Stem Cell Therapy with Overexpressed VEGF and PDGF Genes Improves Cardiac Function in a Rat Infarct Model
Hiranmoy Das,1* Jon C. George,2 Matthew Joseph,1 Manjusri Das,1 Nasreen Abdulhameed,2 Anna Blitz,2 Mahmood Khan,1 Ramasamy Sakthivel,3 Hai-Quan Mao,4 Brian D. Hoit,2 Periannan Kuppusamy,1 and Vincent J. Pompili1
1The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America
2Cardiovascular Research Institute, Case Western Reserve University, Cleveland, Ohio, United States of America
3Arteriocyte, Inc., Cleveland, Ohio, United States of America
4Department of Materials Science and Engineering & Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, Maryland, United States of America
Joseph Najbauer, Editor
City of Hope National Medical Center, United States of America
* E-mail: firstname.lastname@example.org
Conceived and designed the experiments: HD VJP. Performed the experiments: HD JCG MJ MD NA AB MK BDH. Analyzed the data: HD JCG MJ MD NA AB MK BDH PK VJP. Contributed reagents/materials/analysis tools: RS HQM PK. Wrote the paper: HD.
Received May 5, 2009; Accepted September 17, 2009.
Therapeutic potential was evaluated in a rat model of myocardial infarction using nanofiber-expanded human cord blood derived hematopoietic stem cells (CD133+/CD34+) genetically modified with VEGF plus PDGF genes (VIP).
Methods and Findings
Myocardial function was monitored every two weeks up to six weeks after therapy. Echocardiography revealed time dependent improvement of left ventricular function evaluated by M-mode, fractional shortening, anterior wall tissue velocity, wall motion score index, strain and strain rate in animals treated with VEGF plus PDGF overexpressed stem cells (VIP) compared to nanofiber expanded cells (Exp), freshly isolated cells (FCB) or media control (Media). Improvement observed was as follows: VIP>Exp> FCB>media. Similar trend was noticed in the exercise capacity of rats on a treadmill. These findings correlated with significantly increased neovascularization in ischemic tissue and markedly reduced infarct area in animals in the VIP group. Stem cells in addition to their usual homing sites such as lung, spleen, bone marrow and liver, also migrated to sites of myocardial ischemia. The improvement of cardiac function correlated with expression of heart tissue connexin 43, a gap junctional protein, and heart tissue angiogenesis related protein molecules like VEGF, pNOS3, NOS2 and GSK3. There was no evidence of upregulation in the molecules of oncogenic potential in genetically modified or other stem cell therapy groups.
Regenerative therapy using nanofiber-expanded hematopoietic stem cells with overexpression of VEGF and PDGF has a favorable impact on the improvement of rat myocardial function accompanied by upregulation of tissue connexin 43 and pro-angiogenic molecules after infarction.