DIABETES MELLITUS · STEM CELL RESEARCH · DREAM BODY CLINIC
Stem Cells in the Treatment of Diabetes Mellitus – Focus on Mesenchymal Stem Cells
T1DM & T2DM
Disease Focus
ESC · iPSC · MSC
Cell Types
Harvard
Research Cited
Stem cells in the treatment of diabetes mellitus – focus on mesenchymal stem cells
Stem cells in the treatment of diabetes mellitus – focus on mesenchymal stem cells
Günter Päth, Nikolaos Perakakis, Christos S. Mantzoros, Jochen Seufert
PII: S0026-0495(18)30215-4
DOI: doi:10.1016/j.metabol.2018.10.005
Reference: YMETA 53824
To appear in: Metabolism
Received date: 10 August 2018
Accepted date: 14 October 2018
Please cite this article as: Günter Päth, Nikolaos Perakakis, Christos S. Mantzoros, Jochen Seufert, Stem cells in the treatment of diabetes mellitus – focus on mesenchymal stem cells. Ymeta (2018), doi:10.1016/j.metabol.2018.10.005
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ACCEPTED MANUSCRIPT
Stem cells in the treatment of diabetes mellitus – focus on mesenchymal stem cells
Günter Päth1*, Nikolaos Perakakis2, Christos S. Mantzoros2, Jochen Seufert1
1 Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
2 Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Corresponding author
Günter Päth, PhD
Division of Endocrinology and Diabetology
Department of Medicine II
Medical Center – University of Freiburg
Faculty of Medicine, University of Freiburg
Hugstetter Str. 55
79106 Freiburg
GERMANY
Tel.: +49 761 270 73270
Fax: +49 761 270 33720
E-mail: guenter.paeth@uniklinik-freiburg.de
Keywords
Stem cells, diabetes mellitus, transplantation, embryonic stem cells, induced pluripotent stem cells, mesenchymal stromal cells
Abbreviations
ADA, American Diabetes Association; AE, adverse event; α-SMA, alpha smooth muscle actin; ANXA1, annexin-1; AUC, area under the curve; BAD, Bcl-2 antagonist of cell death; Bcl-2b, B-cell lymphoma 2; bFGF, basic fibroblast growth factor; BM, bone marrow; BMI, body mass index; CAR cell, CXCL12-abundant reticular cell; CCL5/RANTES, CC-chemokine ligand 5; CD, cluster of differentiation; CFU-F, colony forming unit-fibroblast; CXCL12, CXC chemokine ligand 12; DC, dendritic cell; Ebf, early B-cell factor; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition; ERK, extracellular signal-regulated kinases; ESC, embryonic stem cells; FDA, Food and Drug Administration; FGFR1, fibroblast growth factor receptor 1; GAD, glutamic acid decarboxylase; GCV, ganciclovir; GM-CSF, granulocyte-macrophage colony-stimulating factor; GSIS, glucose-stimulated insulin secretion; GVHD, graft-versus-host disease; HbA1c, glycated hemoglobin A1c; HGF, hepatocyte growth factor; HLA, human leukocyte antigen; HNF1A, hepatocyte nuclear factor 1α; HOMA, homeostasis model assessment; HSC, hematopoietic stem cells; HSV-Tk, herpes simplex virus thymidine kinase; ICAM1, intercellular adhesion molecule 1; ICOS, inducible costimulator; IDDM, insulin-dependent diabetes mellitus; IDO, indoleamine 2,3-dioxygnase; IGF, insulin-like growth factor; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; IPF-1, insulin promoter factor 1 (official name, PDX1); IR, insulin resistance; iPSC, induced pluripotent stem cells; ISC, insulin secreting cell; ISL-1, insulin gene enhancer protein 1; IU, international unit; IV, intravenous; MET, mesenchymal to epithelial transition; MHC, major histocompatibility complex; MMP, matrix metalloproteases; MMTT, mixed-meal tolerance test; MNC, mononuclear cells; MODY3, maturity-onset diabetes of the young type 3; MPC, mesenchymal precursor cells; MSC, mesenchymal stem cells; NG2, neural/glial antigen 2; NGF, nerve growth factor; NGN3 neurogenin 3; NKX6.1, NK6 homeobox 1; NO, nitric oxide; NOD, non-obese diabetic; NSG, NOD scid gamma; PAX, paired box protein; PDGF, platelet-derived growth factor; PD-L1, programmed cell death ligand 1; PDX1, pancreatic and duodenal homeobox 1; PEDF, pigment epithelium-derived factor; PGE2, Prostaglandin E2; SC, stem cells; SCF, stem cell factor; SCID, severe combined immunodeficiency; STZ, streptozotocin; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGF, transforming growth factor; Th, T helper; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis inducing ligand; Treg, regulatory T cell; TSG-6, tumour necrosis factor-stimulated gene 6; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling; UC, umbilical cord; VCAM1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; WHO, world health organisation; WJ, Wharton’s Jelly.
