Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell–Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine

Autor: Andrew E. Pollard, Ramaswamy Kannappan, Saidulu Mattapally, Jianyi Zhang, Vladimir G. Fast, Ying Ge, Ling Gao, Anton V. Borovjagin, Gregory P. Walcott, Xinyang Hu, Wuqiang Zhu, Xi Lou, Zachery R. Gregorich, Steven G. Lloyd, Yasin Oduk
Rok vydání: 2018
Předmět:
0301 basic medicine
Pathology
medicine.medical_specialty
Time Factors
Induced Pluripotent Stem Cells
Myocytes
Smooth Muscle
Sus scrofa
Transplantation
Heterologous
Myocardial Infarction
Ventricular Function
Left
Article
03 medical and health sciences
Tissue engineering
Smooth muscle
Physiology (medical)
medicine
Animals
Humans
Regeneration
Myocytes
Cardiac
Myocardial infarction
Induced pluripotent stem cell
Cells
Cultured
Tissue Engineering
Tissue Scaffolds
Ventricular Remodeling
Ventricular function
business.industry
Myocardium
Cardiac muscle
Endothelial Cells
Cell Differentiation
Recovery of Function
medicine.disease
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Cardiology and Cardiovascular Medicine
business
Stem Cell Transplantation
Zdroj: Circulation. 137:1712-1730
ISSN: 1524-4539
0009-7322
DOI: 10.1161/circulationaha.117.030785
Popis: Background: Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform. Methods: In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch. Results: The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival. Conclusions: We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity.
Databáze: OpenAIRE
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