Enhancing the function of CD34+ cells by targeting plasminogen activator inhibitor-1

Sugata Hazra, Valerie Stepps, Ashay D. Bhatwadekar, Sergio Caballero, Michael E. Boulton, Paul J. Higgins, Elena V. Nikonova, Carl J. Pepine, Catherine Thut, Eva M. Finney, David J. Stone, Stephen H. Bartelmez, Maria B. Grant

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Previously, we showed that transient inhibition of TGF-β1 resulted in correction of key aspects of diabetes-induced CD34+ cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1), a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34+ cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34+ cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO) reduced PAI-1 mRNA in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. To reduce PAI-1 in human CD34+ cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro, likely through increased PI3(K) activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34+ cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.

Original languageEnglish (US)
Article numbere79067
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hazra, S., Stepps, V., Bhatwadekar, A. D., Caballero, S., Boulton, M. E., Higgins, P. J., Nikonova, E. V., Pepine, C. J., Thut, C., Finney, E. M., Stone, D. J., Bartelmez, S. H., & Grant, M. B. (2013). Enhancing the function of CD34+ cells by targeting plasminogen activator inhibitor-1. PloS one, 8(11), [e79067]. https://doi.org/10.1371/journal.pone.0079067