This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.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 in the aging population interfering with everyday functions such as reading and driving, and has become a major public health concern. AMD is particularly amenable to cell-replacement therapy 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 subretinal injections using currently available surgical techniques.Autologous stem cell transplantation is the safest and, thus, clinically preferred approach in patients with AMD. This implies using adult stem cells obtained from an easily accessible and abundant tissue source from the same patient, such as bone marrow. Evidence that human bone marrow-derived stem cells (hBMSCs) are able to promote repair of neural tissues including RPE has been growing, although therapeutic avenues to promote homing and engraftment of hBMSCs into damaged or diseased tissues remain unclear.Xenotransplantation of human cells into early chick embryos has been proposed as an in vivo system for differentiation of human BMSCs into spinal cord neurons by our collaborators Darwin Prockop and Joel Glover. Here we utilize a robust, convenient and rapid in vivo engraftment and differentiation approach using primitive eyes of chick embryos for guiding the developmental program of hBMSCs towards their RPE differentiation. Embryonic optic neuroepithelium is more permissive for stem cell engraftment compared to adult ocular tissues and provides a natural developmental microenvironment for the donor stem cell differentiation in vivo within the native RPE developmental program. However, the engraftment efficiency of adult stem cells remains suboptimal. Thus, we propose to utilize laser energy to modulate interactions between hBMSCs and the recipient embryonic ocular microenvironment to improve the engraftment potential of the donor cells and enhance the recipient tissue permissiveness to stem cell incorporation. Specifically, we propose to use laser irradiation to: 1) Create a controllable intraocular injury mechanism prior to stem cell transplantation into the embryonic chick eye in order to inhibit the endogenous ocular cells from competing with the transplanted donor cells, and also to stimulate regenerative tissue response to enhance homing and engraftment of the donor cells; 2) Investigate the effects of low energy (e.g. sub-damage threshold) lasers of various wavelengths (such as 530, 690, 810 and 950 nm, but particularly 810 nm) on the recipient tissue permissiveness (i.e. irradiate the primitive chick eyes in ovo) and the donor cells engraftment potential (i.e. irradiate adult human stem cells in vitro prior to their transplantation); 3) Measure the oxygen concentration in the developing embryonic eye in ovo and to use these conditions to pre-condition the adult human stem cells prior to their transplantation in order to enhance their survival and engraftment, and also to evaluate the effect of laser irradiation of the embryonic chick eye on oxygen concentration in vivo; 4) Evaluate the effect of laser irradiation on the permissiveness of the retina/RPE complex in the adult RCS rat model of retinal degeneration (also see 1 and 2).In summary, the proposed studies of laser-assisted cell transplantation (LACT) provide the foundation for development of a broad therapeutic platform for a variety of poorly treatable diseases such as AMD.
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