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Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants

Published on Feb 1, 2019in Biomaterials10.27
· DOI :10.1016/j.biomaterials.2018.11.033
Fahimeh Varzideh2
Estimated H-index: 2
(Royan Institute),
Sara Pahlavan6
Estimated H-index: 6
(Royan Institute)
+ 7 AuthorsHossein Baharvand42
Estimated H-index: 42
(University of Science and Culture)
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Abstract
Abstract Human cardiomyocytes (CM) differentiated from pluripotent stem cells (PSCs) are relatively immature when generated in two-dimensional (2D) in vitro cultures, which limits their biomedical applications. Here, we devised a strategy to enhance maturation of human CM in vitro by assembly of three-dimensional (3D) cardiac organoids (CO) containing human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs), endothelial cells (ECs), and mesenchymal stem cells (MSCs). In contrast to corresponding 2D cultures, 3D CO not only developed into structures containing spontaneously beating CM, but also showed enhanced maturity as indicated by increased expressions of sarcomere and ion channel genes and reduced proliferation. Heterotopic implantation of CO into the peritoneal cavity of immunodeficient mice induced neovascularization, and further stimulated upregulation of genes coding for the contractile apparatus, Ca 2+ handling and ion channel proteins. In addition, CM in implanted CO were characterized by a more mature ultrastructure compared to CM implanted without CO support. Functional analysis revealed the presence of working cardiomyocytes in both in vivo and ex ovo chorioallantoic membrane implanted CO. Our results demonstrate that cultivation in 3D CO and subsequent heterotopic implantation enhance maturation of CM towards an adult-like phenotype. We reason that CO-derived CM represent an attractive source for drug discovery and other biomedical applications.
  • References (64)
  • Citations (3)
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References64
Newest
Published on May 1, 2018in Cell Reports7.82
Yoshinobu Takahashi2
Estimated H-index: 2
(YCU: Yokohama City University),
Keisuke Sekine22
Estimated H-index: 22
(YCU: Yokohama City University)
+ 2 AuthorsHideki Taniguchi32
Estimated H-index: 32
(YCU: Yokohama City University)
Summary Clinical transplantation of tissue fragments, including islets, faces a critical challenge because of a lack of effective strategies that ensure efficient engraftment through the timely integration of vascular networks. We recently developed a complex organoid engineering method by "self-condensation" culture based on mesenchymal cell-dependent contraction, thereby enabling dissociated heterotypic lineages including endothelial cells to self-organize in a spatiotemporal manner. Here, we ...
Published on Dec 1, 2017in Nature Communications11.88
Ilya Y. Shadrin6
Estimated H-index: 6
(Duke University),
Brian W. Allen2
Estimated H-index: 2
(Duke University)
+ 4 AuthorsNenad Bursac38
Estimated H-index: 38
(Duke University)
Despite increased use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for drug development and disease modeling studies, methods to generate large, functional heart tissues for human therapy are lacking. Here we present a “Cardiopatch” platform for 3D culture and maturation of hiPSC-CMs that after 5 weeks of differentiation show robust electromechanical coupling, consistent H-zones, I-bands, and evidence for T-tubules and M-bands. Cardiopatch maturation markers and func...
Published on Oct 1, 2017in Biomaterials10.27
Dylan J. Richards7
Estimated H-index: 7
(Clemson University),
Robert C. Coyle4
Estimated H-index: 4
(Clemson University)
+ 5 AuthorsYing Mei26
Estimated H-index: 26
(Clemson University)
Abstract Recent progress in human organoids has provided 3D tissue systems to model human development, diseases, as well as develop cell delivery systems for regenerative therapies. While direct differentiation of human embryoid bodies holds great promise for cardiac organoid production, intramyocardial cell organization during heart development provides biological foundation to fabricate human cardiac organoids with defined cell types. Inspired by the intramyocardial organization events in coro...
Published on May 9, 2017in Circulation23.05
Malte Tiburcy17
Estimated H-index: 17
,
James E. Hudson13
Estimated H-index: 13
+ 28 AuthorsEdgar Wingender32
Estimated H-index: 32
Background:Advancing structural and functional maturation of stem cell–derived cardiomyocytes remains a key challenge for applications in disease modeling, drug screening, and heart repair. Here, we sought to advance cardiomyocyte maturation in engineered human myocardium (EHM) toward an adult phenotype under defined conditions. Methods:We systematically investigated cell composition, matrix, and media conditions to generate EHM from embryonic and induced pluripotent stem cell–derived cardiomyoc...
Published on Dec 15, 2016in Stem Cells and Development3.15
Majid Lotfinia4
Estimated H-index: 4
,
Mehdi Kadivar10
Estimated H-index: 10
+ 5 AuthorsHossein Baharvand42
Estimated H-index: 42
Adult tissue-derived mesenchymal stem cells (MSCs) show tremendous promise for a wide array of therapeutic applications predominantly through paracrine activity. Recent reports showed that human embryonic stem cell (ESC)-derived MSCs are an alternative for regenerative cellular therapy due to manufacturing large quantities of MSCs from a single donor. However, no study has been reported to uncover the secretome of human ESC-MSCs as treatment of an acute liver failure (ALF) mouse model. We demons...
