Photoreceptor failure in the retina is a leading cause of adult vision loss. Transplantation of stem cells into damaged retina presents an exciting potential for restoring vision. However, the poor migration and survival of transplanted cells within retinal lamina remains a major impediment. Our laboratory has reported that retinal progenitors respond to signaling from EGF via migration, and our most recent preliminary data suggest that photoreceptor precursor cells (PPCs) respond chemotactically to dose-dependent signaling from SDF-1. We hypothesize that receptor-driven, chemotactic mechanisms can be exploited to goad PPC migration into retinal lamina and promote integration to improve transplantation outcomes. The immediate goal of this SC3 proposal is to develop a predictive, bioengineering model able to recapitulate the migratory responses of photoreceptor precursor cells (PPCs) within adult retina, in order to optimize transplantation selectivity for motile cells In this work, we will use bioinformatics to develop a focused library of chemotactic factors present within rhodopsin knock out retina (rho -/- as a model of retinal degeneration) paired with corresponding receptor proteins expressed by PPCs. We will then quantify chemotactic responses of PPCs to candidate motogen-receptor couples using our microfluidics-based assays to determine specific conditions of motogen concentration and gradient needed to spur reproducible PPC chemotaxis. Lastly, we will examine the extent to which PPCs with highly chemotactic responses to targeted, retinal motogens express enriched capabilities to infiltrate explanted, degenerated retina.
Photoreceptor failure in the retina is a leading cause of adult vision loss in the USA. Transplantation of stem cells into damaged retina presents an exciting potential for restoring vision, but the amount of restored visual response is limited by the poor migration of transplanted cells. Our project directly addresses the nature of chemotactic signals produced by degenerating, adult retinal tissue and the specific conditions needed for these signals to effectively promote photoreceptor progenitor cell (PPC) migration into retina by using a rhodopsin knock-out mouse (rho -/-) model. Successful completion will determine whether PPCs with superior chemotactic responses achieve higher levels of integration with host retina, and develop motile cell selectivity approaches that can be applied in vivo.
|McCutcheon, Sean; Unachukwu, Uchenna; Thakur, Ankush et al. (2017) In vitro formation of neuroclusters in microfluidic devices and cell migration as a function of stromal-derived growth factor 1 gradients. Cell Adh Migr 11:1-12|
|Unachukwu, Uchenna John; Warren, Alice; Li, Ze et al. (2016) Predicted molecular signaling guiding photoreceptor cell migration following transplantation into damaged retina. Sci Rep 6:22392|