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Interplay of Genotype and Substrate Stiffness in Driving the Hypertrophic Cardiomyopathy Phenotype in iPSC-Micro-Heart Muscle Arrays

Abstract

Introduction

In clinical and animal studies, Hypertrophic Cardiomyopathy (HCM) shares many similarities with non-inherited cardiac hypertrophy induced by pressure overload (hypertension). This suggests a potential role for mechanical stress in priming tissues with mutation-induced changes in the sarcomere to develop phenotypes associated with HCM, including hypercontractility and aberrant calcium handling. Here, we tested the hypothesis that heterozygous loss of function of Myosin Binding Protein C (MYBCP3+/−, mutations in which account for almost 50% of inherited HCM) combines with environmental stiffness to drive HCM phenotypes.

Methods

We differentiated isogenic control (WTC) and MYBPC3+/− iPSC into cardiomyocytes using small molecule manipulation of Wnt signaling, and then purified them using lactate media. The purified cardiomyocytes were seeded into “dog bone” shaped stencil molds to form micro-heart muscle arrays (μHM). To mimic changes in myocardial stiffness stemming from pressure overload, we varied the rigidity of the substrates μHM contract against. Stiffness levels ranged from those corresponding to fetal (5 kPa), healthy (15 kPa), pre-fibrotic (30 kPa) to fibrotic (65 kPa) myocardium. Substrates were embedded with a thin layer of fluorescent beads to track contractile force, and parent iPSC were engineered to express the genetic calcium indicator, GCaMP6f. High speed video microscopy and image analysis were used to quantify calcium handling and contractility of μHM.

Results

Substrate rigidity triggered physiological adaptation for both genotypes. However, MYBPC3+/− μHM showed a lower tolerance to substrate stiffness with the peak traction on 15 kPa, while WTC μHM had peak traction on 30 kPa. MYBPC3+/− μHM exhibited hypercontractility, which was exaggerated by substrate rigidity. MYBPC3+/− μHM hypercontractility was associated with longer rise times for calcium uptake and force development, along with higher overall Ca2+ intake.

Conclusion

We found MYBPC3+/− mutations cause iPSC-μHM to exhibit hypercontractility, and also a lower tolerance for mechanical stiffness. Understanding how genetics work in combination with mechanical stiffness to trigger and/or exacerbate pathophysiology may lead to more effective therapies for HCM.

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References

  1. Barefield, D., M. Kumar, J. Gorham, et al. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J. Mol. Cell Cardiol. 79:234–243, 2015. https://doi.org/10.1016/j.yjmcc.2014.11.018.

    Article  Google Scholar 

  2. Benjamin, E. J., S. S. Virani, C. W. Callaway, et al Heart Disease and Stroke Statistics - 2018 Update: A Report from the American Heart Association. 2018. https://doi.org/10.1161/CIR.0000000000000558.

  3. Bers, D. M. Cardiac excitation–contraction coupling. Nature 415(January):198–205, 2002. https://doi.org/10.1201/b16783.

    Article  Google Scholar 

  4. Birket, M. J., M. C. Ribeiro, G. Kosmidis, et al. Contractile defect caused by mutation in MYBPC3 revealed under conditions optimized for human article contractile defect caused by mutation in MYBPC3 revealed under conditions optimized for human PSC-cardiomyocyte function. Cell Rep. 13(4):733–745, 2015. https://doi.org/10.1016/j.celrep.2015.09.025.

    Article  Google Scholar 

  5. Carrier, L., G. Mearini, K. Stathopoulou, and F. Cuello. Cardiac myosin-binding protein C (MYBPC3) in cardiac pathophysiology. Gene 573(2):188–197, 2015. https://doi.org/10.1016/j.gene.2015.09.008.

    Article  Google Scholar 

  6. Chang, H. J., C. Lynm, and R. M. Glass. Hypertrophic cardiomyopathy. JAMA 302(15):1720, 2009. https://doi.org/10.1001/jama.302.15.1720.

