Mesenchymal stem cells as a gene delivery vehicle for successful islet transplantation

Hao Wu, Wenli Lu, Ram I. Mahato

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Purpose:To evaluate the efficacy of human bone marrowderived mesenchymal stem cells (hBMSCs) as gene delivery vehicles to simultaneously express human hepatocyte growth factor (HGF) and interleukin 1 receptor antagonist (IL-1Ra) to improve the outcome of islet transplantation. Methods:Morphology and islet-binding affinity of hBMSCs were checked by microscope. The expression of target genes and endogenous genes was determined by ELISA. Protection of islets by hBMSCs was evaluated in vitro by Calcein-AM/Propidium Iodide staining and in vivo by allogeneic islet transplantation study. Function and revascularization of islets was evaluated by immune fluorescence study. Results: Non-donor-specific hBMSCs showed strong binding affinity to human islets and protected viability and function. Transduction of hBMSCs with adenovirus encoding human HGF and human IL-1Ra (Adv-hHGF-hIL-1Ra) prior to coculturing with islets further protected from apoptotic cell death, helped maintain 3D structures and morphology, and enhanced insulin secretion. Transplantation of human islets reconstituted with Adv-hHGF-hIL-1Ra transduced hBMSCs under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice reversed diabetes by reducing blood glucose levels to ≤200 mg/dL for up to 15 weeks and reduced the number of islets required to achieving normoglycemia. Blood glucose levels of mice transplanted with islets alone reversed to ≥500 mg/dL 4 weeks posttransplantation. Conclusions:Results: indentified hBMSCs as effective gene delivery vehicles to improve the outcome of islet transplantation.

Original languageEnglish (US)
Pages (from-to)2098-2109
Number of pages12
JournalPharmaceutical Research
Volume28
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • Adenovirus
  • Gene therapy
  • Islet transplantation
  • Mesenchymal stem cells

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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