Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Commentary

Mesenchymal Stem Cells for the Treatment of Diabetes

  1. Antonello Pileggi⇓
  1. Cell Transplant Center, Diabetes Research Institute, DeWitt Daughtry Family Department of Surgery, Department of Microbiology and Immunology, and Department of Biomedical Engineering, University of Miami, Miami, Florida
  1. Corresponding author: Antonello Pileggi, apileggi{at}med.miami.edu.
Diabetes 2012 Jun; 61(6): 1355-1356. https://doi.org/10.2337/db12-0355
PreviousNext
  • Article
  • Info & Metrics
  • PDF
Loading

The field of regenerative medicine is rapidly evolving, paving the way for novel therapeutic interventions through cellular therapies and tissue engineering approaches that are reshaping the biomedical field. The remarkable plasticity of different cell subsets obtained from human embryonic and adult tissues from disparate sources (including bone marrow, umbilical cord, amniotic fluid, placenta, and adipose tissue) has sparked research endeavors evaluating use of these cells for numerous conditions, including diabetes and its complications (1).

A readily accessible source for multipotent stem cells is the bone marrow, which comprises progenitors of hematopoietic, endothelial, and mesenchymal stem cells (MSCs). Unfractioned and fractioned bone marrow–derived stem cells have been used in experimental and clinical settings to improve diabetes and diabetes complications. Bone marrow–derived MSCs are stromal, nonhematopoietic cells generally obtained from iliac crest aspirates following enrichment based on their preferential adhesion on culture vessels in defined media. MSC characterization relies on expression of specific surface markers and on their ability to differentiate into fat, bone, and cartilage when exposed to appropriate culture conditions (2).

Recent clinical trials have demonstrated powerful immunomodulatory effects of the inoculum of MSCs to treat graft-versus-host disease (3,4), to improve allogeneic renal transplant outcomes using lower immunosuppressive regimens (5), and to reduce immune cell activation in patients with multiple sclerosis and amyotrophic lateral sclerosis (6). Autologous MSCs were shown to improve Crohn disease lesions refractory to other therapies (7,8) and were tested for treatment of ischemic hearts (9).

In the context of diabetes research, MSCs have been used to generate insulin-producing cells (10), counteract autoimmunity (11,12), enhance islet engraftment and survival (13,14), and to treat diabetic ulcers and limb ischemia (15). Also, MSC inoculum improved metabolic control in experimental models of type 2 diabetes (T2D) (16). Nonrandomized, pilot trials in T2D suggest a positive impact of bone marrow–derived mononuclear cells on metabolic control (i.e., reduction of insulin requirements and of A1C values) in the absence of adverse events following intra-arterial injection by selective cannulation of the pancreas vasculature (17,18). Unfortunately, because these studies are small and lack in-depth mechanistic analyses, it is yet unknown how MSCs exert their beneficial effects in T2D.

The interesting study by Si et al. (19) attempts to understand the effects of autologous MSC inoculum in a rat model of T2D (induced by high-fat diet for 2 weeks followed by a suboptimal dose of the β-cell toxin streptozotocin [STZ] to induce a hyperglycemic state). Autologous MSCs were administered either 1 or 3 weeks after STZ treatment. Improved metabolic control, measured by enhanced insulin secretion, amelioration of insulin sensitivity, and increased islet numbers in the pancreas, was observed in animals receiving MSCs particularly when MSCs were given early (7 days) after STZ treatment. Consistent with previous reports, the metabolic effects of MSC inoculum were short-lived (for a period of 4 weeks), and reinoculum provided an additional, comparable, and transient effect.

Clamp studies demonstrated significantly improved blood glucose metabolism and insulin sensitivity in animals receiving MSC therapy. A set of novel mechanistic data emerging from this study indicates that MSC therapy is associated with improved insulin sensitivity via increased signaling (insulin receptor substrate-1 [IRS-1] and Akt phosphorylation upon feeding, as well as translocation of GLUT-4 on cell membrane upon insulin administration) in the muscle, liver, and adipose tissue of animals receiving MSC inoculum, when compared with controls. Although many questions remain unanswered, these data shed new light on the effects of autologous MSC inoculum on insulin target tissues in this rodent model of T2D.