    Article  Google Scholar 

  7. Cohn, R., K. Thakar, A. Lowe, et al. A contraction stress model of hypertrophic cardiomyopathy due to sarcomere mutations. Stem Cell Rep. 12(1):71–83, 2019. https://doi.org/10.1016/j.stemcr.2018.11.015.

    Article  Google Scholar 

  8. Coppini, R., C. Ferrantini, A. Mugelli, C. Poggesi, and E. Cerbai. Altered Ca2+ and Na+ homeostasis in human hypertrophic cardiomyopathy: implications for arrhythmogenesis. Front Physiol. 9:1–16, 2018. https://doi.org/10.3389/fphys.2018.01391.

    Article  Google Scholar 

  9. Coppini, R., C. Ferrantini, L. Yao, et al. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation 127(5):575–584, 2013. https://doi.org/10.1161/CIRCULATIONAHA.112.134932.

    Article  Google Scholar 

  10. Davis, J., L. C. Davis, R. N. Correll, et al. A Tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165(5):1147–1159, 2016. https://doi.org/10.1016/j.cell.2016.04.002.

    Article  Google Scholar 

  11. Dutsch, A., P. J. M. Wijnker, S. Schlossarek, et al. Phosphomimetic cardiac myosin-binding protein C partially rescues a cardiomyopathy phenotype in murine engineered heart tissue. Sci. Rep. 9(1):1–12, 2019. https://doi.org/10.1038/s41598-019-54665-2.

    Article  Google Scholar 

  12. Fraysse, B., F. Weinberger, S. C. Bardswell, et al. Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J. Mol. Cell Cardiol. 52(6):1299–1307, 2012. https://doi.org/10.1016/j.yjmcc.2012.03.009.

    Article  Google Scholar 

  13. Fridericia, L. S. The duration of systole in an electrocardiogram in normal humans and in patients with heart disease. Ann. Noninvasive Electrocardiol. 8(4):343–351, 2003. https://doi.org/10.1046/j.1542-474X.2003.08413.x.

    Article  Google Scholar 

  14. Garcia, A. J., M. D. Vega, and D. Boettiger. Modulation of cell proliferation and differentiation through substrate-dependent changes in fibronectin conformation. Mol. Biol. Cell. 10(3):785–798, 1999. https://doi.org/10.1016/j.cpc.2005.06.001.

    Article  Google Scholar 

  15. Green, E. M., H. Wakimoto, R. L. Anderson, et al. Heart disease: a small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 351(6273):617–621, 2016. https://doi.org/10.1126/science.aad3456.

    Article  Google Scholar 

  16. Gunda, N. S. K., M. Singh, L. Norman, K. Kaur, and S. K. Mitra. Optimization and characterization of biomolecule immobilization on silicon substrates using (3-aminopropyl)triethoxysilane (APTES) and glutaraldehyde linker. Appl. Surf. Sci. 305:522–530, 2014. https://doi.org/10.1016/j.apsusc.2014.03.130.

    Article  Google Scholar 

  17. Guo, J., and N. Huebsch. Modeling the response of heart muscle to mechanical stimulation in vitro. Curr. Tissue Microenviron. Rep. 2020. https://doi.org/10.1007/s43152-020-00007-8.

    Article  Google Scholar 

  18. Guo, J., D. W. Simmons, G. Ramahdita, et al. Elastomer-grafted iPSC-derived micro heart muscles to investigate effects of mechanical loading on physiology. ACS Biomater. Sci. Eng. 2020. https://doi.org/10.1021/acsbiomaterials.0c00318.

    Article  Google Scholar 

  19. Hamilton, P. K., C. J. Lockhart, C. E. Quinn, and G. E. McVeigh. Arterial stiffness: clinical relevance, measurement and treatment. Clin. Sci. 113(3–4):157–170, 2007. https://doi.org/10.1042/CS20070080.

    Article  Google Scholar 

  20. Harris, S. P., C. R. Bartley, T. A. Hacker, et al. Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ. Res. 90(5):594–601, 2002. https://doi.org/10.1161/01.RES.0000012222.70819.64.

