Cobalt Protoporphyrin Pretreatment Protects Human Embryonic Stem Cell‐Derived Cardiomyocytes From Hypoxia/Reoxygenation Injury In Vitro and Increases Graft Size and Vascularization In Vivo

These experiments demonstrate that ex vivo pretreatment of human embryonic stem cell‐derived cardiomyocytes with a single dose of cobalt protoporphyrin before intramyocardial implantation more than doubled resulting graft size and improved early graft vascularization in acutely infarcted hearts. The...

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Bibliographic Details
Published in:Stem cells translational medicine 2014-06, Vol.3 (6), p.734-744
Main Authors: Luo, Jun, Weaver, Matthew S., Cao, Baohong, Dennis, James E., Van Biber, Benjamin, Laflamme, Michael A., Allen, Margaret D.
Format: Article
Language:English
Subjects:
Acute myocardial infarction
Animals
Apoptosis - drug effects
Cardiomyocytes
Cell Differentiation
Cell Line
Cell Proliferation
Cell therapy
Cloning
Cobalt
Data analysis
Disease Models, Animal
Embryonic Stem Cells - drug effects
Embryonic Stem Cells - enzymology
Embryonic Stem Cells - pathology
Embryonic Stem Cells - transplantation
Enzyme Induction
Experiments
Female
Gene therapy
Graft Survival
Heart
Heart attacks
Heme oxygenase-1
Heme Oxygenase-1 - biosynthesis
Human embryonic stem cell
Humans
Hypoxia
Infarct repair
Ischemia
Male
Myocardial infarction
Myocardial Infarction - enzymology
Myocardial Infarction - pathology
Myocardial Infarction - surgery
Myocardial Reperfusion Injury - enzymology
Myocardial Reperfusion Injury - prevention & control
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - enzymology
Myocytes, Cardiac - pathology
Myocytes, Cardiac - transplantation
Neovascularization, Physiologic
Phenotype
Phosphorylation
Preconditioning
Proto-Oncogene Proteins c-akt - metabolism
Protoporphyrin
Protoporphyrins - pharmacology
Rats
Rats, Nude
Reactive Oxygen Species - metabolism
Regeneration
Stem cells
Time Factors
Tissue Engineering and Regenerative Medicine
Transplants & implants
Vascular Endothelial Growth Factor A - metabolism
Vascularization
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Summary:These experiments demonstrate that ex vivo pretreatment of human embryonic stem cell‐derived cardiomyocytes with a single dose of cobalt protoporphyrin before intramyocardial implantation more than doubled resulting graft size and improved early graft vascularization in acutely infarcted hearts. These findings open the door for delivery of these, or other, stem cells during acute interventional therapy following myocardial infarction or ischemia. Human embryonic stem cell‐derived cardiomyocytes (hESC‐CMs) can regenerate infarcted myocardium. However, when implanted into acutely infarcted hearts, few cells survive the first week postimplant. To improve early graft survival, hESC‐CMs were pretreated with cobalt protoporphyrin (CoPP), a transcriptional activator of cytoprotective heme oxygenase‐1 (HO‐1). When hESC‐CMs were challenged with an in vitro hypoxia/reoxygenation injury, mimicking cell transplantation into an ischemic site, survival was significantly greater among cells pretreated with CoPP versus phosphate‐buffered saline (PBS)‐pretreated controls. Compared with PBS‐pretreated cells, CoPP‐pretreated hESC‐CM preparations exhibited higher levels of HO‐1 expression, Akt phosphorylation, and vascular endothelial growth factor production, with reduced apoptosis, and a 30% decrease in intracellular reactive oxygen species. For in vivo translation, 1 × 107 hESC‐CMs were pretreated ex vivo with CoPP or PBS and then injected intramyocardially into rat hearts immediately following acute infarction (permanent coronary ligation). At 1 week, hESC‐CM content, assessed by quantitative polymerase chain reaction for human Alu sequences, was 17‐fold higher in hearts receiving CoPP‐ than PBS‐pretreated cells. On histomorphometry, cardiomyocyte graft size was 2.6‐fold larger in hearts receiving CoPP‐ than PBS‐pretreated cells, occupying up to 12% of the ventricular area. Vascular density of host‐perfused human‐derived capillaries was significantly greater in grafts composed of CoPP‐ than PBS‐pretreated cells. Taken together, these experiments demonstrate that ex vivo pretreatment of hESC‐CMs with a single dose of CoPP before intramyocardial implantation more than doubled resulting graft size and improved early graft vascularization in acutely infarcted hearts. These findings open the door for delivery of these, or other, stem cells during acute interventional therapy following myocardial infarction or ischemia.
ISSN:2157-6564
2157-6580
DOI:10.5966/sctm.2013-0189