Engineering human embryonic stem cells into ectodermal organs

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00340
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Recent progress in human embryonic stem cells (hES) offers tremendous hope in regenerative medicine. hES have been guided to replace several key cell types for some devastating diseases. However, the potential of hES in skin and associated ectodermal appendages, the organ that suffers from constant wear and tear, has not been widely explored to date. The overall goal of this proposal is 1) to understand how human embryonic stem cells (hES) can be guided to form ectodermal organs, including epithelial components (hair, teeth, skin, glands, etc.) and mesenchymal tissues (bone and periodontium), and 2) to explore the potential use of hES in tissue regeneration to repair or replace orofacial epithelial and mesenchymal defects. These defects often result from burns, accident injuries, congenital anomalies, genetic diseases, cancers, infectious diseases, etc. There is also a great demand for tooth replacement and bioengineered hair follicles. One of the major problems for regenerative medicine is the lack of sufficient numbers of precursor cells. We expect that advances in the field will help generate sufficient numbers of precursor cells from hES. In this proposal, we will focus to develop and establish novel procedures so these hES cells or derivatives can be guided to form the epithelial component of ectodermal organs and the associated mesenchymal structures. To this end we will mimic different microenvironments and do experiments to identify the appropriate key ingredients of molecular signals that specify hES to build ectodermal organs and associated structures. If the work proposed here is accomplished, it would significantly expand the therapeutic potential of hES. Furthermore, hES mediated ectodermal organ formation will be a major novel scientific progress. As we know, bone marrow transplantation is already a mature technology. This is because the derived blood cells are released to the blood stream without the need to build a complex three-dimensional architecture. Ectodermal organs, endodermal organs (e.g., liver) and neural tissues (neural circuits, but not including dopaminergic neurons for Parkinsons disease, in which only the released neurotransmitters are required) all require organized arrangements of cells/tissues for proper function. Learning how to build ectodermal organs will have implications beyond ectodermal organs. This is also more than just making a flat epidermis, which currently is already achieved by foreskin keratinocyte transplantation. The head is the body part in which ectodermal organs and associated structures are most important as well as most subject to injury. Therefore, we will have ectodermal organs in the head and orofacial regions as our priority goals. We also have been interacting with {REDACTED} in {REDACTED}, and will explore future clinical possibilities after we accomplish the work proposed here.
Statement of Benefit to California: 
Recent progress in human embryonic stem cells (hES) offers tremendous hope in regenerative medicine. hES have been guided to replace several key cell types for some devastating diseases. However, the potential of hES in skin and associated ectodermal appendages, the organ that suffers from constant wear and tear, has not been widely explored to date. The overall goal of this proposal is 1) to understand how human embryonic stem cells (hES) can be guided to form ectodermal organs, including epithelial components (hair, teeth, skin, glands, etc.) and mesenchymal tissues (bone and periodontium), and 2) to explore the potential use of hES in tissue regeneration to repair or replace orofacial epithelial and mesenchymal defects. These defects often result from burns, accident injuries, congenital anomalies, genetic diseases, cancers, infectious diseases, etc. There is also a great demand for tooth replacement and bioengineered hair follicles. In this proposal, we will focus to develop and establish novel procedures so hES cells or their derivatives can be guided to form the epithelial component of ectodermal organs and the associated mesenchymal structures. To this end we will mimic different microenvironments and do experiments to identify the key ingredients in molecular signals that specify hES to build ectodermal organs and associated structures. The head is the body part in which ectodermal organs and associated structures are most important as well as most subject to injury. Therefore, ectodermal organs in the head and orofacial regions will be our priority targets. In California, people live an outdoor lifestyle and are subject to more UV irradiation and associated diseases. Californians are also more conscious of their appearance and having imperfect ectodermal organs (e.g., alopecia) can cause psychological distress. With CIRM funding, we hope to develop remedies for these conditions. To do this, we wish to find the best possible hES lines for this purpose. Current Federally approved hES have some problems (see text) and we should not be limited to them. If we can produce ectodermal organs using methods as routine as bone marrow transplantation (which works easier because it does not require the complex three dimensional structures found in other organ systems), the need for replacement / regenerative ectodermal organ therapy will be huge. It will not only benefit Californians but also the California biotechnology industry. We also have been interacting with {REDACTED}, and {REDACTED} in {REDACTED}. We will explore future clinical possibilities after we accomplish the work proposed here. This field is ready. With CIRM support, we will be able to delve into this novel, risky but high return endeavor.

© 2013 California Institute for Regenerative Medicine