Dysfunction of the retinal pigmented epithelium (RPE) has been linked to a variety of ocular disorders including age-related macular degeneration (AMD) as well as hereditary disorders such as Stargardt's disease and Retinitis Pigmentosa. The RPE has a wide variety of crucial functions that serve to protect the other cells of the retina and maintain proper retinal physiology. For the Eye the RPE layer Functions as tissue macrophages do in other organs. In this capacity the RPE are constantly exposed to free radical release and other metabolic breakdown products. With age the accumulated damage serves to decrease overall RPE function, which appears to be a critical step in the establishment and progression of AMD. RPE are generally considered to be terminally differentiated cells with little or no evidence that the layer turns over or regenerates. Several therapeutic models attempt to replace RPE within the eye by direct transplant. These models have so far yielded very limited success. One hallmark of the RPE layer is the production of a variety of cytokines such as MCP-1 and SDF-1. SDF-1 is one of the primary recruitment Factors for the hematopoietic stem and progenitor cells (HSC/HPC). The ample blood supply of the choroid provides HSC/HPC access to the RPE layer. Based on these data we tested whether HSC/HPC can contribute to repair and regeneration of the RPE layer. We used three models of acute injury to the RPE layer followed by tagged HSC/HPC transplantation. In each model donor HSC/HPC were able to home to and integrate within the injured RPE layer. The donor-HSC/HPC derived cells adopted the characteristic cuboidal morphology of RPE, expressed melanin by electron and light microscopy in albino recipients, and the loss of expression of the pan leukocyte marker CD45. Collectively, the data suggests that HSC/HPC can be recruited to an injured RPE layer where they differentiate into RPE or RPE-like cells. In this proposal we seek to extend these initial findings and test the following specific hypotheses:
Aim 1 : HSC/HPC can repair RPE function following an acute injury.
Aim 2 : Recruitment of HSC/HPC to areas of acute RPE injury requires specific cytokine expression by the injured area. Enhancement of these cytokine responses should improve HSC/HPC repair.
Aim 3 : HSC/HPC can also regenerate the RPE in response to chronic injury.
|Pi, Liya; Shenoy, Anitha K; Liu, Jianwen et al. (2012) CCN2/CTGF regulates neovessel formation via targeting structurally conserved cystine knot motifs in multiple angiogenic regulators. FASEB J 26:3365-79|
|Xia, Huiming; Krebs, Mark P; Kaushal, Shalesh et al. (2011) Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice. Exp Eye Res 93:862-72|
|Pi, Liya; Xia, Huiming; Liu, Jianwen et al. (2011) Role of connective tissue growth factor in the retinal vasculature during development and ischemia. Invest Ophthalmol Vis Sci 52:8701-10|
|Harris, Jeffrey R; Fisher, Robert; Jorgensen, Marda et al. (2009) CD133 progenitor cells from the bone marrow contribute to retinal pigment epithelium repair. Stem Cells 27:457-66|