It is important to consider the potential confounding elements that can be introduced by the disease model used in this and other similar studies. In the model used by Si et al., it is prudent to be cautious because of the relatively short duration of diabetes before initiation of the intervention. This model may not fully reflect the physiopathology of the progressive development of human T2D.

Si et al. (19) present important data that highlight the importance of a cautious interpretation of the results of their T2D model. For instance, the positive impact of MSC treatment on metabolic function was more pronounced when administered early (7 days) than late (21 days) after induction of diabetes. STZ is a naturally occurring nitrosourea with various biological actions as well as induction of acute and chronic cellular injury on several tissues, including pancreatic β-cells, liver, and kidney. In the animals receiving labeled MSC inoculum “early” after STZ (but not in those in the “late” STZ group), MSCs accumulated in pancreatic islets and liver where they may have contributed to tissue repair or remodeling, thereby mitigating the injury induced by STZ and a high-fat diet and improving metabolic function. Preservation of β-cell mass was also observed in the “early” MSC group, an observation that did not appear to result from increased replication (assessed by Ki67 immunoreactivity), but rather from tissue repair and the cytoprotective properties of MSCs.

MSCs offer new opportunities in the treatment of diabetes, but they also raise many scientific questions that need to be addressed, particularly those related to safety and efficacy. These issues have obvious implications for the clinical application of MSC and other innovative cellular therapies.

Further in-depth mechanistic studies are needed to understand how MSCs affect metabolic function in T2D and to help overcome the transient results that have been observed in several studies. It remains to be determined whether the diabetic microenvironment and/or comorbidities alter the quality or efficacy of MSCs isolated from and/or after inoculum in patients with diabetes (20). Identity, stability, potency, and safety of cellular products are of paramount importance in order to obtain reproducible results and prevent undesirable side effects.

The increasing body of evidence on the potential therapeutic properties of MSCs justifies cautious optimism concerning development of effective cellular therapies for treatment of diabetes in the future.

ACKNOWLEDGMENTS

This work was supported by grants from the National Institutes of Health (5U19AI050864-10, U01DK089538, 5U42RR016603-08S1, 1DP2DK083096-01, 1R01EB008009-02, 5R01DK059993-06, 1 R21 DK076098-01, 1 U01 DK70460-02, 5R01DK25802-24, 5R01DK56953-05), the Juvenile Diabetes Research Foundation International (17-2010-5, 4-2008-811, 6-39017G1, 4-2004-361, 4-2000-947), The Leona M. and Harry B. Helmsley Charitable Trust, the University of Miami Interdisciplinary Research Development Initiative, the Diabetes Research Institute Foundation, and Converge Biotech. The funders had no role in the content, presentation, decision to publish, or preparation of the manuscript.

A.P. is a co-founder, member of the scientific advisory board, and stock option holder of Converge Biotech and NEVA Pharmaceuticals. There are no patents, products in development, or marketed products to declare. A.P. has performed research supported by PositiveID Corporation, Extended Delivery Pharmaceuticals, Pfizer, Advanced Technologies, and Regenerative Medicine. No other potential conflicts of interest relevant to this article were reported.

Footnotes

  • See accompanying original article, p. 1616.

  • © 2012 by the American Diabetes Association.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

