Human Engineered Myocardium

Coulombe Lab Scale Bar

The Coulombe Lab has funding to support multiple projects focused on regenerating the muscular wall of the heart and developing in vitro models of disease states. These projects have basic science and translational components, working across the continuum from molecules and cells to tissue and the whole heart. Heart Regeneration Images

in vitro models research images

This work is funded by:

NIH, NSF, AHA, etc

Heart Regeneration

Engineering Mature, Contractile Cardiac Tissue

Using human induced pluripotent stem cells (hiPSCs) to derive cardiomyocytes, we form engineered cardiac tissue (ECT) and stimulate them mechanically, electrically, and biochemically to promote cardiomyocyte maturation in vitro. A combination of approaches enables targeting unique cellular processes to induce maturation. Biochemical stimulation with insulin-like growth factor-1 (IGF1) and neuregulin-1 (NRG1) induces cardiomyocyte proliferation and promotes maturation of metabolic pathways and contractility to enable a positive force-frequency response (Rupert et al 2017 Stem Cells Int.).  Purification of cardiomyocytes, co-culture of cardiomyocytes with other cardiac cell types, and understanding the non-myocyte hiPSC-derived population alters excitation-contraction coupling and the biophysics of contraction (Rupert et al 2020 Plos One, Rupert et al 2020 Stem Cells Int).  Embedding of wet-spun collagen microfibers in a defined, anisotropic architecture aligns myofilaments and sarcomeres in ECTs (Kaiser et al 2019 ACS Biomater Sci Eng). With collaborators in the Srivastava lab at Brown, we developed a three-dimensional strain continuum predictive model to allow for micro-structural design optimization and analysis of effectiveness of the implanted patches (Bai et al 2021), and with collaborators in the Callanan lab at the University of Edinburgh, we are utilizing biomaterials beyond collagen in anisotropic scaffolds for applications in the heart and beyond (Reid et al 2021).

Developing Vasculature in Engineered Tissue

We are inducing the host heart to more efficiently vascularize implanted human cardiac tissue using embedded alginate microspheres to deliver angiogenic growth factors.  Microspheres release VEGF-A, FGF-2, and sonic hedgehog into the local microenvironment after implantation on ischemia/reperfusion injured rat hearts. Vascular perfusion enables detection of patent and efficiently perfused vessels originating from the host. This localized delivery of angiogenic factors from biomaterials within the implanted muscle tissue increased global heart function in ischemia/reperfusion injured rat hearts (Munarin et al 2020). We have also shown that patterned endothelial cell-lined vessels promote early chemotaxis from host vascular populations (Kant et al 2021). Heparin modification of alginate microspheres allows for controlled release of VEGF to improve vascularization (Munarin et al 2021) and or can be utilized with pleiotrophin (PTN), a heparin-binding factor with significant angiogenic activity (Rountree et al 2021).

Electrical Coupling of Implanted and Host Tissue

In Vitro Models

Assessing arrhythmogenic risk in in vitro models of cardiac tissue

Utilizing a human iPSC-cardiomyocyte 3D microtissue platform, we assess dose sensitivity of environmental toxicants and pharmaceuticals for arrhythmic events by evaluating voltage and calcium handling via optical mapping in collaboration with Drs. Bum-Rak Choi and Ulrike Mende (RI Hospital).  Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we have shown that our microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range (Kofron et al 2021). We continue to validate our model with known toxicants over large concentration ranges, and with collaborators at ScitoVation, Inc, we are developing in vitro to in vivo extrapolation (IVIVE) and other models to maximize the risk assessment capabilities of our platform.

