Synthetic LXR Agonists Enhances Vasoreparative Function and Proliferation of Bone Marrow-Derived Stem Cells in Diabetic Mouse Models

Abstract

Purpose : Purpose: Despite advances in pharmacological therapy, diabetic retinopathy (DR) remains the most common cause of visual impairment and blindness among working-age adults. Clinical evidence demonstrates an intriguing association of lipid abnormalities and DR and studies in diabetic rodents reveal prevention of DR via activation of nuclear hormone liver X receptors (LXRα/LXRβ). In this study, we asked whether the synthetic LXR agonists GW3965 or DMHCA can delay the development of DR in part through enhancing the vascular reparative function of circulating angiogenic cells (CACs).

Methods : Methods: db/db mice were given LXR agonists either GW3965 (20 mg/kg) through feeding with chow containing this test agent from 8 weeks of age until 24 weeks of age or DMHCA (80 mg/kg) injected daily for 2 weeks. Eyes were used for enumeration of acellular capillaries and bone marrow was harvested for migration studies and flow cytometry analysis. GW3965 (20 mg/kg) was administered short term (7 days) to diabetic mice via oral gavage, and freshly isolated hematopoietic stem cells were used for proliferation assay at 12 hour and 24 hour.

Results : Results: CACs from db/db mice treated with GW3965 showed significantly greater migration towards hypoxia-regulated factors, CXCL-12 and VEGF (p < 0.05) than CACs from db/db mice on normal chow. In parallel with this result, we observed a significant reduction in the number of acellular capillaries in the retina of db/db mice on GW3965 compared to diabetic mice on normal chow (p<0.05). Interestingly, DMHCA treatment significantly increased overall stem cell populations, specifically the short-term repopulating cells and only a trend increase in long-term repopulating cells. Intriguingly, seven-days of GW3965 significantly increased the proliferation rate of murine hematopoietic stem cells (HSCs) (p < 0.05).

Conclusions : Conclusions: Short-term LXR activation by LXR agonists in diabetic mice significantly enhanced proliferation capacity and the overall HSCs population and long-term administration of LXR agonist in T2DM mice reduced the number of acellular capillaries by favorably influencing the vasoreparative function of circulating CACs.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.