Innovation Showcase: Advancing Human iPSC-derived Organoids for Cardiac Mechanism Discovery, Drug Screening, and Personalized Medicine Date/Time: Wednesday, July 8, 12:30 - 1:30 p.m. Location: Room 513B, 5th Floor, Palais de Congress, Montreal, Canada Summary
Human induced pluripotent stem cell (hiPSC)-derived organoids are emerging as powerful platforms for mechanistic biology, translational drug discovery, and precision medicine. This symposium highlights how advanced human 3D cardiac and pancreatic organoid systems can enable both disease-relevant functional analysis and scalable screening applications. In the first presentation, Lu Ren, Ph.D., will describe how hiPSC-derived sinoatrial node cells and 3D sinoatrial node cardiac organoids were used to define the direct effects of tirzepatide on human pacemaker tissue, revealing a mechanism involving compartmentalized cAMP signaling, PKA-dependent phospholamban phosphorylation, enhanced calcium cycling, and increased spontaneous beating. In the second presentation, Todd J. Herron, Ph.D., will present scalable workflows for generating large batches of patient-specific hiPSC-derived organoids using Corning Elplasia® platforms, together with high-content imaging and optical phenotyping methods for cardiac and pancreatic functional analysis. Together, these talks illustrate how reproducible, human-relevant organoid models can bridge mechanistic insight with industrial-scale screening, supporting drug discovery, toxicity testing, and personalized therapeutic development. Speakers Lu Ren, Ph.D., Stanford University Todd Herron, Ph.D., Greenstone Biosciences Detailed presentation titles/abstracts: |
Part 1: Tirzepatide Regulates Pacemaker Function by Modulating cAMP and Calcium Dynamics in Human Sinoatrial Node Cells | Dual glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists, including tirzepatide, have revolutionized type 2 diabetes mellitus clinical management but have been linked to an increase in resting heart rate, raising cardiovascular concerns in patients with comorbidities such as heart failure. Conversely, these agents may offer therapeutic benefits for pathological bradycardia, including sick sinus syndrome. Understanding the mechanisms by which these drugs modulate heart rate is therefore essential.
To investigate this at the cellular and 3D level in a human-relevant system, we generated human induced pluripotent stem cell-derived sinoatrial node cells (iPSC-SAN) using our established differentiation protocol, validated by canonical SAN markers (SHOX2, ISL1, TBX18). iPSC-SAN cells were combined with iPSC-derived cardiac fibroblasts to form 3D SAN cardiac organoids (SAN-CO). Tirzepatide increased SAN-CO spontaneous beating rate, an effect attenuated by combined GLP1R and GIPR antagonism. Using fluorescence resonance energy transfer (FRET) biosensors targeted to subcellular compartments, we found that tirzepatide elevated cAMP at the plasma membrane and sarcoplasmic reticulum (SR), with the SR response more pronounced. Proximity ligation assays demonstrated spatial co-localization of GLP1R and GIPR with phospholamban (PLN) at SR nanodomains. Tirzepatide accelerated Ca2+ cycling and increased PLN phosphorylation at Serine-16, a protein kinase A (PKA) site, in a GLP1R/GIPR-dependent manner. Reanalysis of a published phosphoproteomic dataset further supported coordinated remodeling of Ca2+ handling. These findings demonstrate that tirzepatide acts directly on human iPSC-SAN cells by elevating cAMP at SR nanodomains, activating PKA-mediated PLN phosphorylation and enhancing Ca2+ cycling to drive pacemaker activity. This mechanism provides a molecular explanation for the chronotropic effects of dual GLP1R/GIPR agonists and may help optimize therapy while minimizing potential cardiovascular risks in vulnerable patient populations.
| Lu Ren, Ph.D. Stanford University |
Part 2: Patient Specific hiPSC-3D Organoids: Large Scale Production and Functional Phenotype Analysis for Drug Discovery, Personalized Medicine and Toxicity Screening | Human induced pluripotent stem cell (hiPSC)-derived 3D organoids are emerging as transformative platforms for disease modeling, drug discovery, personalized medicine, and safety pharmacology. Despite rapid advances in differentiation technologies, significant barriers remain that limit widespread implementation of organoid-based screening workflows. Current challenges include variability in organoid size and composition, low-throughput production methods, inconsistent maturation, limited scalability, and difficulties integrating functional phenotyping into high-content screening pipelines. These limitations have constrained the reproducibility and industrial adoption of complex 3D human tissue models. At Greenstone Biosciences, we have developed scalable workflows for the large-batch generation and functional analysis of patient-specific hiPSC-derived organoids using Corning Elplasia microwell platforms. Our approach enables robust production of 12,000-48,000 uniform organoids per manufacturing run, including pancreatic islet organoids, pancreatic acinar/ductal organoids, and cardiac organoids. In parallel, we have established single-organoid workflows compatible with one organoid per well in 96-well plate formats, supporting assay standardization and compound screening applications. To address limitations in functional readouts from conventional endpoint assays, we integrate high-content imaging and optical phenotyping approaches for rapid, non-invasive analysis of organoid physiology. For cardiac organoids, electrophysiological assessment enables quantification of beat rate, rhythm, conduction dynamics, calcium handling, and drug-induced functional perturbations. For pancreatic organoids, functional imaging supports dynamic assessment of stimulus-response behavior and endocrine activity. These multimodal datasets provide scalable and information-rich phenotypic signatures suitable for toxicity screening, disease modeling, and precision therapeutic development. This session will discuss manufacturing strategies for reproducible large-scale organoid production, approaches for integrating high-content functional imaging into screening workflows, and future opportunities for combining patient-specific organoid models with artificial intelligence-driven phenotypic analysis to accelerate translational drug discovery and personalized medicine. | Todd J. Herron, Ph.D. Greenstone Biosciences |
Poster Session: Abstract Track: Disease modeling and drug discovery Title: Evaluation of Defined Hydrogels for Promoting the Growth of Patient-derived Organoids Authors: Audrey Bergeron, Samantha Haller, Hannah Gitschier, Corinne Walerack, Melissa Rodrigues, Marie-Maud Bear, David Henry, Wesley (Lien-Yu) Hung, Linda (Wei-Lun) Hsu, and EJ (Yi-Chieh) Chan Date/Time/Poster#/Location - TBD Abstract Patient-derived organoids are increasingly used as disease models and drug development New Approach Methodologies (NAMs). Most 3D organoid cultures rely on the presence of animal-derived basement-membrane extracts and Corning® Matrigel® matrix is the gold standard. However, the desire to move to animal-free reagents has led to the emergence of more defined or even fully synthetic hydrogels. Here, we evaluated defined or fully synthetic hydrogels as alternative matrices for patient-derived pancreatic ductal adenocarcinoma (PDAC) organoids, human colon organoids from a cystic fibrosis patient, and human colon cancer organoids. Organoid fragments or single cells were embedded in hydrogel domes and cultured for 7-10 days, then assessed for growth efficiency, morphology/polarization, and ease of organoid recovery. Hydrogel performance was strongly context dependent: Hydrogels 1 and 2 supported PDAC organoid formation with Matrigel matrix-like morphology, albeit at reduced yield, while only Hydrogel 1 maintained comparable morphology in colon cancer organoids. In contrast, Hydrogels 3 and 4 facilitated rapid matrix dissolution and organoid harvesting but failed to support polarized organoid architecture. Overall, none of the tested defined/synthetic matrices recapitulated the full functional profile of Matrigel matrix across models, underscoring the need for application- and tissue-specific empirical validation when selecting hydrogels for organoid culture. |
