Type 1 diabetes affects 4-5% of the world's population and can be reversed by pancreatic islet transplantation. However, acute shortage of organ donors, lifelong immunosuppression and chronic graft rejection currently limit greater use of this potentially curative therapy. Hence, there is an urgent need to develop novel renewable sources of insulin producing cells (IPCs). In this regard, ES cells and iPS cells offer a unique opportunity of pluripotent stem cells for the generation of unlimited supplies of IPCs that can be used for the treatment of type 1 diabetes (T1D). However, due to the current knowledge gap regarding the molecular mechanisms underlying differentiation of stem cells, robust generation of IPCs using ES cells has so far remained elusive. Our long term goal is to develop a stem cell based therapy for the treatment of type 1 diabetes. We hypothesize that pluripotent stem cells can be coaxed to differentiate into glucose-responsive IPCs. The underlying rationale is that the establishment of a lineage commitment pathway mimicking in vivo development of pancreatic islets using hES cells would ultimately lead to an unlimited supply of IPCs for the treatment of type 1 diabetes.
In Specific Aim 1, we will determine whether mouse ES cells can be coaxed to generate IPCs that can correct hyperglycemia in diabetic mice. ES cells will first be driven to differentiate into pancreatic endodermal (PE) cells that can be purified by their surface expression of CXCR4. These purified IPCs will then be tested for their glucose responsiveness in vitro and in vivo. In addition, we will investigate whether ES cell-derived IPCs survive long-term in vivo.
In Specific Aim 2 we will determine whether human iPS cells generate IPCs in vitro that are glucose responsive in vivo. If successful, our studies will establish pluripotent stem cells as a novel source of IPCs that can cure diabetes. Potential Impact on Veterans Health Care: Veterans are equally susceptible to T1D like the general population. Due to the shortage of donors, most of these patients hardly ever get the chance to be transplanted. Our project is directed towards developing an alternative renewable source of insulin-producing cells. These experiments are based on both mouse ES cells and on human iPS cells. If we are successful, we will establish a novel source of IPCs that will have a direct impact on the health and treatment of Veterans.

Public Health Relevance

- Relevance to Veterans Health Care T1D is a devastating disease to patients that can only be satisfactorily treated with organ transplantation. However, the number of available cadaveric pancreatic organs is too small to allow treatment of patients on the waiting list. Our proposal focuses on deriving insulin producing cells (IPCs) from murine ES cells and from human iPS cells. The cells will be tested for their ability to treat diabetes in mice. If successful, these studies will provide a novel strategy for managing diabetics in the future.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001125-02
Application #
8413422
Study Section
Endocriniology A (ENDA)
Project Start
2012-01-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Iowa City VA Medical Center
Department
Type
DUNS #
028084333
City
Iowa City
State
IA
Country
United States
Zip Code
52245
Sweeney, Sean K; Manzar, Gohar S; Zavazava, Nicholas et al. (2018) Tracking embryonic hematopoietic stem cells to the bone marrow: nanoparticle options to evaluate transplantation efficiency. Stem Cell Res Ther 9:204
Kim, Eun-Mi; Manzar, Gohar; Zavazava, Nicholas (2017) Induced pluripotent stem cell-derived gamete-associated proteins incite rejection of induced pluripotent stem cells in syngeneic mice. Immunology 151:191-197
Kim, Eun-Mi; Miyake, Bob; Aggarwal, Manish et al. (2014) Embryonic stem cell-derived haematopoietic progenitor cells down-regulate the CD3 ? chain on T cells, abrogating alloreactive T cells. Immunology 142:421-30
Zavazava, Nicholas (2014) Progress toward establishing embryonic stem or induced pluripotent stem cell-based clinical translation. Curr Opin Organ Transplant 19:598-602
Kim, Eun-Mi; Manzar, Gohar; Zavazava, Nicholas (2013) Human iPS cell-derived hematopoietic progenitor cells induce T-cell anergy in in vitro-generated alloreactive CD8(+) T cells. Blood 121:5167-75
Raikwar, Sudhanshu P; Zavazava, Nicholas (2013) Differentiation and lineage commitment of murine embryonic stem cells into insulin producing cells. Methods Mol Biol 1029:93-108
Das, Satyabrata; Jena, Snehalata; Kim, Eun-Mi et al. (2012) Transcriptional Regulation of Human NANOG by Alternate Promoters in Embryonic Stem Cells. J Stem Cell Res Ther Suppl 10:009
Fan, Rong; Bonde, Sabrina; Gao, Peng et al. (2012) Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells. Blood 119:e139-47
Fiorina, Paolo; Voltarelli, Julio; Zavazava, Nicholas (2011) Immunological applications of stem cells in type 1 diabetes. Endocr Rev 32:725-54