Abstract
Purpose :
Necrotic cell death pathways appear to play a role in the survival of photoreceptor precursors transplantation. Thus, we sough to promote photoreceptor graft survival through donor-host necroptosis modulation. For this purpose, we investigated the role of receptor interacting protein 3 (RIP3) kinase in a mouse model of inherited retinal degeneration.
Methods :
CD73+ MACS-sorted EGFP photoreceptor precursors were transplanted into 5-6 week old rd10 mice. Furthermore, EGFP and rd10 RIP3-deficient animals were generated to modulate cell death in donor and host, respectively.
Results :
Transplanted EGFP photoreceptors repopulate the outer nuclear layer of rd10 mice. In addition, transplanted CD73+ EGFP precursors do not de-differentiate to retinal pigment epithelial cells (RPE), ganglion cells, bipolar cells, astrocytes or Muller cells. RIP3 deletion in donor photoreceptors precursors increase graft survival, and RIP3 deletion in host rd10 mice maximized graft survival of donor RIP3-deleted EGFP photoreceptors precursors (rd10::EGFP = 1,043; rd10 RIP3 KO::EGFP = 1,050; rd10::EGFP RIP3 KO = 3,284; and rd10 RIP3 KO::EGFP RIP3 KO = 7,425 mean photoreceptors). Prior Transplantation of WT bone marrow to rd10 RIP3-deleted mice reduced the overall graft survival compared to RIP3-deleted bone marrow transplants (rd10::EGFP BMT = 4,216 and rd10 RIP3 KO::EGFP RIP3 KO BMT = 10,424 mean photoreceptors, p = 0.01). Pharmacological necroptosis inhibition with Necrostatin-1 increased survival of EGFP grafted photoreceptors in rd10 hosts (Vehicle = 4,151 and Necrostatin-1 = 9,623 mean photoreceptors, p = 0.04).
Conclusions :
Collectively, these results suggests that neuroprotective strategies in photoreceptor transplantation will aid in restoration therapies.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.