PMID- 33606581
OWN - NLM
STAT- MEDLINE
DCOM- 20210419
LR  - 20220402
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 320
IP  - 4
DP  - 2021 Apr 1
TI  - Human iPSC-engineered cardiac tissue platform faithfully models important cardiac 
      physiology.
PG  - H1670-H1686
LID - 10.1152/ajpheart.00941.2020 [doi]
AB  - Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) may 
      provide an important bridge between animal models and the intact human 
      myocardium. Fulfilling this potential is hampered by their relative immaturity, 
      leading to poor physiological responsiveness. hiPSC-CMs grown in traditional 
      two-dimensional (2D) culture lack a t-tubular system, have only rudimentary 
      intracellular calcium-handling systems, express predominantly embryonic 
      sarcomeric protein isoforms, and preferentially use glucose as an energy 
      substrate. Culturing hiPSC-CM in a variety of three-dimensional (3D) environments 
      and the addition of nutritional, pharmacological, and electromechanical stimuli 
      have proven, to various degrees, to be beneficial for maturation. We present a 
      detailed assessment of a novel model in which hiPSC-CMs and hiPSC-derived cardiac 
      fibroblasts are cocultured in a 3D fibrin matrix to form engineered cardiac 
      tissue constructs (hiPSC-ECTs). The hiPSC-ECTs are responsive to physiological 
      stimuli, including stretch, frequency, and beta-adrenergic stimulation, develop a 
      t-tubular system, and demonstrate calcium-handling and contractile kinetics that 
      compare favorably with ventricular human myocardium. Furthermore, transcript 
      levels of various genes involved in calcium-handling and contraction are 
      increased. These markers of maturation become more robust over a relatively short 
      period of time in culture (6 wk vs. 2 wk in hiPSC-ECTs). A comparison of the 
      hiPSC-ECT molecular and performance variables with those of human cardiac tissue 
      and other available engineered tissue platforms is provided to aid selection of 
      the most appropriate platform for the research question at hand. Important and 
      noteworthy aspects of this human cardiac model system are its reliance on 
      "off-the-shelf" equipment, ability to provide detailed physiological performance 
      data, and the ability to achieve a relatively mature cardiac physiology without 
      additional nutritional, pharmacological, and electromechanical stimuli that may 
      elicit unintended effects on function.NEW & NOTEWORTHY This study seeks to 
      provide an in-depth assessment of contractile performance of human iPSC-derived 
      cardiomyocytes cultured together with fibroblasts in a 3-dimensional-engineered 
      tissue and compares performance both over time as cells mature, and with 
      corresponding measures found in the literature using alternative 3D culture 
      configurations. The suitability of 3D-engineered human cardiac tissues to model 
      cardiac function is emphasized, and data provided to assist in the selection of 
      the most appropriate configuration based on the target application.
FAU - de Lange, Willem J
AU  - de Lange WJ
AD  - Department of Pediatrics, University of Wisconsin School of Medicine and Public 
      Health, Madison, Wisconsin.
FAU - Farrell, Emily T
AU  - Farrell ET
AD  - Department of Pediatrics, University of Wisconsin School of Medicine and Public 
      Health, Madison, Wisconsin.
FAU - Kreitzer, Caroline R
AU  - Kreitzer CR
AD  - Department of Pediatrics, University of Wisconsin School of Medicine and Public 
      Health, Madison, Wisconsin.
FAU - Jacobs, Derek R
AU  - Jacobs DR
AD  - Department of Pediatrics, University of Wisconsin School of Medicine and Public 
      Health, Madison, Wisconsin.
FAU - Lang, Di
AU  - Lang D
AD  - Department of Medicine Cardiovascular Medicine, University of Wisconsin-Madison 
      School of Medicine and Public Health, Madison, Wisconsin.
FAU - Glukhov, Alexey V
AU  - Glukhov AV
AUID- ORCID: 0000-0003-2076-9688
AD  - Department of Medicine Cardiovascular Medicine, University of Wisconsin-Madison 
      School of Medicine and Public Health, Madison, Wisconsin.
FAU - Ralphe, J Carter
AU  - Ralphe JC
AUID- ORCID: 0000-0001-8116-2324
AD  - Department of Pediatrics, University of Wisconsin School of Medicine and Public 
      Health, Madison, Wisconsin.
LA  - eng
GR  - P30 CA014520/CA/NCI NIH HHS/United States
GR  - S10 OD023526/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210219
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Adrenergic beta-Agonists)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adrenergic beta-Agonists/pharmacology
MH  - Calcium/*metabolism
MH  - *Calcium Signaling/drug effects
MH  - *Cell Differentiation
MH  - Cell Line
MH  - Humans
MH  - Induced Pluripotent Stem Cells/drug effects/*metabolism/ultrastructure
MH  - Kinetics
MH  - Myocardial Contraction
MH  - Myocytes, Cardiac/drug effects/*metabolism/ultrastructure
MH  - Phenotype
MH  - *Tissue Engineering
PMC - PMC8260387
OTO - NOTNLM
OT  - contractility
OT  - engineered cardiac tissue
OT  - human iPS cells
OT  - maturation
OT  - t-tubules
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2021/02/20 06:00
MHDA- 2021/04/20 06:00
PMCR- 2022/04/01
CRDT- 2021/02/19 17:10
PHST- 2021/02/20 06:00 [pubmed]
PHST- 2021/04/20 06:00 [medline]
PHST- 2021/02/19 17:10 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - H-00941-2020 [pii]
AID - 10.1152/ajpheart.00941.2020 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2021 Apr 1;320(4):H1670-H1686. doi: 
      10.1152/ajpheart.00941.2020. Epub 2021 Feb 19.