Genetically modified mesenchymal stem cells for improved islet transplantation

Abstract

The use of adult stem cells for therapeutic purposes has met with great success in recent years. Among several types of adult stem cells, mesenchymal stem cells (MSCs) derived from bone marrow (BM) and other sources have gained popularity for basic research and clinical applications because of their therapeutic potential in treating a variety of diseases. Because of their tissue regeneration potential and immune modulation effect, MSCs were recently used as cell-based therapy to promote revascularization, increase pancreatic β-cell proliferation, and avoid allograft rejection in islet transplantation. Taking advantage of the recent progress in gene therapy, genetically modified MSCs can further enhance and expand the therapeutic benefit of primary MSCs while retaining their stem-cell-like properties. This review aims to gain a thorough understanding of the current obstacles to successful islet transplantation and discusses the potential role of primary MSCs before or after genetic modification in islet transplantation.

FIG. 1

Human bone marrow (BM) derived mesenchymal stem cells (MSCs) are plastic adherent, pluripotent fibroblast-like cells under 100X light microscope.

FIG. 2

Construction of bipartite adenoviral vector encoding human hepatocyte growth factor (HGF) and interleukin 1 receptor antagonist (IL-1Ra) (Adv-hHGF-hIL-1Ra) using AdenoQuick cloning system. Briefly, cDNA of HGF and IL-1Ra was isolated and cloned into the shuttle plasmids pE 3.1 and pE 1.2 under CMV promoter. Then the shuttle plasmids were combined by homologous recombination to generate a cosmid containing the entire sequence of recombinant adenovirus. At last, the cosmid was linearized transfected into 293 cells to produce the recombinant adenovirus Adv-hHGF–hIL-1Ra. Reproduced from Panakanti and Mahato (2009) Pharm Res 26: 587–596.

FIG. 3

Differentiation and transdifferentiation of mesenchymal stem cells (MSCs). MSCs have three established differentiation directions: osteoblasts, chondrocytes and adipocytes. Stimulation with chemical or biological signals can induce transdifferentiation of MSCs into vascular endothelial cell,^, myocytes,^, hepatocytes, and pancreatic β cells.^,

FIG. 4

Mesenchymal stem cells (MSCs) avoid allograft rejection by T-cell inhibitory effect. (a) The allograft rejection mediated by T cells. Briefly, antigen-presenting DCs present allogeneic antigens through MHC II to the TCR of T₀ cells. With assistance from co-stimulatory molecules, DCs become activated into mature DCs and simultaneously promote T cell activation into Tc, Th, and Tm. Then the activated T cells lead to a cascade of immune responses to mediate acute graft rejection and long-term graft rejection. (b) MSCs inhibit T cell activation through two mechanisms: (1) Direct T inhibition which is achieved by a so-far unknown cell-cell contract mechanism or IDO induced T cell inhibition or MMP2/MMP9-mediated CD25 cleavage on the surface of activated T cells. (2) Indirect T cell inhibition, which is achieved by releasing soluble factors to inhibit and reverse DC maturation. The antigen presenting process through immature DCs which in the absence of costimulatory molecules, leads to the inactivation of activated T cells, proliferation of immunosuppressive Treg cells, and allogeneic tolerance.

FIG. 5

Use of genetically modified MSCs to improve the outcome of human islet transplantation. (a) MSCs were transduced with Adv-hHGF-hIL-1Ra prior to islet transplantation. (b) After co-transplantation with human islets under the kidney capsule of diabetic NOD-SCID mice, MSCs expressed HGF and IL-1Ra into the surrounding microenvironment to support islet viability and function. (c) Genetically modified human BM derived MSCs express elevated level of HGF and IL-1Ra after adv-transduction in transient manner. (d) Genetically modified MSCs prolonged the duration of normoglycemia after co-transplantion with human islets into diabetic NOD-SCID mice. Reproduced from Wu et al. (2011) Pharm Res. 2011 Apr 16. [Epub ahead of print]