Molecular Therapy 2013 Sep; 21 (9): 1778-1786.

Third-party mesenchymal stem cells improved human islet transplantation in a humanized diabetic mouse model.

Hao Wu, Di Wen and Ram I. Mahato

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA

 

Abstract

Human islet transplantation can be a permanent treatment of type 1 diabetes if the immune rejection and primary nonfunction (PNF) of transplanted islet grafts were properly addressed. In this study, we determined whether cotransplantation of human bone marrow-derived mesenchymal stem cells (hBMSCs) could prevent immune rejection and improve human islet transplantation in a humanized NOD scid gamma (NSG) mouse model. Human immunity was rebuilt and maintained in NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice up to 13 weeks after intraperitoneal injection of mature human peripheral blood mononuclear cells (PBMCs). The blood glucose control and the levels of serum insulin and c-peptide clearly indicated a better outcome of islet transplantation when islets were cotransplanted with hBMSCs. hBMSCs actively interacted with interleukin-10 (IL-10)-producing CD14+ monocytes to suppress the proliferation and activation of T cells in the PBMC/hBMSC coculture and prevent the T cell recruitment into the transplantation site. hBMSCs also increased the percentage of immunosuppressive regulatory T cells (Tregs) and prevented the cytokine-induced loss-of-function of human islets. Taken together, our studies demonstrated that transplantation of islets with hBMSCs is a promising strategy to improve the outcome of human islet transplantation.

PMID: 23765442

 

Supplements:

This study focused on investigating the role of bone marrow derived mesenchymal stem cell (BMSC) as a novel immunosuppressant in human islet transplantation. Human islet transplantation has failed to become a permanent treatment for type 1 diabetes during the past two decades, mostly due to the limited supply of human islets and inadequate immune suppression. The commonly used immunosuppressant such as tacrolimus, sirolimus and mycophenolic acid hold strong pro-apoptotic effect against human islets, making them improper for human islet transplantation.

Ram I. Mahato-1

Mesenchymal stem cells have been extensively studies as a novel regenerative medicine in tissue repairing and organ regeneration. They were known to suppress immune response in many preclinical studies. However, their application in human islet transplantation has not been explored. This study addressed the issue. They first characterize the immunosuppressive effect of BMSCs in vitro in a mixed lymphocyte reaction, demonstrating that BMSCs worked through an IL-10 dependent pathway by secreting a soluble factor. Human islets were transplanted in a humanized NSG mice, since human immune system was rebuilt in immunodeficient NSG gamma and thus represented an immune rejection to transplanted islets similar to what happens clinically. These authors demonstrated that the presence of BMSCs in the islet preparation reduced the T cell infiltration into the transplantation site, improved the viability and function of human islets, and increased the ratio of immunosuppressive Tregs in the mouse serum post-transplantation. These results suggested that BMSCs may be a novel immunosuppressive strategy for human islet transplantation.

BMSC has many favorable properties as a cell-type immunosuppressant. These stem cells reside at multiple tissues and are relatively easy to isolate and manipulate. As adult stem cells, they are hypo immunogenic and hypo-tumorigenic. Therefore, BMSCs are safer for clinical applications than embryonic stem cells. Most importantly, BMSCs can be isolated from a type 1 diabetic patient, expanded in vitro and infused back into the same patient to help allogenic islet transplantation, paving the way for personalized medicine for treating type 1 diabetes. Collectively, this study shed some lights into the future of human islet transplantation.

 

Contact:

Ram I. Mahato, PhD

Professor and Chair

Department of Pharmaceutical Sciences

University of Nebraska Medical Center

986025 Nebraska Medical Center

Omaha, NE 68198-6025

Tel: (402) 559-5422/4598; Lab 559-6987; Fax: (402) 559-9543

E-mail: ram.mahato@unmc.edu

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