Abstract
Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient’s care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC). ESC display a virtually unlimited plasticity, including the differentiation into insulin producing β-cells, but they raise ethical concerns and bear, like iPSC, the risk of tumours. IPSC may further inherit somatic mutations and remaining somatic transcriptional memory upon incomplete reprogramming, but allow the generation of patient/disease-specific cell lines. MSC avoid such issues but have not been successfully differentiated into β-cells. Instead, MSC and their pericyte phenotypes outside the bone marrow have been recognized to secrete numerous immunomodulatory and tissue regenerative factors. On this account, the term ‘medicinal signaling cells’ has been proposed to define the new conception of a ‘drug store’ for injured tissues and to stay with the MSC nomenclature. This review presents the biological background and the resulting clinical potential and limitations of ESC, iPSC and MSC, and summarizes the current status quo of cell therapeutic concepts and trials.
Introduction
Human organs and tissues possess a limited capacity to completely recover their structure and function in a number of pathologic conditions and degenerative diseases. This fact initiated the multidisciplinary field of regenerative medicine which investigates the potential of stem cells (SC) for tissue repair and restoration of organ function. Based on their nature and origin, SC exhibit features of interest for cell therapies; e.g. targeting functional degeneration and loss of insulin producing pancreatic β-cells in diabetes mellitus (DM). The diverse potential of embryonic SC (ESC), induced pluripotent SC (iPSC) and adult mesenchymal SC (MSC) has been exploited to restore or maintain insulin secretion as well as to investigate patient-specific disease aspects. MSC are currently the most investigated cells in DM-related trials while clinical testing of ESC has just started. This review summarizes the biological aspects and the application strategies for the treatment of DM by stem cell therapy.
β-cell replacement
Patients with autoimmune DM type 1 (T1DM) experience a loss of insulin producing pancreatic β-cells and rely on daily insulin injections. Despite modern insulin therapies, exogenous application of insulin can never be as accurate and dynamic like insulin secretion from endogenous β-cells and therefore can only partially reduce the risk for the development of micro- (i.e. nephropathy, retinopathy) or macrovascular (i.e. coronary artery disease, peripheral artery disease, cerebrovascular disease) complications. Additionally, efforts to develop effective immunosuppressive treatments to prevent β-cell loss before disease onset had limited success so far [1]. Consequently, restoration of endogenous insulin secretion represents an important aim to prevent hyper- and hypoglycemia as well as to reduce or avoid diabetic complications and the patient’s requirement for self-management of glycemic control by exogenous insulin administration.
Clinical islet transplantation aims to re-establish endogenous insulin secretion and has been steadily refined since its beginning in the 1980s [2]. An important step was the ‘Edmonton Protocol’ from 1999 which avoids β-cell toxic glucocorticoids by using sirolimus, tacrolimus and daclizumab for immunosuppression [3]. Ongoing clinical research improved isolation, culture and transplant techniques, and evaluated advanced anti-inflammatory and immunomodulatory interventions [4-6]. As a result, a multicenter analysis with 18 diabetic patients receiving 34 islet transplantations showed a graft survival (defined by C-peptide concentrations of ≥ 0.3 ng/ml) of about 72.2%, 44.4% and 22.2% after 1, 2 and 5 years, respectively [7]. Subsequently, a multicenter phase 3 trial, which enrolled 48 participants receiving 75 islet transplantations, successfully improved glycemic control to a median glycated hemoglobin A1c (HbA1c) level of 5.6% after 1 and 2 years [8]. Compared to standard insulin therapy, islet transplantation more efficiently improved glycemic control and progression of retinopathy, and resolved hypoglycemia even in patients with only partially remaining graft function [9, 10].
