The Effect of Induction of Recipient Stem Cells on Immune Modulation and Tissue Regeneration in an Experimental Composite Tissue Allotransplant Model

Composite tissue allotransplantation (CTA, including skin, muscle, peripheral nerve, or even bone and joint) has tremendous application for reconstructive surgery. Recently, important advances, such as hand or face transplantation, have been made in human clinical trials. Owing to the highly immunogenity of CTA, the development of a new strategy preventing the long-term use of immunosuppressants has been investigated. Kuo YR, MD, PhD, PI of this project, has applied these unique characters of donor allogeneic bone marrow–derived mesenchymal stem cells (MSCs) (NSC98-2314-B-182-014-MY3) and adipose–derived stem cells (ASCs) to CTA in a rodent hind-limb model. Our studies have demonstrated that multiple donor allogeneic stem cells have immunomodulatory effects to prolong allograft survival and increasing the percentages of CD4+/CD25+/foxp3+ regulatory T-cells population (Kuo YR et al, Transplantation, 2009; Plast Reconstr Surg, 2010 and Plast Reconstr Surg, 2011). However, no migration of recipient bone marrow cells into donor bone was detected. Recently, we and others have revealed that recipient mesenchymal stem cells have the immune modulatory effect to regulate T-cells function. We also fantastically detected the recipient white hair follicle tissue of Lewis rat exist in the donor (Brown-Norway rat) brown alloskin area. This demonstrated the recipient stem cells have a trend to increase allo-tissue regeneration and prevent allograft rejection. Recent studies revealed combining granulocyte colony-stimulating factor (G-CSF) with dipeptidylpeptidase IV (DDP-IV) inhibitor could promote mobilization and migration of recipient bone marrow stem cells into ischemically injured areas by increasing stromal-cell derived factor-1 (SDF-1), resulting in tissue regeneration after myocardial infarct. Therefore, we will investigate whether recipient endogenous stem cells induced by G-CSF and DPP-IV inhibitor could enhance their abilities such as immunosuppressive activity and mobilization/migration into donor allografts in a rodent hind-limb CTA models. The scheme and specific aims are as follows: 1. First year: 􀁺 To investigate whether combination of recipient endogenous stem cells induced by G-CSF and DPP-IV inhibitor (Sitagliptin phsophate) and short-term immunosuppressant could modulate allograft rejection 2. Second year 􀁺 To detect the bio-signals of cellular and humeral mechanisms of immuno-modulatory effects of recipient endogenous stem cells in CTA hind-limb model 3. Third year 􀁺 To investigate the bio-mechanisms of modulation of SDF-1 expression in endogenous stem cells and T-cells interaction in vitro 􀁺 To evaluate the characteristics of induction of recipient stem cells increasing the tissue regeneration and migrated to donor grafts using Luciferase transgenic rats. Results obtained from this project will provide important information regarding future clinical application of recipient endogenous stem cells for immuno-modulation in induction of allograft tolerance and tissue regeneration.

Project ID:PC10107-0370
External Project ID:NSC101-2314-B182-020-MY3