Telomerase and self-renewal in human embyronic stem cells
Embryonic stem cells are unique in their ability to give rise to all mammalian tissues. Their potential application to human disease is enormous because they could be employed to repair or replaced damaged tissue. Although tremendous strides have been made in recent years in treating human disease, replacing damaged tissue remains almost completely beyond our grasp. Harnessing human embryonic stem cells for this purpose will open completely new areas of regenerative medicine. One shared characteristic of embryonic stem cells and adult stem cells that reside in many of our tissues is the ability to self-renew. Self-renewal is the ability of a stem cell to divide and give rise to a daughter cell that is undifferentiated and capable of giving rise to all the same lineages as the parent stem cell. Understanding how embryonic stem cells self-renew is critical for determining how to maintain these cells, how to differentiate them toward specific tissue lineages and how to expand more committed stem cells or progenitor cells in cell culture. A small number of genes that control embryonic stem cell self-renewal have been discovered, but our understanding of this process remains in its infancy.
In this proposal, we investigate the molecular mechanism by which telomerase contributes to embryonic stem cell self-renewal. Telomerase is an enzyme complex expressed in embryonic stem cells, some tissue stem cells and in almost all human cancers. Most differentiated cells lack telomerase expression. Telomerase adds DNA repeats to structures at the ends of our chromosomes, termed telomeres. Telomeres are very important in protecting chromosome ends and in preventing chromosome ends from breaking down or sticking to other ends inappropriately. By maintaining telomeres, telomerase supports the ability of stem cells to divide a large number of times. In addition to its function in telomere synthesis, we recently discovered a second role for telomerase. We expressed the TERT protein component of telomerase in mouse skin and unexpectedly found that TERT activated resting tissue stem cells. Activation of skin stem cell by TERT triggered a regenerative program in skin leading to robust hair growth. We used a rigorous technique to show that this new activity does not involve TERT’s other role in telomere lengthening. It is absolutely essential to understand how telomerase carries out its functions in stem cells. Therefore, we have isolated proteins that strongly interact with TERT. In this proposal, we investigate the function of TERT in embryonic stem cells and determine the role of several TERT associated proteins in embryonic stem cell self-renewal.
This proposal will benefit California and its citizen in two general ways. First, I have recruited two new scientists to California from Texas to work on this proposal. These are new taxpayers and consumers, which will benefit local businesses. They would have been less likely to come to California in the absence of the CIRM grant program. Second, this novel grant will generate new intellectual property in the form of patents. These patents may in fact be licensed to California companies or be used to support the formation of new start-up companies. The growth of such companies has historically fueled much of the profound growth in California. The future of California is linked to new technologies in the stem cell, biotechnology and other technology sectors.