Transplantation of whole pancreases is an established alternative to islets and both procedures display advantages and limitations [11]. The standard procedure of islet infusion into the liver is much safer with less complications than pancreas transplantation which is considered a major surgery with accordingly enhanced risks for the patient. Thus, pancreas transplantation is rarely performed alone and is most commonly combined with a kidney transplantation in patients with T1DM and end-stage renal disease. The major obstacle of the less risky islet transplantation is the limited graft survival. Insulin independence after islet transplantation initially reached barely 10% at 1 year but has been improved by the Edmonton protocol to 10-15% at 5 years [12] and by later developments, such as T cell-depleting agents and blockade of tumour necrosis factor (TNF), to 50% at 5 years [4]. Thereby, at least experienced islet transplantation centers have substantially improved long-term graft function towards the reported 5 year outcomes in pancreas transplantation; 55% for pancreas alone and after kidney, and 72% for pancreas together with kidney [2, 13].
As with other organ transplantation, there is a great scarcity of human donor material which evoked intensive research on the generation of insulin producing β-cells from SC. Whole pancreas transplantation strictly depends on high quality organs while generation of insulin producing β-cells from SC has the potential to solve the problem of limited availability of donor material for islet transplantation. However, the need for immunosuppression reserves both pancreas and islet transplantation as a therapeutic choice to a limited patient population such as brittle diabetics with life-threatening hypoglycemic events or subjects who anyway receive immunosuppression; e.g. because of kidney transplantations for renal failure due to diabetic nephropathy.
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I. ESC (Embryonic Stem Cells)
ESC represent the inner cell mass of the blastocyst and possess a pluripotent differentiation capacity. This makes them capable to form all three germ layers (ectoderm, endoderm and mesoderm) which subsequently give rise to all cell types of the body. On this account, these cells are considered the superior tool for tissue generation but they evoke ethical concerns regarding their origin from human embryos. Moreover, they bear a clinical risk since their pluripotent nature makes undifferentiated ESC capable to form teratomas and malignant teratocarcinomas in vivo. The development of clinically safe differentiation protocols and testing routines for tumorigenicity in rodents represents an important challenge in the field [14, 15].
The differentiation of human ESC into functional β-cells is not trivial since transforming processes have to mimic complex embryonal organogenesis in vitro. Differentiation protocols therefore established a number of factors and inhibitors that modulate molecular pathways in an exact sequential timing to resemble the natural development of pancreatic β-cells. Generally, human ESC were firstly differentiated into definitive endoderm cells and then sequentially into primitive gut tube and posterior foregut, pancreatic endoderm and finally β-cells using multiple specified media and supplementation in each step [16, 17]. The earlier attempts proved the concept but did not achieve high yields; e.g. a typical early study resulted in an average percentage of insulin+ cells in differentiated human ESC cultures of 7.3% [16]. Meanwhile, the exact media compositions have been further improved and current protocols reached the level of scalable production of β-cell phenotypes with functional insulin secretion [17-20]. However, the complexity of protocols and differences in employed ESC and iPSC lines raise difficulties in reproducibility outside experienced laboratories since stem cell differentiation is despite all progress not a routine procedure.
A major step in differentiation of human ESC towards β-cells is the expression of the transcription factors pancreatic and duodenal homeobox 1 (PDX1) and NK6 homeobox 1 (NKX6.1) which are markers of pancreatic endoderm and endocrine precursor cells. It has been shown that comparable human embryonic pancreas tissue from fetal weeks 6-9, which contained very few β-cells at that stage, is capable to mature into functional β-cells after transplantation into non-obese diabetic mice with severe combined immunodeficiency (NOD/SCID mice) [21]. Based on these findings, in vivo maturation of PDX1+/NKX6.1+ progenitors into β-cells has been recognized to be more efficient than mimicking this months-long process in vitro [22]. Furthermore, scalable in vitro differentiation of ESC into endocrine pancreatic precursor cells is to date more robust and less complicated [23, 24] than generation of fully functional β-cell phenotypes by advanced protocols [17, 19] and therefore the favoured strategy of the company ViaCyte [25].
