April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Plasminogen Activator Inhibitor (PAI)-1: Potential Therapeutic Target For Autologous Cell Therapy For Treatment Of Macular Ischemia (MI) And Vasodegenerative Phase Of Diabetic Retinopathy (DR)
Author Affiliations & Notes
  • Sugata Hazra
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Yagna P. Jarajapu
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Sergio Caballero
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Li Liu
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Valerie Stepps
    BetaStem Therapeutics, Inc.,, San Francisco, California
  • Ashay Bhatwadekar
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Michael E. Boulton
    Anatomy and Cell Biology,
    University of Florida, Gainesville, Florida
  • Paul J. Higgins
    Pharamacology, Albany Medical College, Albany, New York
  • Stephen H. Bartelmez
    BetaStem Therapeutics, Inc.,, San Francisco, California
  • Maria Grant
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Footnotes
    Commercial Relationships  Sugata Hazra, None; Yagna P. Jarajapu, None; Sergio Caballero, None; Li Liu, None; Valerie Stepps, None; Ashay Bhatwadekar, None; Michael E. Boulton, None; Paul J. Higgins, None; Stephen H. Bartelmez, None; Maria Grant, None
  • Footnotes
    Support  EY007739, EY012601, HLB 099980 (MBG), HLB R01 HL091005-01A1 (CJP) and U01 HLB 087366 (CJP)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3179. doi:
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      Sugata Hazra, Yagna P. Jarajapu, Sergio Caballero, Li Liu, Valerie Stepps, Ashay Bhatwadekar, Michael E. Boulton, Paul J. Higgins, Stephen H. Bartelmez, Maria Grant; Plasminogen Activator Inhibitor (PAI)-1: Potential Therapeutic Target For Autologous Cell Therapy For Treatment Of Macular Ischemia (MI) And Vasodegenerative Phase Of Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2011;52(14):3179.

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

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Abstract

Purpose: : The dysfunction of human diabetic(D) CD34+ endothelial progenitor cells limits their utility in autologous cell therapy for vascular complications such as MI and DR. Previously, we showed that transient inhibition of transforming growth factor-beta 1 (TGF-β1) enhances vascular reparative function of human DCD34+ cells . Expression of PAI-1, the major gene product of TGF-β1 activation, is increased by high glucose and insulin exposure and in the serum of diabetics. We tested whether the beneficial effects of TGF-β1 blockade on CD34+ cells function were mediated by inhibition of PAI-1 and whether blocking PAI-1 could correct diabetes associated dysfunction of these cells.

Methods: : Plasma determinations of PAI-1 and TGF-β1 were compared in type(T)2 and T1D patients. CD34+ cells from these individuals were isolated and analyzed for cell survival (in presence and absence of growth factors), proliferation, cell cycle analysis and migration. The effect of TGF-β1 phosphorodiamidate morpholino oligomers (PMO) treatment on PAI-1 level was determined in CD34+ cells.PAI-1 was blocked using either lentivirus expressing PAI-1 shRNA or PAI-1 siRNA. In vivo homing ability of PAI-1 inhibited cells was assessed using an ocular model of ischemia/reperfusion (I/R) injury.

Results: : Plasma PAI-1 level was increased in T2D patients compared to T1D (p<0.05) and directly correlated with TGF-β1 plasma levels (r= 0.44).TGF-β1 PMO treatment resulted in a reduction of PAI-1 mRNA expression (p<0.05). PAI-1 blockade 1) promoted G0-G1transition of these cells resulting in enhanced EPC proliferation in vitro even in the absence of growth factors (p<0. 05); 2) bypassed the inhibitory effect of TGF-β1 on cell survival (p<0.001); facilitated 3) increased migration in response to SDF-1α (p<0.01); and 4) improved in vivo re-endothelialization in the I/R model.

Conclusions: : Our results suggest that the cytostatic activity of TGF-β1 in CD34+ cells is mediated largely through PAI-1 inhibition. Blocking PAI-1 corrects multiple defects in CD34+ cells from T2D patients. This approach may offer a promising therapeutic strategy for restoring vascular reparative function in diabetic cells and facilitate their use in autologous cell therapy for MI or DR.

Keywords: diabetes • diabetic retinopathy • ischemia 
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