Atrial Arrhythmias

Publications

Minor, A.J., Coulombe, K.L.K., 2022. Stimulating Calcium Handling in hiPSC-Derived Engineered Cardiac Tissues Enhances Force Production. Stem Cells Translational Medicine 11, 97–106. https://doi.org/10.1093/stcltm/szab002

Soepriatna, A.H., Kim, T.Y., Daley, M.C., Song, E., Choi, B.-R., Coulombe, K.L.K., 2021. Human Atrial Cardiac Microtissues for Chamber-Specific Arrhythmic Risk Assessment. Cel. Mol. Bioeng. 14, 441–457. https://doi.org/10.1007/s12195-021-00703-x

Reid, J.A., Dwyer, K.D., Schmitt, P.R., Soepriatna, A.H., Coulombe, K., Callanan, A., 2021. Architected fibrous scaffolds for engineering anisotropic tissues. Biofabrication. https://doi.org/10.1088/1758-5090/ac0fc9

Bai, Y., Kaiser, N.J., Coulombe, K.L.K., Srivastava, V., 2021. A continuum model and simulations for large deformation of anisotropic fiber-matrix composites for cardiac tissue engineering. J Mech Behav Biomed Mater 121, 104627. https://doi.org/10.1016/j.jmbbm.2021.104627

Kofron, C.M., Kim, T.Y., Munarin, F., Soepriatna, A.H., Kant, R.J., Mende, U., Choi, B.-R., Coulombe, K.L.K., 2021. A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues. Sci Rep 11, 10228. https://doi.org/10.1038/s41598-021-89478-9

Dwyer, K.D., Coulombe, K.L.K., 2021. Cardiac mechanostructure: Using mechanics and anisotropy as inspiration for developing epicardial therapies in treating myocardial infarction. Bioact Mater 6, 2198–2220. https://doi.org/10.1016/j.bioactmat.2020.12.015

Rountree, I., Polucha, C., Coulombe, K.L.K., Munarin, F., 2021. Assessing the Angiogenic Efficacy of Pleiotrophin Released from Injectable Heparin-Alginate Gels. Tissue Eng Part A. https://doi.org/10.1089/ten.TEA.2020.0335

Munarin, F., Kabelac, C., Coulombe, K.L.K., 2021. Heparin-modified alginate microspheres enhance neovessel formation in hiPSC-derived endothelial cells and heterocellular in vitro models by controlled release of vascular endothelial growth factor. J Biomed Mater Res A. https://doi.org/10.1002/jbm.a.37168

Kant, R.J., Bare, C.F., Coulombe, K.L.K., 2021. Tissues with patterned vessels or protein release induce vascular chemotaxis in an in vitro platform. Tissue Eng Part A. https://doi.org/10.1089/ten.TEA.2020.0269

Munarin, F., Kant, R.J., Rupert, C.E., Khoo, A., Coulombe, K.L.K., 2020. Engineered human myocardium with local release of angiogenic proteins improves vascularization and cardiac function in injured rat hearts. Biomaterials 251, 120033. https://doi.org/10.1016/j.biomaterials.2020.120033

Minor, A.J., Coulombe, K.L.K., 2020. Engineering a collagen matrix for cell-instructive regenerative angiogenesis. J Biomed Mater Res B Appl Biomater. https://doi.org/10.1002/jbm.b.34573

Bloise, N., Rountree, I., Polucha, C., Montagna, G., Visai, L., Coulombe, K.L.K., Munarin, F., 2020. Engineering Immunomodulatory Biomaterials for Regenerating the Infarcted Myocardium. Front Bioeng Biotechnol 8, 292. https://doi.org/10.3389/fbioe.2020.00292

Rupert, C.E., Irofuala, C., Coulombe, K.L.K., 2020. Practical adoption of state-of-the-art hiPSC cardiomyocyte differentiation techniques. PLoS One 15, e0230001. https://doi.org/10.1371/journal.pone.0230001

Rupert, C.E., Kim, T.Y., Choi, B.-R., Coulombe, K.L.K., 2020. Human Cardiac Fibroblast Number and Activation State Modulate Electromechanical Function of hiPSC-Cardiomyocytes in Engineered Myocardium. Stem Cells Int 2020, 9363809. https://doi.org/10.1155/2020/9363809

