Tacrolimus inhibits the revascularization of isolated pancreatic islets

PLoS One. 2013 Apr 17;8(4):e56799. doi: 10.1371/journal.pone.0056799. Print 2013.

Abstract

Aims: Immunosuppressive drugs could be crucial factors for a poor outcome after islet allotransplantation. Unlike rapamycin, the effects of tacrolimus, the current standard immunosuppressant used in islet transplantation, on graft revascularization remain unclear. We examined the effects of tacrolimus on islet revascularization using a highly sensitive imaging system, and analyzed the gene expression in transplanted islets by introducing laser microdissection techniques.

Methods: Islets isolated from C57BL/6-Tg (CAG-EGFP) mice were transplanted into the nonmetallic dorsal skinfold chamber on the recipients. Balb/c athymic mice were used as recipients and were divided into two groups: including a control group (n = 9) and tacrolimus-treated group (n = 7). The changes in the newly-formed vessels surrounding the islet grafts were imaged and semi-quantified using multi-photon laser-scanning microscopy and a Volocity system. Gene expression in transplanted islets was analyzed by the BioMark dynamic system.

Results: The revascularization process was completed within 14 days after pancreatic islet transplantation at subcutaneous sites. The newly-formed vascular volume surrounding the transplanted islets in the tacrolimus-treated group was significantly less than that in the control group (p<0.05). Although the expression of Vegfa (p<0.05) and Ccnd1 (p<0.05) was significantly upregulated in the tacrolimus-treated group compared with that of the control group, no differences were observed between the groups in terms of other types of gene expression.

Conclusions: The present study demonstrates that tacrolimus inhibits the revascularization of isolated pancreatic islets without affecting the characteristics of the transplanted grafts. Further refinements of this immunosuppressive regimen, especially regarding the revascularization of islet grafts, could improve the outcome of islet allotransplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation / drug effects
  • Imaging, Three-Dimensional
  • Islets of Langerhans / blood supply*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects*
  • Skinfold Thickness
  • Tacrolimus / administration & dosage
  • Tacrolimus / blood
  • Tacrolimus / pharmacology*
  • Time Factors

Substances

  • Tacrolimus

Grant support

This study has been supported by grants from the Japanese Grant-in-Aid for Scientific Research (B), the Takeda Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Japanese Ministry of Health, Welfare and Labor (20120101). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.