CoChat
Sign Up
Cited by 467Pluripotent Stem Cells ResearchTissue Engineering and Regenerative MedicineCellular Mechanics and Interactions

Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue

Open access
Ruan, Jia-Ling, Tulloch, Nathaniel L., Razumova, Maria V., Saiget, Mark, Muskheli, Veronica, Pabon, Lil, Reinecke, Hans, Regnier, Michael +1 more·2016·Circulation
DOI 10.1161/circulationaha.114.014998PMC PMC5123912
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Tissue engineering enables the generation of functional human cardiac tissue with cells derived in vitro in combination with biocompatible materials. Human-induced pluripotent stem cell-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 electric pacing on the maturation of human-induced pluripotent stem cell-derived cardiac tissues. Methods: Cardiomyocytes derived from human-induced pluripotent stem cells were used to generate collagen-based bioengineered human cardiac tissue. Engineered tissue constructs were subjected to different mechanical stress and electric pacing conditions. Results: The engineered human myocardium exhibits Frank-Starling–type force-length relationships. After 2 weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility (0.63±0.10 mN/mm 2 vs 0.055±0.009 mN/mm 2 for no stress), tensile stiffness, construct alignment, and cell size. Stress conditioning also increased SERCA2 (Sarco/Endoplasmic Reticulum Calcium ATPase 2) expression, which correlated with a less negative force-frequency relationship. When electric pacing was combined with static stress conditioning, the tissues showed an additional increase in force production (1.34±0.19 mN/mm 2 ), with no change in construct alignment or cell size, suggesting maturation of excitation-contraction coupling. Supporting this notion, we found expression of RYR2 (Ryanodine Receptor 2) and SERCA2 further increased by combined static stress and electric stimulation. Conclusions: These studies demonstrate that electric pacing and mechanical stimulation promote maturation of the structural, mechanical, and force generation properties of human-induced pluripotent stem cell-derived cardiac tissues.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1161/circulationaha.114.014998

