Cell-based therapies for cardiovascular diseases (CVD) have proliferated over the past decade, but with limited success. The major hurdles for successful cell therapies are 1) cell type selection (e.g. progenitor vs. differentiated), 2) time or cell delivery (e.g. acute vs. chronic), 3) cell delivery mode (e.g. peripheral vs. directly into tissue), 4) rejection of transplanted cells (e.g. autologous vs. heterologous), and most importantly, 5) targeting delivery of cells to damaged organs to maximize therapeutic effects. We have developed an innovative strategy to overcome these hurdles by i.v. transfusing endothelial cells (ECs) overexpressing neutrophil interleukin-8 (IL8) receptors into rats with endoluminal injury of the carotid artery or myocardial infarction. Studies outlined in this proposa will extend this targeted cell delivery strategy to a more applicable stem cell type, autologous iPS-ECs (induced pluripotent endothelial stem cells);to avoid possible cell rejection problems in future translational and/or clinical studies and enhances the efficacy of tissue repair. We will delineate the mechanism(s) of the protective effects of i.v. administered adult ECs or iPS-ECs overexpressing IL8RA and IL8RB in rats with experimental vascular or cardiac injury. We hypothesize that adult ECs or iPS-ECs that overexpress IL8 receptors will mimic the behavior of neutrophils that target and adhere to injured tissues (e.g. to endoluminal surface and adventitia of injured arteries) and in doing so will compete with and inhibit neutrophil infiltration and attenuate subsequent inflammatory responses and structural and functional damage to tissues.
The Aims of this proposal are: 1) Generation of induced pluripotent endothelial stem cells (iPS-ECs) that overexpress neutrophil interleukin-8 (IL8) receptor genes (IL8RA and IL8RB) for targeted cell delivery to injured vascular and cardiac tissues.2) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8 receptors (IL8RA and/or IL8RB) promotes structural and functional recovery of arteries following endoluminal vascular injury. 3) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8RA and IL8RB promotes structural and functional recovery of the left ventricle (LV) following experimentally induced myocardial infarction (MI). The results of the proposed studies are significant because they are expected to provide an innovative strategy for therapeutic interventions for cardiovascular injury. In addition, it is expected that the results wll fundamentally advance the field of cell-based therapy by providing a noninvasive and cost effective treatment modality.

Public Health Relevance

Cell-based therapies for cardiovascular diseases have proliferated over the past decade, but with limited success and only moderate benefit in clinical application. The proposed studies will utilize a novel strategy to intravenously transfuse adult endothelial cells (ECs) and induced pleuripotent endothelial stem cells (iPS-ECs) equipped with a homing device into rats with balloon injury of the carotid artery or coronary ligation injury of he heart to accelerate repair of the injury. Results of the proposed studies will provide an innovativ strategy for therapeutic interventions for cardiovascular injury and inflammation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL116727-02
Application #
8703772
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Buxton, Denis B
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294