Branch vein occlusion (BVO) and diabetic retinopathy (DR) are the major causes of new onset blindness in the US. Both disorders result in acellular capillaries due to ischemic death of retinal vascular endothelial cells (ECs) and contractile pericytes. If acellular retinal capillaries could be repopulated with autologous vascular/pericytic progenitors, ischemia could be relieved and end stage blindness reversed in these diseases. One such approach is to transplant patient-specific embryonic vascular progenitors (VP) with prolific vascular and mesenchymal-pericytic potential. Such progenitors could be generated from human induced pluripotent stem cells (hiPSC) and transplanted directly into the eye. This approach could be combined with parallel differentiation from the same hiPSC line to replace ischemic degenerated retinal neural tissue along with their requisite vascular niche. To date, no one has evaluated hiPSC-derived embryonic VP for capacity to engraft and rescue degenerated vasculature in the ischemic retina. In this proposal, we will test the potential of hiPSC-derived embryonic VP to efficiently differentiate to ECs and pericytes following engraftment into damaged ischemic retina. We will use animal models that mimic human BVO [i.e., ischemia/reperfusion (I/R) injury] or DR (induced in athymic rats) for testing the potential of hiPSC-derived VP to form patent blood vessels and rescue ischemic retina. We will inject hiPSC-derived CXCR4+ VP expressing endothelial (CD31+) and pericytic- mesenchymal (CD146+) markers directly into the vitreous space (or IV orbital sinus) of immunodeficient NOD/scid mouse eyes that have been experimentally degenerated by I/R injury or diabetes. We will then test the ability of these progenitors for their ability to repopulate and regenerate viabe capillaries, rescue neural retina, and improve visual function. We will also determine the retinal micro-environmental injury and hypoxia-related signals that regulate homing and engraftment of CXCR4+ embryonic VPs to acellular retinal capillaries. We hypothesize that efficient generation of vascular progenitors from nonviral myeloid-iPSC will ultimately have superior clinical utility fr the treatment of ischemic ocular diseases. If successful, our approach would allow facile generation of autologous, multipotent, and clinically useful vascular-forming precursors reprogrammed from a patient's own blood cells to be used in clinical therapies for BVO and DR.

Public Health Relevance

This study will explore novel stem cell regeneration approaches for treating ischemic blinding disorders. We will regenerate damaged retinal vasculature by converting a patient's blood sample to clinically safe human induced pluripotent stem cells (hiPSC) that can be re-differentiated to transplantable vascular progenitors capable of making new blood vessels. Our hope is that patient-specific hiPSC-derived vascular progenitors will ultimately be used to rescue the chronic, blinding complications of various retinopathies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01EY023962-01A1
Application #
8758998
Study Section
(DPVS)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Huo, Jeffrey S; Baylin, Stephen B; Zambidis, Elias T (2014) Cancer-like epigenetic derangements of human pluripotent stem cells and their impact on applications in regeneration and repair. Curr Opin Genet Dev 28:43-9