The resulting improvements in differentiation of ESC towards PDX1+/NKX6.1+ pancreatic progenitors during the last decade have also reduced the risk of tumour formation in vivo which occurred in a typically early study of the company NovoCell (name changed to ViaCyte in 2010) with a rate of 7 out of 46 transplanted mice [22]. Since then, ViaCyte has steadily optimized the approach to efficient large-scale production and embedded their pancreatic endoderm and endocrine progenitor cells into a macroencapsulation device to generate immune isolated VC-01 implants [18, 25, 26].
Macroencapsulation improved graft survival and clinical safety. Although ESC-derived progenitors are hypoimmunogenic, transplanted cells are challenged by adaptive immune responses such as local inflammation and rejection. In addition, once maturated into insulin producing β-cells, graft cells will be attacked by persistent autoreactive T cells in patients with T1DM. Several studies have demonstrated that macroencapsulation protects embedded cells by isolation from immune responses and thereby avoids rejection and the need for immunosuppression [27, 28]. Furthermore, macroencapsulation prevents escape of embedded cells into the body. This is an important safety issue since any ESC transplanted in an undifferentiated state bears the potential of malignant transformation. In this view, subcutaneously transplanted devices could be retrieved and removed easily. Using this concept, Viacyte has achieved a milestone by initiating the first-in-man clinical trial to test safety and efficacy of their pancreatic endoderm implant VC-01 in patients with T1DM and hypoglycemic unawareness (ClinicalTrials.gov: NCT02239354, currently enrolling patients, estimated completion in January 2021).
This trial will answer the question whether the established in vivo maturation of human ESC-derived PDX1+/NKX6.1+ progenitors in rodents can be comparably recapitulated in human subjects. In addition, two of three further trials initiated by Viacyte aim to test a modified implantation device with reduced immuno isolation that allows vascularisation of the macroencapsulated cells. Provided that outcome of all these trials will prove safety, efficacy and significant long-term graft function, this approach holds the potential to pave the way towards clinical β-cell replacement without immunosuppression and independent of the limited availability of donor islets.
II. iPSC (Induced Pluripotent Stem Cells)
The ethical criticism related to the use of human pre-implantation embryos for extraction of ESC inspired researchers to refine the work of John B. Gurdon. His key study demonstrated that enucleated Xenopus laevis eggs that were transplanted with nuclei from differentiated intestinal epithelium could, at least in small numbers, develop into living tadpoles [29]. This demonstrated for the first time that somatic cell nuclei have the potential to revert into a pluripotent state. Decades passed by before this finding gained broad acceptance in the scientific community and the progression of this idea culminated in the birth of the first mammal, clone sheep Dolly, on July 5, 1996 [30].
Gurdon’s basic concept of reprogrammable somatic cells was further developed and one decade after Dolly’s birth, Takahashi and Yamanaka induced embryonic-like pluripotency in somatic mouse fibroblasts by viral overexpression of the four transcription factors Sox2, Oct4, Klf4 and c-Myc [31]. For their groundbreaking discoveries Gurdon and Yamanaka were honored by the Noble Prize in 2012 (www.nobelprize.org).
As a major achievement, iPSC overcome the ethic obstacle of using embryos for harvest of ESC. During ongoing research, the original Yamanaka protocol has been diversely modified and viral integration was effectively replaced by treatment with recombinant proteins, small molecules and microRNAs [32, 33]. Following the principle route of pancreatic development as used for ESC, researchers have successfully differentiated iPSC into functional β-cell phenotypes [34, 35] and also established scalable production of both endocrine pancreatic progenitors and β-cells [20, 36].
Nevertheless, further refinement of procedures is still an issue and new tools were created for the identification of compounds and conditions which enhance yield and functionality of generated β-cells. For example, human iPSC expressing the fluorescent reporters Venus and mCherry markers under the control of intrinsic neurogenin 3 and insulin promoters have been generated for screening of differentiation efficiency [37]. These cells have served to identify an inhibitor of fibroblast growth factor receptor 1 (FGFR1) that, while blocking the early development of pancreatic progenitors, promoted the terminal differentiation of pancreatic endocrine progenitors into endocrine cells including β-cells.
