Details
| Original language | English |
|---|---|
| Pages (from-to) | 1134-1146 |
| Number of pages | 13 |
| Journal | European heart journal |
| Volume | 34 |
| Issue number | 15 |
| Publication status | Published - 14 Apr 2013 |
Abstract
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.
Keywords
- Cardiac differentiation, Embryonic stem cells, Induced pluripotent stem cells, Myocardial tissue engineering
ASJC Scopus subject areas
- Medicine(all)
- Cardiology and Cardiovascular Medicine
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In: European heart journal, Vol. 34, No. 15, 14.04.2013, p. 1134-1146.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro
AU - Kensah, George
AU - Lara, Angelica Roa
AU - Dahlmann, Julia
AU - Zweigerdt, Robert
AU - Schwanke, Kristin
AU - Hegermann, Jan
AU - Skvorc, David
AU - Gawol, Anke
AU - Azizian, Azadeh
AU - Wagner, Stefan
AU - Maier, Lars S.
AU - Krause, Andreas
AU - Dräger, Gerald
AU - Ochs, Matthias
AU - Haverich, Axel
AU - Gruh, Ina
AU - Martin, Ulrich
N1 - Funding information: This work was funded by the Cluster of Excellence REBIRTH (DFG EXC 62/1), by the German Ministry for Education and Science (BMBF, 01GN0958), and by the Cortiss foundation.
PY - 2013/4/14
Y1 - 2013/4/14
N2 - 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.
AB - 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.
KW - Cardiac differentiation
KW - Embryonic stem cells
KW - Induced pluripotent stem cells
KW - Myocardial tissue engineering
UR - http://www.scopus.com/inward/record.url?scp=84876529379&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehs349
DO - 10.1093/eurheartj/ehs349
M3 - Article
C2 - 23103664
AN - SCOPUS:84876529379
VL - 34
SP - 1134
EP - 1146
JO - European heart journal
JF - European heart journal
SN - 0195-668X
IS - 15
ER -