June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Cell Therapy Model of Diabetic Retinopathy Using Vascular Progenitor Cells Derived from Human iPSC
Author Affiliations & Notes
  • Tea Soon Park
    Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland, United States
    Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, United States
  • Imran Ahmed Bhutto
    Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Ludovic Zimmerlin
    Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland, United States
    Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, United States
  • Il Minn
    Department of Radiology, Johns Hopkins University, Baltimore, Maryland, United States
  • Nensi Ruzgar
    Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland, United States
    Health Sciences, McMaster University, Toronto, Ontario, Canada
  • Martin Pomper
    Department of Radiology, Johns Hopkins University, Baltimore, Maryland, United States
  • Mary A Johnson
    Department of Ophthalmology, University of Maryland, Baltimore, Maryland, United States
  • Gerard A Lutty
    Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States
  • Elias Zambidis
    Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland, United States
    Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Tea Soon Park, JHU (P); Imran Bhutto, None; Ludovic Zimmerlin, None; Il Minn, JHU (P); Nensi Ruzgar, None; Martin Pomper, JHU (P); Mary Johnson, None; Gerard Lutty, None; Elias Zambidis, JHU (P), Thermo Fisher Scientific (R)
  • Footnotes
    Support  NIH/NHLBI grant U01HL099775 (ETZ), NIH/NICHD grant R01HD082098 (ETZ), Maryland Stem Cell Research Fund (MSCRF) grants 2011-MSCRF-II-0008-00 (ETZ), 2007-MSCRF-II-0379-00 (ETZ), 2014-MSCRF-II-118153 (TSP), 2013-MSCRF-III-114936 (LZ), core NIH grants P30 CA006973 and EY01765
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4051. doi:
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    • Get Citation

      Tea Soon Park, Imran Ahmed Bhutto, Ludovic Zimmerlin, Il Minn, Nensi Ruzgar, Martin Pomper, Mary A Johnson, Gerard A Lutty, Elias Zambidis; Cell Therapy Model of Diabetic Retinopathy Using Vascular Progenitor Cells Derived from Human iPSC. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4051.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Successful cellular therapy of diabetic vascular complications (DVC) will require novel sources of angiogenic progenitors that can sustain long-term functional recovery in a clinical setting. Since adult stem cell sources such as diabetic endothelial progenitor cells (D-EPC) have proven to be scarce or have impaired migration into the injury sites, human induced pluripotent stem cell (hiPSC) technology may offer unlimited amounts of embryonic vascular progenitor (VP) to repair ischemic diabetic tissues with clinically relevant and efficient protocols for reprogramming and differentiation.

Methods : To test this potential, we generated diabetic iPSC (D-iPSC) from skin fibroblasts of type-I diabetic patient using non-integrative episomal reprogramming system. Short exposure to a GSK3β inhibitor and ascorbic acid dramatically facilitated the reprogramming kinetics. Additionally, we recently developed novel chemical methods [LIF with GSK3β, ERK and tankyrase inhibitors (L3i)] that stably revert hPSC to a mouse ESC-like naïve state. We demonstrated that LIF-3i-reverted hPSC acquired transcriptomic, epigenetic, and signaling signatures of naïve-pluripotency, and significantly improved multi-lineage differentiation efficiencies with reduced lineage bias.

Results : This L3i reversion method was successfully applied to generating naïve D-iPSC to obtain higher quality of therapeutic VP. Primed- (traditional) and naïve-D-iPSC were compared for differentiation potential, vascular functional assays in vitro and in vivo. To investigate the regenerative capacity of iPSC-VP in a DVC-relevant model, we employed a streptozotocin (STZ) injected diabetic athymic nude rat model that exhibited hyperglycemia over 24 weeks and decreased retinal function as measured by electroretinography. Our preliminary results showed that injection of healthy hiPSC-VP into this diabetic rat model validated human cell capacity to migrate and engraft to injured sites. We are currently examining the engraftment of D-iPSC-VP, naïve-D-iPSC-VP, healthy cord blood- and fibroblast-iPSC-VP. Furthermore, intravitreous injection of hiPSC-VP expressing a luciferase transgene allowed detection of human cell migration using noninvasive live animal bioluminescent imaging.

Conclusions : This STZ-induced diabetic rat model provides a translational opportunity to evaluate the use of patient specific iPSC-VP for treatment of DVC.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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