However, due to their origin from adult somatic cells, iPSC can inherit somatic mutations and incomplete reprogramming can maintain somatic transcriptional memory including cancer associated gene activity [38, 39]. These dangers currently do not define them as the first choice for clinical use but, more importantly, iPSC enable the successful generation of patient-specific cell phenotypes that allow to recapitulate disease processes in vitro and can serve as platforms for drug development and testing [40-42]. For example, researchers successfully generated an iPSC line from a patient carrying a hepatocyte nuclear factor 1α (HNF1A) mutation resulting in maturity-onset diabetes of the young type 3 (MODY3). In the near future, patient-specific cell lines will help to develop disease-related models that overcome the obstacle of species differences between human subjects and animal models.
III. MSC (Mesenchymal Stem Cells)
For an excellent graphical overview on MSC biology discussed in section III we recommend the poster by Somoza et al. [43].
MSC within the bone marrow (BM)
The discovery of MSC has been generally attributed to A. J. Friedenstein who observed that BM explants form plastic adherent fibroblast-like clonogenic cells with a high replicative capacity in vitro and named them colony forming unit-fibroblasts (CFU-F) [44]. Friedenstein et al. further figured out that culture expanded CFU-F are capable to differentiate into osteoblasts, chondrocytes and adipocytes, and to reconstitute a hematopoietic microenvironment after transplantation in irradiated mice [45, 46]. These findings supported the pioneering study of Tavassoli and Crosby who demonstrated that autologous BM fragments transplanted into extramedullary sites can reconstitute hematopoietic and adventitial structures in rats [47]. The observed process started from a developing network of proliferating reticular cells and was successively followed by the occurrence of osteoblasts, osteoid tissue, endothelial layers of sinusoidal structure and finally hematopoietic repopulation. These findings pointed out that CFU-F include a group of cells with the capacity of multipotent differentiation into mesenchymal lineages. Based on these features, multipotent CFU-F were renamed ‘mesenchymal stem cells’ by A. I. Caplan in 1991 [48]. Caplan later commented that the term ‘stem cell’ was provocative at that time but justified by ongoing research displaying that CFU-F could generate bone, cartilage, fat, muscle and other mesodermal phenotypes in vitro [49].
Pericyte-MSC outside the BM
The early view on MSC as BM stroma cells has nowadays completely changed and the occasionally used term ‘mesenchymal stromal cell’ became misleading. Instead, it became obvious that MSC within the BM are not part of the connective tissue stroma but are forming the endosteal and perivascular niches. Most BM-MSC are of perivascular origin [54]. In a landmark study, Crisan et al. clearly documented that MSC phenotypes exist outside the BM in multiple organs as perivascular pericytes expressing typical BM-MSC markers like CD146, NG2 and α-SMA, and being multipotent for osteogenic, chondrogenic, adipogenic and myogenic lineages in vitro [66].
In vivo function of pericyte-MSC
Pericytes have been discovered in the early 1870s by C.J. Ebert and C.M.B. Rouget [73] and were named by K.W. Zimmermann describing their contractile nature in 1923 [74]. Pericytes attach to the epithelium by their tips and their contractile apparatus consisting of microfilaments containing actin, myosin and tropomyosin enables them to regulate the capillary diameter or to move along the microvessels [76]. This indicated that perivascular pericyte-MSC and their BM counterparts are not static but dynamic and their close proximity to the vasculature enables them to readily mobilize and travel in the bloodstream to sites of injury.
A.I. Caplan, who once coined the term MSC, has meanwhile suggested to rename these cells ‘medicinal signalling cells’ to more accurately reflect the new conceptional view on MSC as a ‘drug store’ for injured tissues in vivo and to preserve the MSC nomenclature [84].
MSC in cancer
Tumours recruit pericytes by e.g. platelet-derived growth factor (PDGF) to maintain their tumour vessels [88] and consequently, inhibition of PDGF receptor signalling causes pericyte detachment and vessel regression, and diminishes tumour growth in several cancer models [89-91]. However, it seems unlikely that transplanted MSC have a significant role in inducing or promoting tumours in human subjects, as their clinical use has been considered safe since 1995 [56] and clinicians did not notice a tumour risk. In support of this notion, a meta-analysis has studied 1012 participants who received MSC for treatment of ischemic stroke, Crohn’s disease, cardiomyopathy, myocardial infarction, graft versus host disease or served as healthy volunteers but did not find any indication of malignancy [106].
