The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation

PLoS One. 2015 Feb 13;10(2):e0117561. doi: 10.1371/journal.pone.0117561. eCollection 2015.

Abstract

Aims/hypothesis: Although the muscle is one of the preferable transplant sites in islet transplantation, its transplant efficacy is poor. Here we attempted to determine whether an intramuscular co-transplantation of mesenchymal stem cells (MSCs) could improve the outcome.

Methods: We co-cultured murine islets with MSCs and then analyzed the morphological changes, viability, insulin-releasing function (represented by the stimulation index), and gene expression of the islets. We also transplanted 500 islets intramuscularly with or without 5 × 105 MSCs to diabetic mice and measured their blood glucose level, the glucose changes in an intraperitoneal glucose tolerance test, and the plasma IL-6 level. Inflammation, apoptosis, and neovascularization in the transplantation site were evaluated histologically.

Results: The destruction of islets tended to be prevented by co-culture with MSCs. The stimulation index was significantly higher in islets co-cultured with MSCs (1.78 ± 0.59 vs. 7.08 ± 2.53; p = 0.0025). In terms of gene expression, Sult1c2, Gstm1, and Rab37 were significantly upregulated in islets co-cultured with MSCs. Although MSCs were effective in the in vitro assays, they were only partially effective in facilitating intramuscular islet transplantation. Co-transplanted MSCs prevented an early inflammatory reaction from the islets (plasma IL-6; p = 0.0002, neutrophil infiltration; p = 0.016 inflammatory area; p = 0.021), but could not promote neovascularization in the muscle, resulting in the failure of many intramuscular transplanted islets to engraft.

Conclusions: In conclusion, co-culturing and co-transplanting MSCs is potentially useful in islet transplantation, especially in terms of anti-inflammation, but further augmentation for an anti-apoptosis effect and neovascularization is necessary.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Culture Techniques
  • Coculture Techniques
  • Diabetes Mellitus, Experimental
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Inflammation / etiology*
  • Inflammation / pathology
  • Inflammation / therapy*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans Transplantation* / adverse effects
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Neovascularization, Physiologic

Grant support

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (B: 22390253 (SE); B: 22390252 to YK); Challenging Exploratory Research: 24659582 (to NS), the Gonryo Medical Foundation, and the Suzuken Memorial Foundation (to NS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.