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [1]Ogle BM Bursac N Domian I Huang NF Menasche P Murry CE Pruitt B Radisic M Wu JC Wu SM Zhang J Zimmermann WH Vunjak-Novakovic G Distilling complexity to advance cardiac tissue engineering Sci Transl Med 2016 8 342ps13 PMC4959426 27280684
  2. [2]Jackman CP Shadrin IY Carlson AL Bursac N Human Cardiac Tissue Engineering: From Pluripotent Stem Cells to Heart Repair Curr Opin Chem Eng 2015 7 57 64 25599018 PMC4293542
  3. [3]Kurokawa YK George SC Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening Adv Drug Deliv Rev 2016 96 225 33 26212156 PMC4869857
  4. [4]Tzatzalos E Abilez OJ Shulda P Wu JC Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies Advanced Drug Delivery Reviews 2016 96 234 244 26428619 PMC4698222
  5. [5]Feric NT Radisic M Strategies and Challenges to Myocardial Replacement Therapy Stem Cells Translational Medicine 2016 5 410 416 26933042 PMC4798743
  6. [6]Kreutziger KL Muskheli V Johnson P Braun K Wight TN Murry CE Developing Vasculature and Stroma in Engineered Human Myocardium Tissue Engineering Part A 2011 17 1219 1228 21187004 PMC3079173
  7. [7]Madden LR Mortisen DJ Sussman EM Dupras SK Fugate JA Cuy JL Hauch KD Laflamme MA Murry CE Ratner BD Proangiogenic scaffolds as functional templates for cardiac tissue engineering Proceedings of the National Academy of Sciences 2010 107 15211 15216 PMC2930533 20696917
  8. [8]Dar A Shachar M Leor J Cohen S Optimization of cardiac cell seeding and distribution in 3D porous alginate scaffolds Biotechnol Bioeng 2002 80 305 312 12226863
  9. [9]Birla RK Huang YC Dennis RG Development of a Novel Bioreactor for the Mechanical Loading of Tissue-Engineered Heart Muscle Tissue Engineering 2007 13 2239 2248 17590151
  10. [10]Hirt MN Boeddinghaus J Mitchell A Schaaf S Börnchen C Müller C Schulz H Hubner N Stenzig J Stoehr A Neuber C Eder A Luther PK Hansen A Eschenhagen T Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation Journal of Molecular and Cellular Cardiology 2014 74 151 161 24852842
  11. [11]Schaaf S Shibamiya A Mewe M Eder A Stöhr A Hirt MN Rau T Zimmermann W-H Conradi L Eschenhagen T Hansen A Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology PLoS ONE 2011 6 e26397 22028871 PMC3197640
  12. [12]Liau B Christoforou N Leong KW Bursac N Pluripotent stem cell-derived cardiac tissue patch with advanced structure and function Biomaterials 2011 32 9180 9187 21906802 PMC3190071
  13. [13]Thomson KS Korte FS Giachelli CM Ratner BD Regnier M Scatena M Prevascularized Microtemplated Fibrin Scaffolds for Cardiac Tissue Engineering Applications Tissue Engineering Part A 2013 19 967 977 23317311 PMC3589898
  14. [14]Thomson KS Dupras SK Murry CE Scatena M Regnier M Proangiogenic microtemplated fibrin scaffolds containing aprotinin promote improved wound healing responses Angiogenesis 2013 17 195 205 24127199 PMC3888647
  15. [15]Zhang D Shadrin IY Lam J Xian H-Q Snodgrass HR Bursac N Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes Biomaterials 2013 34 5813 5820 23642535 PMC3660435
  16. [18]Nunes SS Miklas JW Liu J Aschar-Sobbi R Xiao Y Zhang B Jiang J Massé S Gagliardi M Hsieh A Thavandiran N Laflamme MA Nanthakumar K Gross GJ Backx PH Keller G Radisic M Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes Nature Methods 2013 10 781 787 23793239 PMC4071061
  17. [19]Zimmermann WH Didie M Wasmeier GH Nixdorff U Hess A Melnychenko I Boy O Neuhuber WL Weyand M Eschenhagen T Cardiac grafting of engineered heart tissue in syngenic rats Circulation 2002 106 I151 7 12354725
  18. [20]Thavandiran N Dubois N Mikryukov A Masse S Beca B Simmons CA Deshpande VS McGarry JP Chen CS Nanthakumar K Keller GM Radisic M Zandstra PW Design and formulation of functional pluripotent stem cell-derived cardiac microtissues Proceedings of the National Academy of Sciences 2013 110 E4698 E4707 PMC3856835 24255110
  19. [21]Shimko VF Claycomb WC Effect of Mechanical Loading on Three-Dimensional Cultures of Embryonic Stem Cell-Derived Cardiomyocytes Tissue Engineering Part A 2008 14 49 58 18333804 PMC2562769
  20. [22]Zimmermann W-H Melnychenko I Wasmeier G Didié M Naito H Nixdorff U Hess A Budinsky L Brune K Michaelis B Dhein S Schwoerer A Ehmke H Eschenhagen T Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts Nature Medicine 2006 12 452 458 16582915
  21. [24]Kensah G Roa Lara A Dahlmann J Zweigerdt R Schwanke K Hegermann J Skvorc D Gawol A Azizian A Wagner S Maier LS Krause A Drager G Ochs M Haverich A Gruh I Martin U Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro European Heart Journal 2012 34 1134 1146 23103664
  22. [25]Kensah G Gruh I Viering J Schumann H Dahlmann J Meyer H Skvorc D Bär A Akhyari P Heisterkamp A Haverich A Martin U A Novel Miniaturized Multimodal Bioreactor for Continuous In Situ Assessment of Bioartificial Cardiac Tissue During Stimulation and Maturation Tissue Engineering Part C: Methods 2011 17 463 473 21142417 PMC3103055
  23. [26]Zimmermann WH Schneiderbanger K Schubert P Didie M Munzel F Heubach JF Kostin S Neuhuber WL Eschenhagen T Tissue engineering of a differentiated cardiac muscle construct Circ Res 2002 90 223 30 11834716
  24. [27]Fomovsky GM Thomopoulos S Holmes JW Contribution of extracellular matrix to the mechanical properties of the heart Journal of Molecular and Cellular Cardiology 2010 48 490 496 19686759 PMC2823835
  25. [28]Granzier HL Irving TC Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments Biophysical Journal 1995 68 1027 1044 7756523 PMC1281826
  26. [29]Vunjak Novakovic G Eschenhagen T Mummery C Myocardial Tissue Engineering: In Vitro Models Cold Spring Harbor Perspectives in Medicine 2014 4 a014076 a014076 24591534 PMC3935388
  27. [31]Chong JJH Yang X Don CW Minami E Liu Y-W Weyers JJ Mahoney WM Van Biber B Cook SM Palpant NJ Gantz JA Fugate JA Muskheli V Gough GM Vogel KW Astley CA Hotchkiss CE Baldessari A Pabon L Reinecke H Gill EA Nelson V Kiem H-P Laflamme MA Murry CE Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts Nature 2014 510 273 277 24776797 PMC4154594
  28. [32]Kamakura T Makiyama T Sasaki K Yoshida Y Wuriyanghai Y Chen J Hattori T Ohno S Kita T Horie M Yamanaka S Kimura T Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture Circulation Journal 2013 77 1307 1314 23400258
  29. [33]Lundy SD Zhu W-Z Regnier M Laflamme MA Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells Stem Cells and Development 2013 22 1991 2002 23461462 PMC3699903
  30. [34]Yang X Rodriguez M Pabon L Fischer KA Reinecke H Regnier M Sniadecki NJ Ruohola-Baker H Murry CE Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells Journal of Molecular and Cellular Cardiology 2014 72 296 304 24735830 PMC4041732
  31. [35]Földes G Mioulane M Wright JS Liu AQ Novak P Merkely B Gorelik J Schneider MD Ali NN Harding SE Modulation of human embryonic stem cell-derived cardiomyocyte growth: A testbed for studying human cardiac hypertrophy? Journal of Molecular and Cellular Cardiology 2011 50 367 376 21047517 PMC3034871
  32. [36]Shinozawa T Imahashi K Sawada H Furukawa H Takami K Determination of Appropriate Stage of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Screening and Pharmacological Evaluation In Vitro Journal of Biomolecular Screening 2012 17 1192 1203 22706346
  33. [37]Soares CP Midlej V Oliveira MEWd Benchimol M Costa ML Mermelstein C 2D and 3D-Organized Cardiac Cells Shows Differences in Cellular Morphology, Adhesion Junctions, Presence of Myofibrils and Protein Expression PLoS ONE 2012 7 e38147 22662278 PMC3360656
  34. [38]Lasher RA Pahnke AQ Johnson JM Sachse FB Hitchcock RW Electrical stimulation directs engineered cardiac tissue to an age-matched native phenotype Journal of Tissue Engineering 2012 3 PMC3424978 22919458
  35. [39]Ruwhof C Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovascular Research 2000 47 23 37 10869527
  36. [40]Laflamme MA Chen KY Naumova AV Muskheli V Fugate JA Dupras SK Reinecke H Xu C Hassanipour M Police S O’Sullivan C Collins L Chen Y Minami E Gill EA Ueno S Yuan C Gold J Murry CE Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts Nat Biotechnol 2007 25 1015 1024 17721512
  37. [41]Ruifrok AC Katz RL Johnston DA Comparison of Quantification of Histochemical Staining By Hue-Saturation-Intensity (HSI) Transformation and Color-Deconvolution Applied Immunohistochemistry & Molecular Morphology 2003 11 85 91 12610362
  38. [42]Willems E Leyns L Vandesompele J Standardization of real-time PCR gene expression data from independent biological replicates Analytical Biochemistry 2008 379 127 129 18485881
  39. [44]Fink C Ergun S Kralisch D Remmers U Weil J Eschenhagen T Chronic stretch of engineered heart tissue induces hypertrophy and functional improvement FASEB J 2000 14 669 79 10744624
  40. [45]Moreno-Gonzalez A Korte FS Dai J Chen K Ho B Reinecke H Murry CE Regnier M Cell therapy enhances function of remote non-infarcted myocardium Journal of Molecular and Cellular Cardiology 2009 47 603 613 19683533 PMC2763233
  41. [46]Holubarsch C Shortening versus isometric contractions in isolated human failing and non-failing left ventricular myocardium: dependency of external work and force on muscle length, heart rate and inotropic stimulation Cardiovascular Research 1998 37 46 57 9539857
  42. [47]Mulieri LA Hasenfuss G Leavitt B Allen PD Alpert NR Altered myocardial force-frequency relation in human heart failure Circulation 1992 85 1743 1750 1572031
  43. [48]Leontyev S Schlegel F Spath C Schmiedel R Nichtitz M Boldt A Rübsamen R Salameh A Kostelka M Mohr F-W Dhein S Transplantation of engineered heart tissue as a biological cardiac assist device for treatment of dilated cardiomyopathy European Journal of Heart Failure 2013 15 23 35 23243122
  44. [49]Wiegerinck RF Cojoc A Zeidenweber CM Ding G Shen M Joyner RW Fernandez JD Kanter KR Kirshbom PM Kogon BE Wagner MB Force Frequency Relationship of the Human Ventricle Increases During Early Postnatal Development Pediatr Res 2009 65 414 419 19127223 PMC2788428

