Allogeneic Mesenchymal Stromal Cells Overexpressing Mutant Human Hypoxia‐Inducible Factor 1‐α (HIF1‐α) in an Ovine Model of Acute Myocardial Infarction

Autor: Won Hee Lee, Joseph C. Wu, Anna Hnatiuk, Andrea De Lorenzi, Rubén Laguens, Johannes Riegler, Sang-Ging Ong, Paola Locatelli, Alberto J. Crottogini, Carlos Sebastián Giménez, Cheng Hao Jen, Fernanda Daniela Olea
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
medicine.medical_specialty
CIENCIAS MÉDICAS Y DE LA SALUD
Angiogenesis
Immunoblotting
Ischemia
Myocardial Infarction
030204 cardiovascular system & hematology
Mesenchymal Stem Cell Transplantation
ANGIOGENESIS
Biotecnología de la Salud
Neovascularization
03 medical and health sciences
Paracrine signalling
angiogenesis
0302 clinical medicine
Internal medicine
medicine
Animals
purl.org/becyt/ford/3.4 [https]
Original Research
2. Zero hunger
Cardioprotection
Heart Failure
Tecnologías que involucran la manipulación de células
tejidos
órganos o todo el organismo
Sheep
GROWTH SUBSTANCES
business.industry
MYOCARDIAL INFARCTION
Mesenchymal stem cell
Mesenchymal Stem Cells
Transfection
growth substances
medicine.disease
Flow Cytometry
Hypoxia-Inducible Factor 1
alpha Subunit
Magnetic Resonance Imaging
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Cancer research
Cardiology
purl.org/becyt/ford/3 [https]
Bone marrow
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
ISSN: 2047-9980
Popis: Background Bone marrow mesenchymal stromal cells ( BMMSC s) are cardioprotective in acute myocardial infarction ( AMI ) because of release of paracrine angiogenic and prosurvival factors. Hypoxia‐inducible factor 1‐α ( HIF 1‐α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSC s engineered to overexpress mutant, oxygen‐resistant HIF 1‐α would confer greater cardioprotection than nontransfected BMMSC s in sheep with AMI . Methods and Results Allogeneic BMMSC s transfected with a minicircle vector encoding mutant HIF 1‐α ( BMMSC ‐ HIF ) were injected in the peri‐infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance ( CMR ) imaging decreased by 71.7±1.3% ( P LV ) percent ejection fraction (% EF ) increased near 2‐fold ( P BMMSC s ( BMMSC ; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo‐treated animals (n=6), neither parameters changed over time. HIF 1‐α‐transfected BMMSC s ( BMMSC ‐ HIF ) induced angio‐/arteriogenesis and decreased apoptosis by HIF 1‐mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin‐1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long‐term retention of BMMSC ‐ HIF . Conclusions Intramyocardial delivery of BMMSC ‐ HIF reduced infarct size and improved LV systolic performance compared to BMMSC , attributed to increased neovascularization and cardioprotective effects induced by HIF 1‐mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSC s for allogeneic application, this treatment may be potentially useful in the clinic.
Databáze: OpenAIRE
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