Stem Cell Transdifferentiation in the Testis

Funding Type: 
SEED Grant
Grant Number: 
RS1-00259
ICOC Funds Committed: 
$0
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 
Testicles have two main functions: they produce sperm and testosterone. Evidence from clinical and population based surveys suggests an increasing incidence of male reproductive damages. Our long term goal is to study how to let stem cells become testosterone producing cells (Leydig cell), sperm production supporting cells (Sertoli cell) in the testis. In this proposal, we will focus on how to turn stem cells into Leydig cells in the testis. Testis is not closely monitored by immune system. We hypothesize that 1) a proper cells coming from human embryonic stem cells (hESCs) in culture once transplanted into the interstitial space of recipient testes can become Leydig cells in a proper testicular environment; 2) certain hormones promote and stimulate transplanted stem cells turning into Leydig cells in testes. This study has high significance because: 1) we can establish an experimental model to test the plasticity of stem cells (adult or embryonic) in the testis. Utilizing this model we can demonstrate the cellular and molecular mechanisms controlling stem cell function and plasticity in testes. This is crucial to the future use of stem cells in regenerative medicine, as well as in understanding aging, tumor formation, testosterone and sperm production; 2) we can translate the results to clinical studies relevant to the novel treatment of male infertility and testosterone deficiency. The cause of male infertility is either due to the germ cell defect or supporting cells’ dysfunction. In many cases, germ cells are present. The presence of donor-derived healthy cells replacing defective nurturing cells is critical since both Leydig and Sertoli cells support sperm production. Defects in these cells have been believed to contribute to abnormal sperm production. The possibility of beneficial hormonal effects of Leydig cell transplantation independent of their support of sperm production also exits. Since Leydig cells are responsible for testosterone production, stem cell transplantations may replace the need of life-long testosterone supplementation in testicle failure males and aging population. The findings from these studies will have a major impact in the understanding reproductive physiology and recovery from testicular pathology, and also may have the potential for novel future therapies in patients with testicular failure.
Statement of Benefit to California: 
California is the biggest state in population in the United States. Infertility affects 15% of couples and evidence from clinical and population based surveys suggests an increasing incidence of male reproductive problems. In addition to the mentally and physically suffering in men, testicle failure sometimes contributes to social instability of the family. Our long term goal is to develop regenerative strategies to maintain, improve and rescue testicular functions through the stem cell research. In addition, understanding the cellular and molecular mechanisms controlling stem cell function and plasticity is crucial to the future use of stem cells in regenerative medicine, as well as in understanding aging, tumor formation, testosterone secretion and sperm production. Techniques generated from this study will contribute to biotech industrial development in California.
Progress Report: 
  • We made tremendous progress on our aims related to this project. We began the grant period having never worked with human embryonic stem cells (hESCs). We ended the project period having published 3 scientific papers in high profile journals (PNAS, Cell Stem Cell, Stem Cells) covering various aspects of this work as outlined in the grant. In addition, at least two more papers will be published in the next year related to this work.
  • To summarize the work, we employed hESCs to model the development of pluripotent cells from undifferentiated "embryonic-like" cells to neural stem cells to neuronal progenitors to committed neurons and finally to fully active mature neurons. Furthermore, we developed methods to purify these cells at each step in order to determine their gene expression profile. We have made fascinating observations of changes in gene expression in these cells as they go from embryonic to fully mature neurons. The simplest way to describe this method is that we have modeled the development of a human tissue in vitro, which, without the use of hESCs would normally be impossible. As a result, we now know more about how these cells development than ever before. With this knowledge in hand, we can now test hypotheses about how neurons develop in the embryo in vitro.
  • How will these results be applied in the future? Because we now have a basic framework by which human motor neurons develop in vitro, we can attempt to affect this process by boosting or ablating expression of those genes that are induced during maturation. This will tells us which genes play a functional role in this process and perhaps hint towards future therapies for motor neuron diseases.

© 2013 California Institute for Regenerative Medicine