Cited by

Sorted by citations

Authors
Ruan, J.-L., Tulloch, N. L., Razumova, M. V., Saiget, M., Muskheli, V., Pabon, L., Reinecke, H., Regnier, M., & Murry, C. E.
Affiliations
University of Washington (US)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-11-15
Volume
134
Issue
20
Pages
1557-1567
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.114.014998
PMC
PMC5123912
OpenAlex
W2531760931
Cited by
467
References
5
Citations by year
2026: 30 · 2025: 45 · 2024: 40 · 2023: 45 · 2022: 47 · 2021: 82 · 2020: 58 · 2019: 58 · 2018: 35 · 2017: 25 · 2016: 2
FWCI
20.80
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fondation Leducq
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL111197, U01HL100405, T32HL007312, P01HL094374, R01HL128362, R01HL084642)
  • National Institute of General Medical Sciences (T32GM007266, P01GM081619)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB001650)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
iPSC-derived cardiomyocytes, cardiac tissue engineering, electrical pacing, cardiomyocyte maturation, contractility, length-tension relationship, SERCA2, RyR2, excitation-contraction coupling, Frank-Starling mechanism
MeSH terms
Animals, Humans, Myocardium, Stress, Mechanical, Tissue Engineering, Myocytes, Cardiac, Induced Pluripotent Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review