    Article  Google Scholar 

  21. Helms, A. S., M. J. Previs, S. M. Day, et al. Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy. JCI Insight. 5(2):2020.

    Article  Google Scholar 

  22. Helms, A. S., A. D. Thompson, A. A. Glazier, et al. Spatial and functional distribution of MYBPC3 pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy. Circ. Genomic Precis Med. 2020. https://doi.org/10.1161/CIRCGEN.120.002929.

    Article  Google Scholar 

  23. Hirt, M. N., N. A. Sörensen, L. M. Bartholdt, et al. Increased afterload induces pathological cardiac hypertrophy: a new in vitro model. Basic Res. Cardiol. 2012. https://doi.org/10.1007/s00395-012-0307-z.

    Article  Google Scholar 

  24. Huebsch, N., P. Loskill, N. Deveshwar, et al. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep. 6(April):1–12, 2016. https://doi.org/10.1038/srep24726.

    Article  Google Scholar 

  25. Huebsch, N., P. Loskill, M. A. Mandegar, et al. Automated video-based analysis of contractility and calcium flux in human-induced pluripotent stem cell-derived cardiomyocytes cultured over different spatial scales. Tissue Eng. 21(5):467–479, 2015. https://doi.org/10.1089/ten.tec.2014.0283.

    Article  Google Scholar 

  26. Jacques, A., A. C. Hoskins, J. C. Kentish, and S. B. Marston. From genotype to phenotype: a longitudinal study of a patient with hypertrophic cardiomyopathy due to a mutation in the MYBPC3 gene. J. Muscle Res. Cell Motil. 29(6–8):239–246, 2008. https://doi.org/10.1007/s10974-009-9174-0.

    Article  Google Scholar 

  27. Kuddannaya, S., Y. J. Chuah, M. H. A. Lee, N. V. Menon, Y. Kang, and Y. Zhang. Surface chemical modification of poly(dimethylsiloxane) for the enhanced adhesion and proliferation of mesenchymal stem cells. ACS Appl. Mater. Interfaces 5(19):9777–9784, 2013. https://doi.org/10.1021/am402903e.

    Article  Google Scholar 

  28. Kumar, A., S. K. Thomas, K. C. Wong, et al. Mechanical activation of noncoding-RNA-mediated regulation of disease-associated phenotypes in human cardiomyocytes. Nat. Biomed. Eng. 3(2):137–146, 2019. https://doi.org/10.1038/s41551-018-0344-5.

    Article  Google Scholar 

  29. Kupfer, M. E., W. H. Lin, V. Ravikumar, et al. In situ expansion, differentiation, and electromechanical coupling of human cardiac muscle in a 3D bioprinted. Chambered Organoid. Circ. Res. 2020. https://doi.org/10.1161/CIRCRESAHA.119.316155.

    Article  Google Scholar 

  30. Lan, F., A. S. Lee, P. Liang, et al. Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells. Cell Stem Cell. 12(1):101–113, 2013. https://doi.org/10.1016/j.stem.2012.10.010.

    Article  Google Scholar 

  31. Lee, S., G. E. Choi, C. Yang, H. C. Wu, and J. Yu. Autofluorescence generation and elimination: a lesson from glutaraldehyde. Chem. Commun. 49(29):3028–3030, 2013. https://doi.org/10.1039/c3cc40799c.

    Article  Google Scholar 

  32. Leonard, A., A. Bertero, J. D. Powers, et al. Afterload promotes maturation of human induced pluripotent stem cell derived cardiomyocytes in engineered heart tissues. J. Mol. Cell Cardiol. 118(March):147–158, 2018. https://doi.org/10.1016/j.yjmcc.2018.03.016.

    Article  Google Scholar 

  33. Lian, X., C. Hsiao, G. Wilson, et al. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc. Natl. Acad. Sci. USA. 109(27):E1848–E1857, 2012. https://doi.org/10.1073/pnas.1200250109.

