Stem cell differentiation to thymic epithelium for inducing tolerance to stem cells

Stem cell differentiation to thymic epithelium for inducing tolerance to stem cells

Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01702
Award Value: 
$1,314,089
Disease Focus: 
Immune Disease
HIV/AIDS
Pediatrics
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Status: 
Active
Public Abstract: 
The thymus is an organ that plays a key role in controlling immune responses and immune tolerance. The thymus promotes immune tolerance by deleting and removing self-reactive T cells from the immune system. In addition, the thymus also helps drive the production of important suppressor T cell populations like regulatory T cells that also control immune tolerance. Thus, strategies that expand and improve thymic function could be critical in improving transplantation of tissues derived from embryonic stem cells. The thymus consists of a supporting network of thymic epithelial cells that help bone marrow derived T cell precursors mature and differentiate into fully functional T lymphocytes. Despite their importance, there has been little progress in methods to grow and expand out the supportive thymic epithelial network. This project will explore strategies to grow and expand out functional thymic epithelial cells from human embryonic stem cells using a multi-step culturing technique. These expanded thymic epithelial cells will be characterized and tested for the ability to support T cell development and differentiation. Finally, the expanded thymic epithelial cells will be put into transplantation models in humanized mice to test their ability to improve and enhance the acceptance of transplanted tissues. These studies offer enormous potential for promoting graft-specific immune tolerance in that embryonic stem cells could be differentiated into both a replacement tissue and into functional thymus
Statement of Benefit to California: 
The work in this proposal is designed to help improve the effectiveness of stem cell treatments by preventing immunological rejection of transplanted tissue derived from stem cells. Although significant progress and promise has been shown to use stem cells to regenerate damaged organs for the treatment of a wide variety of diseases, an important barrier to bringing this to the clinic is the potential of the immune system to reject or damage this regenerated tissue. Currently, there are efforts underway to use stem cells to treat diseases that have a wide impact on the health of Californians, including diabetes, Parkinson’s disease, Alzheimer’s disease, retinal eye diseases, and musculoskeletal diseases to name just a few. The work proposed here will help improve treatment for these diseases by improving the ability to put a break on the immune system to reject or destroy cells or tissues that are derived from stem cells for the treatment of these diseases. Here we will improve methods to grow and expand an important organ that controls the ability of the immune system to be “tolerant” of transplanted tissues called the thymus. If methods to grow and expand the thymus from stem cells can be done, this would represent a significant advance in improving stem cell therapies. Thus, the impact of this work could have a broad impact on a large number of the disease treatments that involve stem cells.
Progress Report: 

Year 1

Through the support of the CIRM we have initiated our efforts to differentiate and grow thymic epithelial cells from human embryonic stem cells. Over the last year we have been culturing human ES cells under different conditions and have examined marker expression in the cells for similarity to thymic epithelium. We have made significant progress, with a number of known markers being upregulated in our cells. We plan to continue similar efforts over the next year and expand our experiments to test whether these cells can induce immune tolerance. These findings are critical for the CIRM in that they may be an important way to keep the immune system in check and prevent immune rejection when ES cell derived material is transplanted.

Year 2

Over the last year we have made significant progress on ability to differentiate stem cells towards a cell lineage that can help contribute to a functional thymus. We have been able to induce a number of key markers of thymic progenitor cells and are also making progress on experiments to confirm the functionality of the differentiated cells. Taken together, these results could have a broad and significant impact on the field of regenerative medicine due to the ability of the thymus to control immune tolerance.

Year 3

Over the last year we have made significant progress on ability to differentiate stem cells towards a cell lineage that can help contribute to a functional thymus. We have been able to induce a number of key markers of thymic progenitor cells and are also making progress on experiments to confirm the functionality of the differentiated cells. Taken together, these results could have a broad and significant impact on the field of regenerative medicine due to the ability of the thymus to control immune tolerance.

© 2013 California Institute for Regenerative Medicine