Transdifferentiation of MSC into insulin producing pancreatic β-cells
There was initially great optimism that MSC could be easily transdifferentiated across the germ layer border into insulin producing pancreatic β-cells and thereby avoid the ethical and tumorigenic obstacles of ESC and iPSC. Several studies reported that transplanted MSC-derived insulin producing cells can improve glycemia in STZ-diabetic rodents [111, 114, 118, 121]. Collectively, these studies exclude significant transdifferentiation of MSC into insulin producing cells in vivo and pave the way for the new understanding that MSC migrate to and engraft at site of injury to support tissue repair by secretion of numerous tissue regenerative factors [81].
Humoral potential of MSC
MSC-released factors have been further reported to improve insulin secretion and glucose-response. Numerous MSC-released factors exhibit potent immunomodulatory characteristics; e.g. transforming growth factor-β1 (TGF-β1), indoleamine 2,3-dioxygnase (IDO), nitric oxide (NO), human leukocyte antigen-G (HLA-G), Prostaglandin E2 (PGE2), interleukin-1 receptor antagonist (IL-1RA) and tumour necrosis factor-stimulated gene 6 (TSG-6) [81, 139, 151]. As a result, MSC have been described to induce regulatory T cells and anti-inflammatory M2 macrophages, and to inhibit T cells, natural killer cells and T helper (Th)17 cell differentiation as well as maturation of dendritic cells (DC).
MSC in clinical trials
To date, ClinicalTrials.gov listed over 850 therapeutic approaches using MSC to target a broad array of diseases including hematological disease, graft-versus-host disease (GVHD), organ transplantation, cardiovascular and neurological diseases, bone and cartilage repair as well as inflammatory and autoimmune diseases [177]. Among these, more than 60 trials address T1DM and T2DM. The International Society for Cell Therapy (ISCT) defined clinically useful MSC by mesenchymal differentiation (into bone, cartilage and fat), plastic-adherent growth in vitro and expression of CD73, CD90 and CD105 in the absence of hematopoietic surface markers [195].
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Conclusion on the Current State of Stem Cell Therapy of Diabetes Mellitus
Stem cell therapy has to deal with a wide array of limitations which are still the subject of current research. See Table 2 for summary and comparison of SC in cell therapy of DM. Differentiation of ESC and iPSC has meanwhile reached clinical large-scale production and current developments of macroencapsulation may provide clinical safe usage of these cells that demonstrate otherwise potentials for tumor development. Macroencapsulation prevents the escape of embedded cells into the body and subcutaneously transplanted devices could be retrieved and removed easily. The outcome of Viacyte’s first-in-man trial of their pancreatic endoderm implant VC-01 will clarify whether the use of ESC and iPSC is an option in DM therapy in the near future.
MSC are clinically safe and several trials exist though they are limited in number and investigated patients. Currently, MSC-based therapy is no cure but shows a potential to ameliorate DM since most studies report decreased requirement of exogenous insulin and/or anti-diabetic drugs. In this regard, MSC may be best used with diabetic patients that have severe problems in controlling glycemia by conventional therapies; e.g. patients with brittle DM. We see potential in optimizing their therapeutical performance by standardizing isolation, characterization, selection, expansion, potency testing and pathogen screening. However, increased efforts will increase costs and MSC have to prove their value.
Declarations of interest: None.
Author contributions: All authors have participated in manuscript preparation and have approved the final article.
Highlights
- Large-scale production of pancreatic endoderm and β-cells from embryonic stem cells
- First-in-man trial investigates macroencapsulated embryonic stem cell-derived β-cells
- Induced pluripotent stem cells allow patient/disease-specific cell lines
- Mesenchymal stem cells secrete immunomodulatory and tissue regenerative factors
- Transplanted mesenchymal stem cells ameliorate human type 1 and type 2 diabetes
Stem Cells in the Treatment of Diabetes Mellitus — Full Study
