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Maulasri Bhatta, Joshua Jianxin Wang, Sarah Xin Zhang; The Role of X-box Binding Protein 1 in Angiogenic Progenitor Cells and Vascular Repair in Diabetes. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5621.
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© ARVO (1962-2015); The Authors (2016-present)
Circulating angiogenic progenitors play a pivotal role in vascular repair in diabetes. Our recent work has implicated endoplasmic reticulum (ER) stress in the dysfunction of diabetic angiogenic progenitor cells. Herein, we investigated the role of X-box binding protein 1 (XBP1), an endoplasmic reticulum (ER) stress-responsive transcription factor, in the regulation of angiogenic progenitors in normal and diabetic conditions.
Diabetes was induced by streptozotocin in conditional XBP1 knockout mice that lack XBP1 in Tie2 expressing cells (Tie-2XBP1KO) and wild-type (WT) mice. Bone marrow (BM) progenitors (Lin-/c-Kit+/Sca-1+/CD34+) and BM-angiogenic progenitors (Flk-1+/Sca-1+/CD34+) as well as CACs (Flk-1+/ Sca-1+/CD34+) in peripheral blood were quantified by flow cytometry. ER stress markers in c-Kit expressing BM cells and early outgrowth cells (EOCs) were determined by real-time qPCR, PCR array and western blot analysis. EOC function was determined by colony formation and migration assays.
Compared to WT mice, Tie-2XBP1KO mice exhibited significantly reduced number of CACs in peripheral blood despite a significant increase in the numbers of BM progenitors and angiogenic progenitors, suggesting possible defects in angiogenic cell mobilization and/or release from the BM. Indeed, cultured EOCs from Tie-2XBP1KO mice demonstrated decreased capacities in colony formation and migration in both normal and high glucose (HG) conditions. Gene expression analyses show upregulation of genes involved in oxidative stress as well as apoptosis (Prdx6, Gpx1, Nfe2l2, Txnrd2, Bad, Casp3, Foxo3) and downregulation of functional genes (Itgb2, Vegfr2, Nos-3 Cxcr4) in EOCs from Tie-2XBP1KO mice compared to WT controls. Under HG conditions, XBP1 deficient EOCs display up to 3-fold increase in the expression of Mapk10 and Duox1 but a decrease in genes encoding antioxidant and ER quality control enzymes (Prdx6, Edem3, Ern1). EOCs isolated from 3-month diabetic Tie-2XBP1KO mice exhibited severe defects in growth and colony formation, which was partially rescued by treatment with chemical chaperone 4-phenylbutyrate (4-PBA).
Our data reveals an essential role of XBP1 in the survival and function of BM angiogenic progenitor cells. Manipulating XBP1 activation may provide a novel approach for restoring angiogenic function in diabetes.
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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