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      Concise Review: Mesenchymal Stem Cell Treatment of the Complications of Diabetes Mellitus

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          Abstract

          Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells that can be found in almost all postnatal organs and tissues. The main functional characteristics of MSCs are their immunomodulatory ability, capacity for self-renewal, and differentiation into mesodermal tissues. The ability of MSCs to differentiate into several cell types, including muscle, brain, vascular, skin, cartilage, and bone cells, makes them attractive as therapeutic agents for a number of diseases including complications of diabetes mellitus. We review here the potential of MSCs as new therapeutic agents in the treatment of diabetic cardiomyopathy, diabetic nephropathy, diabetic polyneuropathy, diabetic retinopathy, and diabetic wounds. Also, in this review we discuss the current limitations for MSCs therapy in humans. S tem C ells 2011;29:5–10

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          A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

          Joshua Hare, Jay Traverse, Timothy D Henry … (2009)
          Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).
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            Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms.

            T Kinnaird, E STABILE, M. Burnett … (2004)
            Bone marrow cell therapy is reported to contribute to collateral formation through cell incorporation into new or remodeling vessels. However, the possible role of a paracrine contribution to this effect is less well characterized. Murine marrow-derived stromal cells (MSCs) were purified by magnetic bead separation of cultured bone marrow. The release of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced proliferation of endothelial cells and smooth muscle cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects. Balb/C mice (n=10) underwent distal femoral artery ligation, followed by adductor muscle injection of 1x10(6) MSCs 24 hours later. Compared with controls injected with media (n=10) or mature endothelial cells (n=8), distal limb perfusion improved, and mid-thigh conductance vessels increased in number and total cross-sectional area. MSC injection improved limb function and appearance, reduced the incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After injection, labeled MSCs were seen dispersed between muscle fibers but were not seen incorporated into mature collaterals. Injection of MSCs increased adductor muscle levels of bFGF and VEGF protein compared with controls. Finally, colocalization of VEGF and transplanted MSCs within adductor tissue was demonstrated. MSCs secrete a wide array of arteriogenic cytokines. MSCs can contribute to collateral remodeling through paracrine mechanisms.
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              A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

              Jin Soo Lee, Ji Hong, Gyeong Joon Moon … (2010)
              We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observer-blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Stem Cells
                Journal ID (publisher-id): stem
                Title: Stem Cells (Dayton, Ohio)
                Publisher: Wiley Subscription Services, Inc., A Wiley Company
                ISSN (Print): 1066-5099
                ISSN (Electronic): 1549-4918
                Publication date (Print): January 2011
                Publication date (Electronic): 09 November 2010
                Volume: 29
                Issue: 1
                Pages: 5-10
                Affiliations
                [a ]simpleCentre for Molecular Medicine, Faculty of Medicine, University of Kragujevac Kragujevac, Serbia
                [b ]simpleDepartment of Microbiology and Immunology, Faculty of Medicine and Health Sciences, UAE University Al Ain, United Arab Emirates
                [c ]simpleSpebo Medical Leskovac, Serbia
                Author notes
                Miodrag Stojkovic, Ph.D., Centre for Molecular Medicine, Faculty of Medicine, University of Kragujevac, Serbia, 69 Svetozara Markovica Street, 34 000 Kragujevac, Spebo Medical, 16 Norvezanska Street, 16 000 Leskovac, Serbia. Telephone: 381-16-21-81-71; Fax: 381-16-23-76-15; e-mail: mstojkovic@ 123456spebo.co.rs

                Author contributions: V.V.: conception and design, manuscript writing; N.A.: manuscript writing and editing; M.L.L.: manuscript writing and editing; M.S.: conception and design, manuscript writing and editing.

                Available online without subscription thorugh the open access option.

                Disclosure of potential conflicts of interest is found at the end of this article.

                Article
                DOI: 10.1002/stem.556
                PMC ID: 3059410
                PubMed ID: 21280154
                SO-VID: b2766e87-3747-4731-a5c1-5c5813519a3a
                Copyright © Copyright © 2010 AlphaMed Press
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 09 August 2010
                Date accepted : 19 October 2010
                Categories
                Subject: Concise Review: Regenerative Medicine

                ScienceOpen disciplines: Molecular medicine
                Keywords: mesenchymal stem cell,cardiomyopathy,nephropathy,neuropathy,wound,diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: mesenchymal stem cell, cardiomyopathy, nephropathy, neuropathy, wound, diabetes mellitus

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