Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro
Creators: name: Kensah, George
name: Lara, Angelica Roa
name: Dahlmann, Julia
name: Zweigerdt, Robert
name: Schwanke, Kristin
name: Hegermann, Jan
name: Skvorc, David
name: Gawol, Anke
name: Azizian, Azadeh
name: Wagner, Stefan
name: Maier, Lars S.
name: Krause, Andreas
name: Dräger, Gerald
name: Ochs, Matthias
name: Haverich, Axel
name: Gruh, Ina
name: Martin, Ulrich
Publisher: name: Oxford : Oxford University Press
Year: 2013
Subjects: subject: Cardiac differentiation
subject: Embryonic stem cells
subject: Induced pluripotent stem cells
subject: Myocardial tissue engineering
subject: ascorbic acid
subject: atrial natriuretic factor
subject: brain natriuretic peptide
subject: collagen fibril
subject: collagen type 1
subject: connectin
subject: troponin T
subject: animal cell
subject: article
subject: bioartificial heart
subject: bioartificial organ
subject: cell aggregation
subject: cell contact
subject: cell count
subject: cell differentiation
subject: cell maturation
subject: cell survival
subject: cell viability
subject: controlled study
subject: diastolic blood pressure
subject: electric potential
subject: embryonic stem cell
subject: extracellular matrix
subject: fibroblast
subject: genetic selection
subject: heart muscle
subject: heart muscle cell
subject: heart muscle contractility
subject: heart preload
subject: human
subject: human cell
subject: in vitro study
subject: intracellular space
subject: long term survival
subject: mechanical stimulation
subject: mouse
subject: nonhuman
subject: pluripotent stem cell
subject: potassium current
subject: priority journal
subject: sarcomere
subject: sarcomere length
subject: systolic blood pressure
subject: transmission electron microscopy
subject: vascularization
subject: Animals
subject: Ascorbic Acid
subject: Bioprosthesis
subject: Cell Culture Techniques
subject: Cell Enlargement
subject: Cell Line
subject: Gene Expression
subject: Humans
subject: Induced Pluripotent Stem Cells
subject: Mice
subject: Myocardial Contraction
subject: Myocardium
subject: Myocytes, Cardiac
subject: Sarcomeres
subject: Tissue Engineering
subject: Vitamins
subject: Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit

description: AimsWe explored the use of highly purified murine and human pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) to generate functional bioartificial cardiac tissue (BCT) and investigated the role of fibroblasts, ascorbic acid (AA), and mechanical stimuli on tissue formation, maturation, and functionality.Methods and resultsMurine and human embryonic/induced PSC-derived CMs were genetically enriched to generate three-dimensional CM aggregates, termed cardiac bodies (CBs). Addressing the critical limitation of major CM loss after single-cell dissociation, non-dissociated CBs were used for BCT generation, which resulted in a structurally and functionally homogenous syncytium. Continuous in situ characterization of BCTs, for 21 days, revealed that three critical factors cooperatively improve BCT formation and function: both (i) addition of fibroblasts and (ii) ascorbic acid supplementation support extracellular matrix remodelling and CB fusion, and (iii) increasing static stretch supports sarcomere alignment and CM coupling. All factors together considerably enhanced the contractility of murine and human BCTs, leading to a so far unparalleled active tension of 4.4 mN/mm2 in human BCTs using optimized conditions. Finally, advanced protocols were implemented for the generation of human PSC-derived cardiac tissue using a defined animal-free matrix composition.ConclusionBCT with contractile forces comparable with native myocardium can be generated from enriched, PSC-derived CMs, based on a novel concept of tissue formation from non-dissociated cardiac cell aggregates. In combination with the successful generation of tissue using a defined animal-free matrix, this represents a major step towards clinical applicability of stem cell-based heart tissue for myocardial repair. © 2013 The Author.