    Article  Google Scholar 

  34. Lopes, L. R., D. Brito, A. Belo, and N. Cardim. Genetic characterization and genotype-phenotype associations in a large cohort of patients with hypertrophic cardiomyopathy—an ancillary study of the Portuguese registry of hypertrophic cardiomyopathy. Int. J. Cardiol. 278:173–179, 2019. https://doi.org/10.1016/j.ijcard.2018.12.012.

    Article  Google Scholar 

  35. Lorenzini, M., G. Norrish, E. Field, et al. Penetrance of hypertrophic cardiomyopathy in sarcomere protein mutation carriers. J. Am. Coll. Cardiol. 76(5):550–559, 2020. https://doi.org/10.1016/j.jacc.2020.06.011.

    Article  Google Scholar 

  36. Luan, J., K. K. Liu, S. Tadepalli, et al. PEGylated artificial antibodies: plasmonic biosensors with improved selectivity. ACS Appl. Mater. Interfaces 8(36):23509–23516, 2016. https://doi.org/10.1021/acsami.6b07252.

    Article  Google Scholar 

  37. Luo, Q., J. Chen, T. Zhang, X. Tang, and B. Yu. Retrospective analysis of clinical phenotype and prognosis of hypertrophic cardiomyopathy complicated with hypertension. Sci. Rep. 10(1):1–9, 2020. https://doi.org/10.1038/s41598-019-57230-z.

    Article  Google Scholar 

  38. Lynn, M. L. Chronic calmodulin-kinase II activation drives disease progression in mutation- specific hypertrophic cardiomyopathy. Circulation 139:1517–1529, 2019. https://doi.org/10.1161/CIRCULATIONAHA.118.034549.

    Article  Google Scholar 

  39. Ma, Z., N. Huebsch, S. Koo, et al. Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload. Nat. Biomed. Eng. 2(12):955–967, 2018. https://doi.org/10.1038/s41551-018-0280-4.

    Article  Google Scholar 

  40. Marian, A. J., and E. Braunwald. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ. Res. 121(7):749–770, 2017. https://doi.org/10.1161/CIRCRESAHA.117.311059.

    Article  Google Scholar 

  41. Maron, B. J. Clinical course and management of hypertrophic cardiomyopathy. N. Engl. J. Med. 379(7):655–668, 2018. https://doi.org/10.1056/nejmra1710575.

    Article  Google Scholar 

  42. Maron, B. J., and M. S. Maron. Hypertrophic cardiomyopathy. Lancet. 381(9862):242–255, 2013. https://doi.org/10.1016/S0140-6736(12)60397-3.

    Article  Google Scholar 

  43. Marston, S. B. How do mutations in contractile proteins cause the primary familial cardiomyopathies ? J Cardiovasc. Transl. Res. 4(3):245–255, 2011. https://doi.org/10.1007/s12265-011-9266-2.

    Article  Google Scholar 

  44. Marston, S., O. Copeland, K. Gehmlich, S. Schlossarek, and L. Carrrier. How do MYBPC3 mutations cause hypertrophic cardiomyopathy? J. Muscle Res. Cell Motil. 33(1):75–80, 2012. https://doi.org/10.1007/s10974-011-9268-3.

    Article  Google Scholar 

  45. Mosqueira, D., I. Mannhardt, J. R. Bhagwan, et al. CRISPR/Cas9 editing in human pluripotent stemcell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur. Heart J. 39(43):3879–3892, 2018. https://doi.org/10.1093/eurheartj/ehy249.

    Article  Google Scholar 

  46. Nerbonne, J. M., C. G. Nichols, T. L. Schwarz, and D. Escande. Genetic manipulation of cardiac K+ channel function in mice: What have we learned, and where do we go from here? Circ. Res. 89(11):944–956, 2001. https://doi.org/10.1161/hh2301.100349.

    Article  Google Scholar 

  47. Ommen, S. R., S. Mital, M. A. Burke, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 76(25):e159–e240, 2020. https://doi.org/10.1161/CIR.0000000000000937.

