Transient inhibition of transforming growth factor-β1 in human diabetic CD34+ cells enhances vascular reparative functions

Ashay D. Bhatwadekar, E. P. Guerin, Yagna P.R. Jarajapu, Sergio Caballero, Carl Sheridan, David Kent, Laurence Kennedy, M. Cecilia Lansang, Frank W. Ruscetti, Carl J. Pepine, Paul J. Higgins, Stephen H. Bartelmez, Maria B. Grant

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

OBJECTIVE - Peripheral blood CD34+ cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation and diminished migratory prowess, largely resulting from decreased nitric oxide (NO) bioavailability. The level of TGF-β, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients. We asked whether transient TGF-β1 inhibition in CD34+ cells would improve their reparative ability. RESEARCH DESIGN AND METHODS - To inhibit TGF-β1 protein expression, CD34+ cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-β1-PMOs) and analyzed for cell surface CXCR4 expression, cell survival in the absence of added growth factors, SDF-1-induced migration, NO release, and in vivo retinal vascular reparative ability. RESULTS - TGF-β1-PMO treatment of diabetic CD34+ cells resulted in increased expression of CXCR4, enhanced survival in the absence of growth factors, and increased migration and NO release as compared with cells treated with control PMO. 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 TGF-β1-PMO treatment compared with control PMO-treated cells. CONCLUSIONS - Transient inhibition of TGF-β1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34+ cells.

Original languageEnglish (US)
Pages (from-to)2010-2019
Number of pages10
JournalDiabetes
Volume59
Issue number8
DOIs
StatePublished - Aug 1 2010

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Bhatwadekar, A. D., Guerin, E. P., Jarajapu, Y. P. R., Caballero, S., Sheridan, C., Kent, D., Kennedy, L., Lansang, M. C., Ruscetti, F. W., Pepine, C. J., Higgins, P. J., Bartelmez, S. H., & Grant, M. B. (2010). Transient inhibition of transforming growth factor-β1 in human diabetic CD34+ cells enhances vascular reparative functions. Diabetes, 59(8), 2010-2019. https://doi.org/10.2337/db10-0287