Kaiser, N.J., Bellows, J.A., Kant, R.J., Coulombe, K.L.K., 2019. Digital Design and Automated Fabrication of Bespoke Collagen Microfiber Scaffolds. Tissue Eng Part C Methods 25, 687–700. https://doi.org/10.1089/ten.TEC.2018.0379

Kaiser, N.J., Kant, R.J., Minor, A.J., Coulombe, K.L.K., 2019. Optimizing Blended Collagen-Fibrin Hydrogels for Cardiac Tissue Engineering with Human iPSC-derived Cardiomyocytes. ACS Biomater Sci Eng 5, 887–899. https://doi.org/10.1021/acsbiomaterials.8b01112

Kaiser, N.J., Munarin, F., Coulombe, K.L.K., 2018. Custom Engineered Tissue Culture Molds from Laser etched Masters. J Vis Exp. https://doi.org/10.3791/57239

Kant, R.J., Coulombe, K.L.K., 2018. Integrated approaches to spatiotemporally directing angiogenesis in host and engineered tissues. Acta Biomater 69, 42–62. https://doi.org/10.1016/j.actbio.2018.01.017

Liu, M., Shi, G., Zhou, A., Rupert, C.E., Coulombe, K.L.K., Dudley, S.C., 2018. Activation of the unfolded protein response downregulates cardiac ion channels in human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 117, 62–71. https://doi.org/10.1016/j.yjmcc.2018.02.011

Munarin, F., Kaiser, N.J., Kim, T.Y., Choi, B.-R., Coulombe, K.L.K., 2017. Laser-Etched Designs for Molding Hydrogel-Based Engineered Tissues. Tissue Eng Part C Methods 23, 311–321. https://doi.org/10.1089/ten.TEC.2017.0068

Rupert, C.E., Coulombe, K.L.K., 2017. IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues. Stem Cells Int 2017, 7648409. https://doi.org/10.1155/2017/7648409

Rupert, C.E., Chang, H.H., Coulombe, K.L.K., 2017. Hypertrophy changes 3D shape of hiPSC cardiomyocytes: Implications for cellular maturation in regenerative medicine. Cell Mol Bioeng 10, 54–62. https://doi.org/10.1007/s12195-016-0462-7

Roberts, M.A., Tran, D., Coulombe, K.L.K., Razumova, M., Regnier, M., Murry, C.E., Zheng, Y., 2016. Stromal Cells in Dense Collagen Promote Cardiomyocyte and Microvascular Patterning in Engineered Human Heart Tissue. Tissue Eng Part A 22, 633–644. https://doi.org/10.1089/ten.TEA.2015.0482

Rupert, C.E., Coulombe, K.L., 2015. The roles of neuregulin-1 in cardiac development, homeostasis, and disease. Biomark Insights 10, 1–9. https://doi.org/10.4137/BMI.S20061

Kaiser, N.J., Coulombe, K.L.K., 2015. Physiologically inspired cardiac scaffolds for tailored in vivo function and heart regeneration. Biomed Mater 10, 034003. https://doi.org/10.1088/1748-6041/10/3/034003

Gerbin, K.A., Yang, X., Murry, C.E., Coulombe, K.L.K., 2015. Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts. PLoS One 10, e0131446. https://doi.org/10.1371/journal.pone.0131446

Coulombe, K.L.K., Bajpai, V.K., Andreadis, S.T., Murry, C.E., 2014. Heart regeneration with engineered myocardial tissue. Annu Rev Biomed Eng 16, 1–28. https://doi.org/10.1146/annurev-bioeng-071812-152344

Coulombe, K.L.K., Murry, C.E., 2014. Vascular Perfusion of Implanted Human Engineered Cardiac Tissue. Proc IEEE Annu Northeast Bioeng Conf 2014. https://doi.org/10.1109/NEBEC.2014.6972763