BackgroundTherapeutic 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 FindingsMyocardial 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.ConclusionRegenerative 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.

Rationale Cortical bone stem cells (CBSCs) have been shown to reduce ventricular remodeling and improve cardiac function in a murine myocardial infarction (MI) model. These effects were superior to other stem cell types that have been used in recent early stage clinical trials. However, CBSC efficacy has not been tested in a preclinical large animal model using approaches that could be applied to patients. Objective To determine if post–MI transendocardial injection of allogeneic CBSCs reduces pathological structural and functional remodeling and prevents the development of heart failure in a swine MI model. Methods and Results Female Göttingen swine underwent left anterior descending coronary artery occlusion, followed by reperfusion (ischemia–reperfusion MI). Animals received, in a randomized, blinded manner, 1:1 ratio, CBSCs (n = 9) (2×107 cells total) or placebo (vehicle; VEH, n = 9) through NOGA® guided transendocardial injections. 5–ethynyl–2’deoxyuridine (EdU), a thymidine analog, containing minipumps were inserted at the time of MI induction. At 72hrs (n=8) initial injury and cell retention were assessed. At 3 Months post–MI, cardiac structure and function was evaluated by serial echocardiography, and terminal invasive hemodynamics. CBSCs were present in the MI border zone and proliferating at 72hrs post–MI but had no effect on initial cardiac injury or structure. At 3 months, CBSC–treated hearts had significantly reduced scar size, smaller myocytes and increased myocyte nuclear density. Noninvasive echocardiographic measurements showed that left ventricular (LV) volumes and ejection fraction were significantly more preserved in CBSC–treated hearts and invasive hemodynamic measurements documented improved cardiac structure and functional reserve. The number of EdU+ cardiac myocytes was increased in CBSC– vs. VEH– treated animals. Conclusions CBSC administration into the MI border zone reduces pathological cardiac structural and functional remodeling and improves LV functional reserve. These effects reduce those processes that can lead to heart failure with reduced ejection fraction (HFrEF).

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