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

Sugata Hazra, Valerie Stepps, Ashay 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

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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+ 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
Externally publishedYes

Fingerprint

Plasminogen Activator Inhibitor 1
Morpholinos
cells
glycemic control
Small Interfering RNA
plasminogen activator inhibitors
Genes
Lentivirus
Messenger RNA
Cell proliferation
major genes
Medical problems
small interfering RNA
ischemia
Reperfusion Injury
cell movement
blood vessels
Cell Movement
Blood Vessels
diabetes

ASJC Scopus subject areas

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

Cite this

Hazra, S., Stepps, V., Bhatwadekar, A., Caballero, S., Boulton, M. E., Higgins, P. J., ... 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

Enhancing the function of CD34+ cells by targeting plasminogen activator inhibitor-1. / Hazra, Sugata; Stepps, Valerie; Bhatwadekar, Ashay; Caballero, Sergio; Boulton, Michael E.; Higgins, Paul J.; Nikonova, Elena V.; Pepine, Carl J.; Thut, Catherine; Finney, Eva M.; Stone, David J.; Bartelmez, Stephen H.; Grant, Maria B.

In: PLoS One, Vol. 8, No. 11, e79067, 11.2013.

Research output: Contribution to journalArticle

Hazra, S, Stepps, V, Bhatwadekar, A, Caballero, S, Boulton, ME, Higgins, PJ, Nikonova, EV, Pepine, CJ, Thut, C, Finney, EM, Stone, DJ, Bartelmez, SH & Grant, MB 2013, 'Enhancing the function of CD34+ cells by targeting plasminogen activator inhibitor-1', PLoS One, vol. 8, no. 11, e79067. https://doi.org/10.1371/journal.pone.0079067
Hazra, Sugata ; Stepps, Valerie ; Bhatwadekar, Ashay ; Caballero, Sergio ; Boulton, Michael E. ; Higgins, Paul J. ; Nikonova, Elena V. ; Pepine, Carl J. ; Thut, Catherine ; Finney, Eva M. ; Stone, David J. ; Bartelmez, Stephen H. ; Grant, Maria B. / Enhancing the function of CD34+ cells by targeting plasminogen activator inhibitor-1. In: PLoS One. 2013 ; Vol. 8, No. 11.
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