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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.

Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Zhou H, Yin Z, Chen Y, Zhang Y, Wang S, Shen J, Thaker H, Jain S, Li Y, Diao Y, Chen Y, Sun X, Fisk MB, Li H - BMC Med (2013)

Bottom Line: 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).In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 W, Polk Street, Chicago, IL 60612, USA. yzhaowhl@yahoo.com

ABSTRACT

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 blood-derived 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.

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Anti-inflammatory effects of stem cell educator therapy. (A) Up-regulation of plasma levels of TGF-β1 in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (B) Flow analysis of intra-cellular cytokines demonstrating differential effects on key interleukins at four weeks post-treatment. (C) Down-regulation percentage of CD86+CD14+monocytes in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (D) Flow Analysis of CD4+CD25+Foxp3+ Tregs demonstrating no change in the percentage of Tregs at four weeks post-treatment.
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Figure 2: Anti-inflammatory effects of stem cell educator therapy. (A) Up-regulation of plasma levels of TGF-β1 in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (B) Flow analysis of intra-cellular cytokines demonstrating differential effects on key interleukins at four weeks post-treatment. (C) Down-regulation percentage of CD86+CD14+monocytes in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (D) Flow Analysis of CD4+CD25+Foxp3+ Tregs demonstrating no change in the percentage of Tregs at four weeks post-treatment.

Mentions: To determine the molecular and cellular mechanisms underlying the improvement of metabolic control, we examined the effects of anti-inflammation and immune modulation of Stem Cell Educator therapy in T2D. We used ELISA to examine pro-inflammatory cytokines IL-1, IL-6 and TNFα in the plasma, which are primarily involved in insulin resistance and T2D [8,26]. We found that IL-1, IL-6 and TNFα were all at background levels in these long-standing T2D subjects and failed to show changes after Stem Cell Educator therapy (P = 0.557, P = 0.316, P = 0.603, respectively), probably because metabolic inflammation is a chronic sub-degree inflammation [8] and the plasma samples which were directly collected from the blood of T2D patients, not from the lipopolysaccharide (LPS)-activated monocytes of T2D subjects [27]. Importantly, we found that anti-inflammatory and immune suppressive cytokine TGF-β1 was markedly increased in the plasma of T2D subjects post-treatment at four weeks relative to the baseline levels (Figure 2A). However, IL-10 was unchanged in all participants (P = 0.497). These findings suggest up-regulation of TGF-β1 may be one of potential mechanisms contributing to the reversal of insulin resistance by Stem Cell Educator therapy.


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.

Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Zhou H, Yin Z, Chen Y, Zhang Y, Wang S, Shen J, Thaker H, Jain S, Li Y, Diao Y, Chen Y, Sun X, Fisk MB, Li H - BMC Med (2013)

Anti-inflammatory effects of stem cell educator therapy. (A) Up-regulation of plasma levels of TGF-β1 in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (B) Flow analysis of intra-cellular cytokines demonstrating differential effects on key interleukins at four weeks post-treatment. (C) Down-regulation percentage of CD86+CD14+monocytes in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (D) Flow Analysis of CD4+CD25+Foxp3+ Tregs demonstrating no change in the percentage of Tregs at four weeks post-treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716981&req=5

Figure 2: Anti-inflammatory effects of stem cell educator therapy. (A) Up-regulation of plasma levels of TGF-β1 in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (B) Flow analysis of intra-cellular cytokines demonstrating differential effects on key interleukins at four weeks post-treatment. (C) Down-regulation percentage of CD86+CD14+monocytes in T2D patients at baseline and four weeks after Stem Cell Educator therapy. (D) Flow Analysis of CD4+CD25+Foxp3+ Tregs demonstrating no change in the percentage of Tregs at four weeks post-treatment.
Mentions: To determine the molecular and cellular mechanisms underlying the improvement of metabolic control, we examined the effects of anti-inflammation and immune modulation of Stem Cell Educator therapy in T2D. We used ELISA to examine pro-inflammatory cytokines IL-1, IL-6 and TNFα in the plasma, which are primarily involved in insulin resistance and T2D [8,26]. We found that IL-1, IL-6 and TNFα were all at background levels in these long-standing T2D subjects and failed to show changes after Stem Cell Educator therapy (P = 0.557, P = 0.316, P = 0.603, respectively), probably because metabolic inflammation is a chronic sub-degree inflammation [8] and the plasma samples which were directly collected from the blood of T2D patients, not from the lipopolysaccharide (LPS)-activated monocytes of T2D subjects [27]. Importantly, we found that anti-inflammatory and immune suppressive cytokine TGF-β1 was markedly increased in the plasma of T2D subjects post-treatment at four weeks relative to the baseline levels (Figure 2A). However, IL-10 was unchanged in all participants (P = 0.497). These findings suggest up-regulation of TGF-β1 may be one of potential mechanisms contributing to the reversal of insulin resistance by Stem Cell Educator therapy.

Bottom Line: 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).In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 W, Polk Street, Chicago, IL 60612, USA. yzhaowhl@yahoo.com

ABSTRACT

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 blood-derived 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.

Show MeSH
Related in: MedlinePlus