Engineering Liver and Cardiac Models for Drug Development and Regenerative Medicine

In vitro engineered models can provide human-relevant data for preclinical evaluations of drug-induced liver injury and cardiotoxicity, speeding up the notoriously lengthy and inefficient drug development pipeline, as well as fundamental investigations into stem cell behavior and cell-cell interactions. Tissue engineering is also increasingly used for regenerative medicine and for modeling of metabolism and physiology. However, there are material challenges associated with cellular organization, tissue integration, vascularization, and structural properties. Liver tissue engineering approaches often do not integrate hepatic and biliary components, leading to incomplete understanding of fundamental cell-cell interactions between hepatocytes and cholangiocytes. This lack of reliable in vitro models incorporating both cell types also leads to unpredicted biliary drug toxicity and inadequate cholangiopathy treatments. Platforms mimicking the bone marrow microenvironment for expansion of hematopoietic stem cells (HSCs) are increasingly studied for cell therapies, but long-term ex vivo expansion of HSCs using the factors identified during these studies has not been achieved. Finally, induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) now allow for personalized prediction of drug responses, but iPSC-derived cells show a fetal phenotype that hinders their utility. Strategies such as micropatterning, coculture with organ-specific fibroblasts, and organoid formation help maintain the phenotype, function, and stability of various cell types. In this proposal we aim to develop models to overcome the barriers in tissue engineering currently limiting the prediction of biliary drug toxicity, the expansion of HSCs for cell therapies, and the maturation of iPSC-aCMs. We showed for the first time the critical role of a hepatic microenvironment in biliary branching and tube formation and assessed dual-compartment drug toxicity. Additionally, we developed a model of the fetal liver, optimized it for HSC ex vivo expansion, and profiled its microenvironment through cytokine analysis. Finally, we developed a novel protocol to cryopreserve iPSC-aCMs that retains their drug responses, and we discovered a role of Ephrin and Connexin signaling by cardiac fibroblasts for iPSC-aCM maturation and organization. Ultimately, these heart/liver platforms developed can be utilized for physiological modeling, drug development, and cell-based therapies.

Author dc:creator

• Ashlin Michell (24400577)

• Engineering
• Biomedical

Statement dc:rights

• In Copyright
• Open Access after 2031-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995643.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995643