Beyond creating replacement tissues for patients, this technology also enables more physiologically relevant testing of pharmaceuticals and the detection of cardiotoxic compounds without requiring the use of animals.
A collaboration of researchers from University of Michigan’s BME department, Boston University and Florida International University aims to improve standardization across the field of cardiac tissue engineering. Supported by an Engineering Research Center called CELL-MET funded by the National Science Foundation (NSF), the team performed a meta-analysis of recent studies focused on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The goal of their meta-review recently published in Nature Methods was to identify field-level trends in the fabrication, maturation, and assessment techniques that lead to the most mature engineered cardiac tissues.
Under the guidance of Dr. Brendon Baker, Associate Professor, Department of Biomedical Engineering at U-M and Dr. Christopher Chen, Professor, Department of Biomedical Engineering at Boston University, CELL-MET trainees analyzed 300 recent publications and compiled this data into an open-access database to facilitate knowledge-sharing and stimulate future advances. “CELL-MET’s goal is to engineer a cardiac patch that can one day assist patients whose hearts have lost function due to heart disease,” said Baker. “For example, a heart attack results in a necrotic region of the heart wall that is replaced with non-functional scar tissue, increasing the risk of subsequent heart attacks or death. Because the heart has no intrinsic capacity to regenerate, replacing this injured tissue with functional engineered cardiac tissue is a promising solution.”
The study focused on human induced pluripotent stem cells (hiPSCs), which can be derived from any patient’s skin or blood cells and subsequently differentiated into beating cardiomyocytes, which are the muscle cells of the heart. Beyond creating replacement tissues for patients, this technology also enables more physiologically relevant testing of pharmaceuticals and the detection of cardiotoxic compounds without requiring the use of animals.
Despite these advances, key challenges remain. “One of the major goals in this field is producing hiPSC-CM tissues that contract with the same force as the adult heart,” Baker explained. Over the past decade, substantial strides have been made towards maturing hiPSC-CMs by integrating multidisciplinary approaches. However, the diverse array of cell lines, differentiation protocols, maturation techniques, and functional assessments employed across so many studies make it difficult to directly compare outcomes and identify successful strategies that should be broadly adopted.
To address this, the research team, including U-M BME Ph.D. graduate students Samuel DePalma and Maggie Jewett, conducted a systematic analysis of a broad swath of studies utilizing hiPSC-CMs, extracting details on cellular and biomaterial components and functional assessment metrics. The review aims to establish best practices for generating and evaluating the maturity of hiPSC-CMs, and as importantly, fostering transparent and collaborative discourse within the scientific community.
Baker noted the central role of CELL-MET trainees in this project, who categorized the diverse techniques and metrics used in different studies to identify overarching trends and field-level insights. “This work is a survey of the literature but in a more quantitative fashion towards a deeper understanding of successes, failures, and outstanding challenges,” he said. “One of the key conclusions is that there is no field-level consensus on what constitutes maturation. Thus, much of our paper provides suggestions and guidance for unifying experiments beginning from the starting stem cell line through to the experiments and metrics used to assess tissues made from these cells.”
As the field of cardiac tissue engineering continues to rapidly grow and evolve, standardization efforts like this one led by U-M BME and their collaborators will be increasingly important. By enabling more effective comparisons and fostering a shared understanding, the research paves the way toward the ultimate goal of engineering functional heart tissue and creating life-saving cardiac therapies.
The full text of this journal article is also available.