Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

Couri, Carlos Eduardo Barra; Oliveira, Maria Carolina de; Simões, Belinda Pinto

doi:10.1007/s11892-012-0309-0

Cited by 17 publications

(14 citation statements)

References 57 publications

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“…In this sense, adult stem cell transplantation represents a promising possibility that must be explored. High-dose immunosuppression followed by autologous hematopoietic stem cell transplantation was shown to increase C-peptide levels with reduction or even suspension of insulin use in the majority of newly diagnosed T1D patients [ 4 ]. In addition, multipotent mesenchymal stromal cells (MSCs) have also attracted great attention as a powerful tool for T1D treatment because of their regenerative and immunomodulatory properties.…”

Section: Introductionmentioning

confidence: 99%

Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties

et al. 2016

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BackgroundType 1 diabetes mellitus (T1D) is characterized by autoimmune responses resulting in destruction of insulin-producing pancreatic beta cells. Multipotent mesenchymal stromal cells (MSCs) exhibit immunomodulatory potential, migratory capacity to injured areas and may contribute to tissue regeneration by the secretion of bioactive factors. Therefore, MSCs are considered as a promising approach to treat patients with different autoimmune diseases (AID), including T1D patients. Phenotypical and functional alterations have been reported in MSCs derived from patients with different AID. However, little is known about the properties of MSCs derived from patients with T1D. Since autoimmunity and the diabetic microenvironment may affect the biology of MSCs, it becomes important to investigate whether these cells are suitable for autologous transplantation. Thus, the aim of the present study was to evaluate the in vitro properties and the in vivo therapeutic efficacy of MSCs isolated from bone marrow of newly diagnosed T1D patients (T1D-MSCs) and to compare them with MSCs from healthy individuals (C-MSCs).MethodsT1D-MSCs and C-MSCs were isolated and cultured until third passage. Then, morphology, cell diameter, expression of surface markers, differentiation potential, global microarray analyses and immunosuppressive capacity were in vitro analyzed. T1D-MSCs and C-MSCs therapeutic potential were evaluated using a murine experimental model of streptozotocin (STZ)-induced diabetes.ResultsT1D-MSCs and C-MSCs presented similar morphology, immunophenotype, differentiation potential, gene expression of immunomodulatory molecules and in vitro immunosuppressive capacity. When administered into diabetic mice, both T1D-MSCs and C-MSCs were able to reverse hyperglycemia, improve beta cell function and modulate pancreatic cytokine levels.ConclusionsThus, bone marrow MSCs isolated from T1D patients recently after diagnosis are not phenotypically or functionally impaired by harmful inflammatory and metabolic diabetic conditions. Our results provide support for the use of autologous MSCs for treatment of newly diagnosed T1D patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0261-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties

et al. 2016

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“…Therapeutic interventions aimed at preserving b-cell mass at the time of diabetes onset thus far have shown transient and limited efficacy (2), mostly consisting of a less decline in insulin secretion but to improvement. Promising results in the experimental and clinical settings support the use of stem cell transplantation (SCT) or bone marrow (BM)-derived hematopoietic stem cells (HSCs) for the treatment of autoimmune diabetes (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Cai

et al. 2015

Diabetes Care

132

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OBJECTIVETo determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). RESEARCH DESIGN AND METHODSBetween January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 3 10 6 /kg UC-MSC, 106.8 3 10 6 /kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC C-Pep ) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life. RESULTSThe treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUC C-Pep increased 105.7% (6.6 6 6.1 to 13.6 6 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 6 6.8 to 7.7 6 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 6 1,012.8 to 2,205.5 6 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 6 630.2 to 1,431.7 6 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA 1c decreased 12.6% (8.6 6 0.81% [70.0 6 7.1 mmol/mol] to 7.5 6 1.0% [58.0 6 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 6 0.9% [72.0 6 7.5 mmol/mol] to 8.8 6 0.9% [73 6 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 6 51.1 to 151.2 6 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 6 35.3 to 184.2 6 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 6 0.2 to 0.6 6 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 6 0.2 to 0.9 6 0.2 IU/day/kg, P < 0.01 vs. SCT). CONCLUSIONSTransplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D.

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“…In the latter study, the mean age of patients was 17.6 ± 3.7 years, and the mean duration of time from symptoms of hyperglycemia to the transplantation (beginning of stem cell mobilization) was 12 ± 4.7 weeks. Young children are generally excluded in HSC transplantation clinical trials because of potential health risks, such as growth arrest/delay, endocrine dysfunctions (e.g., hypogonadism and autoimmune hypothyroidism), and potential infertility, associated with the conditioning regimens [63, 64]. Inclusion criteria broadly comprise a diagnosis of T1D by clinical/metabolic parameters along with the presence of positive antiglutamic acid decarboxylase antibodies.…”

Section: Stem Cell‐based Strategies For β‐Cell Regeneration and Immunmentioning

confidence: 99%

Stem Cell Therapy to Cure Type 1 Diabetes: From Hype to Hope

Chhabra

Brayman

2013

Stem Cells Translational Medicine

139

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Type 1 diabetes mellitus (T1D) is a chronic, multifactorial autoimmune disease that involves the progressive destruction of pancreatic β-cells, ultimately resulting in the loss of insulin production and secretion. The goal of clinical intervention is to prevent or arrest the onset and progression of autoimmunity, reverse β-cell destruction, and restore glycometabolic and immune homeostasis. Despite promising outcomes observed with islet transplantation and advancements in immunomodulatory therapies, the need for an effective cell replacement strategy for curing T1D still persists. Stem cell therapy offers a solution to the cited challenges of islet transplantation. While the regenerative potential of stem cells can be harnessed to make available a self-replenishing supply of glucose-responsive insulin-producing cells, their immunomodulatory properties may potentially be used to prevent, arrest, or reverse autoimmunity, ameliorate innate/alloimmune graft rejection, and prevent recurrence of the disease. Herein, we discuss the therapeutic potential of stem cells derived from a variety of sources for the cure of T1D, for example, embryonic stem cells, induced pluripotent stem cells, bone marrow-derived hematopoietic stem cells, and multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord blood, and adipose tissue. The benefits of combinatorial approaches designed to ensure the successful clinical translation of stem cell therapeutic strategies, such as approaches combining effective stem cell strategies with islet transplantation, immunomodulatory drug regimens, and/or novel bioengineering techniques, are also discussed. To conclude, the application of stem cell therapy in the cure for T1D appears extremely promising.

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Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

Cited by 17 publications

References 57 publications

Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties

Multipotent mesenchymal stromal cells from patients with newly diagnosed type 1 diabetes mellitus exhibit preserved in vitro and in vivo immunomodulatory properties

Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Stem Cell Therapy to Cure Type 1 Diabetes: From Hype to Hope

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