Engraftment and Differentiation of Adult Human Stem Cells in Embryonic Eye

Funding Type: 
New Faculty I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States, for which there is no cure. It has devastating effects on the quality of life as it makes it impossible for affected individuals to read and drive, and has become a major public health concern in the rapidly expanding aging population of California. AMD is particularly amenable to a potential cell-replacement therapeutic strategy because the affected areas of retinal pigment epithelium (RPE, the tissue primarily affected by the disease) can be directly visualized, and transplantation of stem cells could be performed by intraocular injections using currently available surgical techniques.
A number of recent animal studies suggest a great potential for using various populations of stem cells to improve the morphological and functional capacity of the RPE. However, we are yet to develop a stem cell-based approach for the management of specific retinal diseases such as AMD, and to establish clinically acceptable treatment protocols.
Patient-specific stem cell transplantation is currently the safest and, thus, preferred approach in patients with AMD at least for the near future. This implies using adult stem cells obtained from an easily accessible and abundant tissue source (such as bone marrow) from the same patient, which greatly increases their immune compatibility and overall safety. Following their isolation, these cells may be injected into the eyes of patients with age-related macular degeneration over the areas affected by the disease. However, there are two major obstacles that prevent successful RPE regeneration using adult patient-specific stem cells. When transplanted into adult tissues, these cells have a relatively low potential for developing into adult cells bearing the desired function and have relatively low efficiency to engraft within adult microenvironment.
We propose to develop a robust, convenient and rapid engraftment approach using eyes of chick embryos for guiding the developmental program of human bone marrow-derived stem cells towards their development into RPE. Embryonic chick eye is more permissive for stem cell engraftment compared to the adult tissues and provides a natural habitat for the donor stem cells to follow the native RPE developmental program in the context of ocular environment. We will determine and characterize the developmental pathways for native human RPE precursor cells and transplanted adult human stem cells transplanted into chick embryos. We also propose to modulate interactions between donor stem cells and the recipient embryonic ocular microenvironment to enhance the efficiency of stem cell incorporation. The proposed embryonic chick ocular model provides the foundation for future development of a broad platform for patient-specific stem cell-based AMD treatment and, therefore, has important therapeutic implications for the leading cause of blindness in the United States.

Statement of Benefit to California: 

My proposed research focuses on the development of stem cell-based therapeutic approaches to age-related macular degeneration (AMD), and other diseases in which deterioration of the retinal pigment epithelium (RPE) plays a significant role. It will benefit the citizens of the state of California in several important ways. AMD is the leading cause of blindness in the United States, and in California, and it is currently incurable. It has devastating effects on quality of life and independence, and is becoming a major public health concern as California’s population ages, and the state’s older citizens live longer, and require more assistance in the activities of daily living. The socioeconomic and emotional impact of AMD is tremendous because the disease affects central vision, limiting the ability of those who suffer from it to drive or read. Identifying a successful treatment would allow tens of thousands of elderly Californians to enjoy a more functional, productive, and enjoyable years beyond retirement.
Several studies have suggested the great therapeutic potential of various populations of adult stem cells derived from bone marrow for regeneration of RPE. Stem cell transplantation has already received considerable attention as a novel neurotherapeutic strategy, but so far, little work has been devoted to stem cell therapies for specific retinal disorders. We have yet to develop a stem cell approach for the management of specific retinal diseases like AMD, or to establish clinically acceptable treatment protocols. Patient-specific transplantation of adult stem cells obtained from patient’s own bone marrow or blood has many practical advantages over the use of human embryonic stem cells. Most importantly it eliminates the need for immunosuppressant drugs necessary in transplantation of cells or tissue from another individual, and carries no risk of tumor formation. The research proposed in the current application to the California Institute for Regenerative Medicine will utilize the embryonic chick model to lay the groundwork for the use of human bone marrow-derived multi-potential stem cells as a potential therapy for the blinding retinal degenerative and age-related disorders. This will benefit California’s citizens by speeding our progress towards a safe and effective treatment for AMD and other related diseases affecting vision.