    Article  Google Scholar 

  48. Ong, K. C., J. B. Geske, V. B. Hebl, et al. Pulmonary hypertension is associated with worse survival in hypertrophic cardiomyopathy. Eur. Heart J. Cardiovasc. Imaging 17(6):604–610, 2016. https://doi.org/10.1093/ehjci/jew024.

    Article  Google Scholar 

  49. Palchesko, R. N., L. Zhang, Y. Sun, and A. W. Feinberg. Development of polydimethylsiloxane substrates with tunable elastic modulus to study cell mechanobiology in muscle and nerve. PLoS ONE 2012. https://doi.org/10.1371/journal.pone.0051499.

    Article  Google Scholar 

  50. Ribeiro, A. J. S., O. Schwab, M. A. Mandegar, et al. Multi-imaging method to assay the contractile mechanical output of micropatterned human iPSC-derived cardiac myocytes. Circ. Res. 120(10):1572–1583, 2017. https://doi.org/10.1161/CIRCRESAHA.116.310363.

    Article  Google Scholar 

  51. Rodriguez, M. L., T. R. Werner, B. Becker, T. Eschenhagen, and M. N. Hirt. Magnetics-based approach for fine-tuning afterload in engineered heart tissues. ACS Biomater. Sci. Eng. 5(7):3663–3675, 2019. https://doi.org/10.1021/acsbiomaterials.8b01568.

    Article  Google Scholar 

  52. Schmitt, J. P., C. Semsarian, M. Arad, et al. Consequences of pressure overload on sarcomere protein mutation-induced hypertrophic cardiomyopathy. Circulation 108(9):1133–1138, 2003. https://doi.org/10.1161/01.CIR.0000086469.85750.48.

    Article  Google Scholar 

  53. Seeger, T., R. Shrestha, C. K. Lam, et al. A premature termination codon mutation in MYBPC3 causes hypertrophic cardiomyopathy via chronic activation of nonsense-mediated decay. Circulation. 139(6):799–811, 2019. https://doi.org/10.1161/CIRCULATIONAHA.118.034624.

    Article  Google Scholar 

  54. Sen-Chowdhry, S., D. Jacoby, J. C. Moon, and W. J. McKenna. Update on hypertrophic cardiomyopathy and a guide to the guidelines. Nat. Rev. Cardiol. 13(11):651–675, 2016. https://doi.org/10.1038/nrcardio.2016.140.

    Article  Google Scholar 

  55. Spudich, J. A. Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations. Pflugers Arch. Eur. J. Physiol. 471(5):701–717, 2019. https://doi.org/10.1007/s00424-019-02259-2.

    Article  Google Scholar 

  56. Stöhr, A., F. W. Friedrich, F. Flenner, et al. Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice. J. Mol. Cell Cardiol. 63:189–198, 2013. https://doi.org/10.1016/j.yjmcc.2013.07.011.

    Article  Google Scholar 

  57. Taylor, J. Sudden cardiac death in young competitive athletes. Eur. Heart J. 35(44):3081, 2014. https://doi.org/10.1093/eurheartj/ehu390.

    Article  Google Scholar 

  58. Teekakirikul, P., S. Eminaga, O. Toka, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J. Clin. Invest. 120(10):3520–3529, 2010. https://doi.org/10.1172/JCI42028.

    Article  Google Scholar 

  59. Toepfer, C. N., H. Wakimoto, A. C. Garfinkel, et al. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci. Transl. Med. 2019. https://doi.org/10.1126/scitranslmed.aat1199.

    Article  Google Scholar 

  60. Tohyama, S., F. Hattori, M. Sano, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 12(1):127–137, 2013. https://doi.org/10.1016/j.stem.2012.09.013.

    Article  Google Scholar 

  61. Truitt, R., A. Mu, E. A. Corbin, et al. Increased afterload augments sunitinib-induced cardiotoxicity in an engineered cardiac microtissue model. JACC Basic Transl. Sci. 3(2):265–276, 2018. https://doi.org/10.1016/j.jacbts.2017.12.007.