Published on Nov 15, 2016in Circulation23.05
Jia-Ling Ruan2
Estimated H-index: 2
(UW: University of Washington),
Nathaniel L. Tulloch7
Estimated H-index: 7
(UW: University of Washington)
+ 6 AuthorsCharles E. Murry61
Estimated H-index: 61
(UW: University of Washington)
Backgrounds —Tissue engineering enables the generation of functional human cardiac tissue using cells derived in vitro in combination with biocompatible materials. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes provide a cell source for cardiac tissue engineering; however, their immaturity limits their potential applications. Here we sought to study the effect of mechanical conditioning and electrical pacing on the maturation of hiPSC-derived cardiac tissues. Methodss —Cardio...
Published on Jul 25, 2016in Journal of Visualized Experiments1.11
Hananeh Fonoudi4
Estimated H-index: 4
,
Hassan Ansari4
Estimated H-index: 4
+ 6 AuthorsHossein Baharvand42
Estimated H-index: 42
Maximizing the benefit of human pluripotent stem cells (hPSCs) for research, disease modeling, pharmaceutical and clinical applications requires robust methods for the large-scale production of functional cell types, including cardiomyocytes. Here we demonstrate that the temporal manipulation of WNT, TGF-β, and SHH signaling pathways leads to highly efficient cardiomyocyte differentiation of single-cell passaged hPSC lines in both static suspension and stirred suspension bioreactor systems. Empl...
Published on Jul 1, 2016in Biochimica et Biophysica Acta3.79
Chris Denning33
Estimated H-index: 33
(University of Nottingham),
Viola Borgdorff1
Estimated H-index: 1
(University of Nottingham)
+ 12 AuthorsAsha K. Patel7
Estimated H-index: 7
(University of Nottingham)
Cardiomyocytes from human pluripotent stem cells (hPSCs-CMs) could revolutionise biomedicine. Global burden of heart failure will soon reach USD $90bn, while unexpected cardiotoxicity underlies 28% of drug withdrawals. Advances in hPSC isolation, Cas9/CRISPR genome engineering and hPSC-CM differentiation have improved patient care, progressed drugs to clinic and opened a new era in safety pharmacology. Nevertheless, predictive cardiotoxicity using hPSC-CMs contrasts from failure to almost total ...
Published on Jun 1, 2016in Cell36.22
Hans Clevers162
Estimated H-index: 162
(KNAW: Royal Netherlands Academy of Arts and Sciences)
Recent advances in 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina. Organoid technology can therefore be used to model human organ development and various human pathologies ‘in a dish.” Additionally, patient-derived organoids hold promise to predict drug response in a personalized fashion. O...
Cited By3
Newest
Published on Jul 4, 2019in Journal of Clinical Medicine
Kwang Bo Jung5
Estimated H-index: 5
,
Ohman Kwon1
Estimated H-index: 1
+ 8 AuthorsJanghwan Kim19
Estimated H-index: 19
Human intestinal organoids (hIOs), which resemble the human intestine structurally and physiologically, have emerged as a new modality for the study of the molecular and cellular biology of the intestine in vitro. We recently developed an in vitro maturation technique for generating functional hIOs from human pluripotent stem cells (hPSCs). Here, we investigated the function of STAT3 for inducing in vitro maturation of hIOs. This was accompanied by the tyrosine phosphorylation of STAT3, whereas ...
Published on Jan 1, 2019
Christopher W. Anderson2
Estimated H-index: 2
(Yale University),
Jiesi Luo4
Estimated H-index: 4
(Yale University)
+ 7 AuthorsYibing Qyang19
Estimated H-index: 19
(Yale University)
In vitro disease modeling can provide compelling insights into the molecular underpinnings of various pathological conditions. Traditionally, researchers have used two-dimensional (2D) cell culture methods to elucidate the molecular mechanisms that drive diseases. However, this method of cell culture fails to recapitulate the complex, three-dimensional (3D) microenvironment that is present in vivo. Recently, tissue-engineered models have been generated to create culture systems that better recap...
Published on Jan 1, 2019in Journal of Materials Chemistry B5.05
Yan Gao , Nien-Ju Ku1
Estimated H-index: 1
+ 10 AuthorsLassina Barro1
Estimated H-index: 1
Human mesenchymal stem cells (hMSCs), such as human adipose-derived stem cells (hADSCs), present heterogeneous characteristics, including varying differentiation abilities and genotypes. hADSCs isolated under different conditions exhibit differences in stemness. We isolated hADSCs from human fat tissues via culture on different cell culture biomaterials including tissue culture polystyrene (TCPS) dishes and extracellular matrix protein (ECM)-coated dishes in medium supplemented with 5% or 10% se...
View next paperThree‐dimensional co‐culture facilitates the differentiation of embryonic stem cells into mature cardiomyocytes