Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial

Background: The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. Methods: In an open-label, phase 1/phase 2 study, patients (N = 36) with long-standing T2D were divided into three groups (Group A, oral medications, n = 18; Group B, oral medications + insulin injections, n = 11; Group C having impaired β-cell function with oral medications + insulin injections, n = 7). All patients received one treatment with the Stem Cell Educator therapy in which a patient’s blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord bloodderived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient’s circulation. Results: Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61% ± 1.12 at baseline to 7.25% ± 0.58 at 12 weeks (P = 2.62E-06), and 7.33% ± 1.02 at one year post-treatment (P = 0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Conclusions: Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches. Trial registration: ClinicalTrials.gov number, NCT01415726 * Correspondence: yzhaowhl@yahoo.com Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 W. Polk Street, Chicago, IL 60612, USA Tianhe Stem Cell Biotechnologies Inc., 750 Shunhua Road, Jinan, Shandong 250055, PR China Full list of author information is available at the end of the article © 2013 Zhao et al.; licensee BioMed Central L Commons Attribution License (http://creativec reproduction in any medium, provided the or td. This is an Open Access article distributed under the terms of the Creative ommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and iginal work is properly cited. Zhao et al. BMC Medicine 2013, 11:160 Page 2 of 13 http://www.biomedcentral.com/1741-7015/11/160 Background Type 2 diabetes (T2D) is a major global health issue, with prevalence rates exceeding 12.1% of the population in India, 9.7% in China, and 8.3% in the United States [1,2]. According to a report from the American Diabetes Association (ADA, Philadelphia, PA, USA), the total number of Americans living with diabetes will increase 64% by 2025, and diabetes-related Medicare expenditures will increase by 72% to $514 billion/year. Moreover, diabetes and its associated complications (for example, cardiovascular diseases, stroke, kidney failure and poor circulation) markedly decrease the quality of life, limiting the regular activity and productivity of individuals with the disease and creating significant economic and social burdens [3]. Thus, it is a top priority to find a cure for T2D. To date, animal and clinical studies demonstrate that insulin resistance is the key mechanism leading to the development and pathogenesis of T2D, though many factors are known to contribute to the development and severity of the disease (for example, obesity, genetic factors and sedentary lifestyle) [3]. Several medications have been shown to improve the outcome of T2D treatment through various mechanisms and act on various organs and tissues. However, safety concerns limit the utility of known insulin sensitizers. For example, the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists (thiazolidinediones, TZDs) are some of the major frontline insulin-sensitizing drugs for clinical treatment of T2D that directly improve insulin sensitivity, but the risk of adverse effects with long-term use of these compounds is a safety concern [4,5]. Alternative approaches are needed. Increasing evidence reveals that T2D subjects display multiple immune dysfunctions and chronic metabolic inflammation. Specifically, inflammatory cytokines derived from adipocytes and macrophages promote the development of insulin resistance in T2D through JNK and/ or IKKβ/NF-κB pathways, including changes in the levels of tumor necrosis factor-α (TNFα), interleukin-1 (IL-1), IL-6, IL-17, monocyte chemoattractant protein-1 (MCP-1), resistin and plasminogen activator inhibitor-1 (PAI-1) [6-10]. Control or reversal of these immune dysfunctions and chronic inflammation may provide an alternative approach for overcoming insulin resistance and may point to a cure for diabetes. However, the failure of several recent clinical trials in Type 1 diabetes (T1D) highlights the challenges we face in conquering the multiple immune dysfunctions by using conventional immune approaches in humans [11-13]. Based on preclinical studies in mice and humans [14-17], we have developed Stem Cell Educator therapy [18], an innovative technology designed to control or reverse immune dysfunctions. Stem Cell Educator therapy consists of a closed-loop system that circulates a patient’s blood through a blood cell separator (MCS+, Haemonetics, Braintree, MA, USA), briefly co-cultures the patient’s lymphocytes with adherent cord blood-derived multipotent stem cells (CB-SCs) in vitro, and returns the educated lymphocytes (but not the CB-SCs) to the patient’s circulation [18]. Our initial clinical trial in T1D revealed that a single treatment with the Stem Cell Educator provides lasting reversal of immune dysfunctions and allows regeneration of islet β cells and improvement of metabolic control in subjects with long-standing T1D [18,19]. Here, we explore the therapeutic potential of Stem Cell Educator therapy in T2D subjects.