    Article  Google Scholar 

  62. Undrovinas, N. A., V. A. Maltsev, L. Belardinelli, H. N. Sabbah, and A. Undrovinas. Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure. J. Physiol. Sci. 60(4):245–257, 2010. https://doi.org/10.1007/s12576-010-0092-0.

    Article  Google Scholar 

  63. Van Driest, S. L., V. C. Vasile, S. R. Ommen, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 44(9):1903–1910, 2004. https://doi.org/10.1016/j.jacc.2004.07.045.

    Article  Google Scholar 

  64. Velicki, L., D. G. Jakovljevic, A. Preveden, et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy. BMC Cardiovasc. Disord. 20(1):1–10, 2020. https://doi.org/10.1186/s12872-020-01807-4.

    Article  Google Scholar 

  65. Wang, G., M. L. McCain, L. Yang, et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat. Med. 20(6):616–623, 2014. https://doi.org/10.1038/nm.3545.

    Article  Google Scholar 

  66. Wu, H., H. Yang, J. W. Rhee, et al. Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. Eur Heart J. 40(45):3685–3695, 2019. https://doi.org/10.1093/eurheartj/ehz326.

    Article  Google Scholar 

  67. Yoshie, H., N. Koushki, R. Kaviani, et al. Traction force screening enabled by compliant PDMS elastomers. Biophys. J. 114(9):2194–2199, 2018. https://doi.org/10.1016/j.bpj.2018.02.045.

    Article  Google Scholar 

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Achknowledgement

This work was supported by the Department of Biomedical Engineering at Washington University in St. Louis, the American Heart Association (19CDA34730016 to NH, predoctoral fellowship 828938 to JG). Brandon Rios acknowledges support from the National Institutes of Health MARC U-STAR program at Washington University in St. Louis (T34GM083914). We thank Dr. Jonathan Moreno, Dr. Jonathan Silva, and Dr. Sharon Cresci for helpful discussions. We thank Dr. Srikanth Singamaneni and Dr. Jai Rudra for use of Li-COR scanner and flow cytometer, along with Dr. Bruce R. Conklin and Mohammed A. Mandegar for generously providing the MYBPC3+/− iPSC line for these studies.

Conflict of interest

Jingxuan Guo, Huanzhu Jiang, Kasoorelope Oguntuyo, Brandon Rios, Anand Boodram and Nathaniel Huebsch declare that they have no conflicts of interest.

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Correspondence to Nathaniel Huebsch.

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Nate Huebsch completed his PhD training with David J. Mooney, through the Harvard-MIT Division of Health Sciences and Technology, and then worked as a postdoctoral fellow and research scientist with Bruce Conklin at the Gladstone Institute of Cardiovascular Disease where he held fellowships from the NIH (NRSA) and the California Institute of Regenerative Medicine (CIRM). He served as the lead scientist on the Microphysiological Systems team in the laboratory of Kevin Healy at the University of California, Berkeley before joining the department of Biomedical Engineering at Washington University in Saint Louis in 2018. His research focus is on understanding how mechanical loading contributes to pathogenesis of inherited cardiomyopathies and stem cell differentiation, and on developing materials to study synergy between growth factor and integrin signaling. Dr. Huebsch is a recipient of the Career Development Award from the American Heart Association.

Associate Editor Michael R. King oversaw the review of this article.

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Guo, J., Jiang, H., Oguntuyo, K. et al. Interplay of Genotype and Substrate Stiffness in Driving the Hypertrophic Cardiomyopathy Phenotype in iPSC-Micro-Heart Muscle Arrays. Cel. Mol. Bioeng. 14, 409–425 (2021). https://doi.org/10.1007/s12195-021-00684-x

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Keywords

  • Induced pluripotent stem cells (iPSC)
  • Hypertrophic cardiomyopathy (HCM)
  • Overload