REFERENCES

  1. ↵
    1. Fotino C,
    2. Ricordi C,
    3. Lauriola V,
    4. Alejandro R,
    5. Pileggi A
    . Bone marrow-derived stem cell transplantation for the treatment of insulin-dependent diabetes. Rev Diabet Stud 2010;7:144–157pmid:21060973
    OpenUrlCrossRefPubMed
  2. ↵
    1. Dominici M,
    2. Le Blanc K,
    3. Mueller I,
    4. et al
    . Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–317pmid:16923606
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Le Blanc K,
    2. Rasmusson I,
    3. Sundberg B,
    4. et al
    . Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363:1439–1441pmid:15121408
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Le Blanc K,
    2. Frassoni F,
    3. Ball L,
    4. et al.,
    5. Developmental Committee of the European Group for Blood and Marrow Transplantation
    . Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008;371:1579–1586pmid:18468541
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Tan J,
    2. Wu W,
    3. Xu X,
    4. et al
    . Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012;307:1169–1177pmid:22436957
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Karussis D,
    2. Karageorgiou C,
    3. Vaknin-Dembinsky A,
    4. et al
    . Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187–1194pmid:20937945
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Ciccocioppo R,
    2. Bernardo ME,
    3. Sgarella A,
    4. et al
    . Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 2011;60:788–798pmid:21257987
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Duijvestein M,
    2. Vos AC,
    3. Roelofs H,
    4. et al
    . Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 2010;59:1662–1669pmid:20921206
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Hare JM,
    2. Traverse JH,
    3. Henry TD,
    4. et al
    . A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277–2286pmid:19958962
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    1. Karnieli O,
    2. Izhar-Prato Y,
    3. Bulvik S,
    4. Efrat S
    . Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation. Stem Cells 2007;25:2837–2844pmid:17615265
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Madec AM,
    2. Mallone R,
    3. Afonso G,
    4. et al
    . Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 2009;52:1391–1399pmid:19421731
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    1. Fiorina P,
    2. Jurewicz M,
    3. Augello A,
    4. et al
    . Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 2009;183:993–1004pmid:19561093
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Ding Y,
    2. Xu D,
    3. Feng G,
    4. Bushell A,
    5. Muschel RJ,
    6. Wood KJ
    . Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 2009;58:1797–1806pmid:19509016
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Berman DM,
    2. Willman MA,
    3. Han D,
    4. et al
    . Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes 2010;59:2558–2568pmid:20622174
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Lu D,
    2. Chen B,
    3. Liang Z,
    4. et al
    . Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011;92:26–36pmid:21216483
    OpenUrlCrossRefPubMed
  16. ↵
    1. Lee RH,
    2. Seo MJ,
    3. Reger RL,
    4. et al
    . Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 2006;103:17438–17443pmid:17088535
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Bhansali A,
    2. Upreti V,
    3. Khandelwal N,
    4. et al
    . Efficacy of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cells Dev 2009;18:1407–1416pmid:19686048
    OpenUrlCrossRefPubMed
  18. ↵
    1. Estrada EJ,
    2. Valacchi F,
    3. Nicora E,
    4. et al
    . Combined treatment of intrapancreatic autologous bone marrow stem cells and hyperbaric oxygen in type 2 diabetes mellitus. Cell Transplant 2008;17:1295–1304pmid:19364067
    OpenUrlCrossRefPubMed
  19. ↵
    1. Si Y,
    2. Zhao Y,
    3. Hao H,
    4. et al
    . Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes 2012;61:1616–1625
  20. ↵
    1. Jurewicz M,
    2. Yang S,
    3. Augello A,
    4. et al
    . Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. Diabetes 2010;59:3139–3147pmid:20841611
    OpenUrlAbstract/FREE Full Text
View Abstract
PreviousNext
Back to top
Diabetes: 61 (6)

In this Issue

June 2012, 61(6)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Mesenchymal Stem Cells for the Treatment of Diabetes
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Mesenchymal Stem Cells for the Treatment of Diabetes
Antonello Pileggi
Diabetes Jun 2012, 61 (6) 1355-1356; DOI: 10.2337/db12-0355

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Mesenchymal Stem Cells for the Treatment of Diabetes
Antonello Pileggi
Diabetes Jun 2012, 61 (6) 1355-1356; DOI: 10.2337/db12-0355
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • ACKNOWLEDGMENTS
    • Footnotes
    • REFERENCES
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Lifting the Veil on the “Phosphate Flush,” a Cryptic Phenomenon of Experimental Pancreatic Islet Physiology
  • Window of Opportunity: Targeting ANGPTL4 Improves Triglyceride Levels in Maternal Obesity During Pregnancy
  • New Antidiabetes Agent Targeting Both Mitochondrial Uncoupling and Pyruvate Catabolism: Two Birds With One Stone
Show more Commentary

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.