Cited By ~ 16

Author(s):

Mihai Girlovanu ◽

Sergiu Susman ◽

Olga Soritau ◽

Dan Rus-Ciuca ◽

Carmen Melincovici ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Therapy ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Molecular Mechanisms ◽

Embryonic Stem ◽

Type I ◽

Differentiation Potential ◽

Induced Pluripotent

In recent years, the advances in stem cell research have suggested that the human body may have a higher plasticity than it was originally expected.Until now, four categories of stem cells were isolated and cultured in vivo: embryonic stem cells, fetal stem cells, adult stem cells and induced pluripotent stem cells (hiPSCs).Although multiple studies were published, several issues concerning the stem cells are still debated, such as: the molecular mechanisms of differentiation, the methods to prevent teratoma formation or the ethical and religious issues regarding especially the embryonic stem cell research.The direct differentiation of stem cells into specialized cells: cardiac myocytes, neural cells, pancreatic islets cells, may represent an option in treating incurable diseases such as: neurodegenerative diseases, type I diabetes, hematologic or cardiac diseases.Nevertheless, stem cell-based therapies, based on stem cell transplantation, remain mainly at the experimental stages and their major limitation is the development of teratoma and cancer after transplantation. The induced pluripotent stem cells (hiPSCs) represent a prime candidate for future cell therapy research because of their significant self-renewal and differentiation potential and the lack of ethical issues.This article presents an overview of the biological advances in the study of stem cells and the current progress made in the field of regenerative medicine.

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