Creating a Pulmonary Valve that Grows with the Child: a Story of Discovery

Robert Tranquillo, PhD, Professor of Biomedical Engineering and Chemical Engineering & Materials Science at the University of Minnesota

Abstract: We have developed a biologically-engineered tube of cell-produced collagenous matrix, which is allogeneic upon a decellularization performed prior to implantation and thus “off-the-shelf.”  It is grown from donor dermal fibroblasts entrapped in a sacrificial fibrin hydrogel tube that is then decellularized using sequential detergent treatments. The resulting cell-produced matrix tube possesses physiological strength, compliance, alignment (circumferential) and growth potential, demonstrated in a growing lamb pulmonary artery replacement model because the matrix becomes a living tissue with the recipient’s cells post-implantation (Nat Comms 2016). Using the concept of a tubular heart valve, where the tube collapses inward with back-pressure between 3 equi-spaced constraints placed around the periphery to create one-way valve action, we have created a set of novel heart valves for adults and children that offer indefinite durability and growth potential, demonstrated by implantation in the growing lamb pulmonary artery for 52 weeks (Science 2021).

Evolution of Gene Regulatory Networks During Human Cardiogenesis

Eugin Destici, PhD, Assistant Project Scientist at the University of California San Diego (Neil Chi Laboratory)

Abstract: The heart, a vital organ which is first to develop, has adapted its size, structure and function in order to accommodate the circulatory demands for a broad range of animals.  Although heart development is controlled by a relatively conserved network of transcriptional/chromatin regulators, how the human heart has evolved species-specific features to maintain adequate cardiac output and function remains to be defined.  Here, we show through comparative epigenomic analysis the identification of enhancers and promoters that have gained activity in humans during cardiogenesis.  These cis-regulatory elements are associated with genes involved in heart development and function, and may account for species-specific differences between human and mouse hearts.  Supporting these findings, genetic variants that are associated with human cardiac phenotypic/disease traits, particularly those differing between human and mouse, are enriched in human-gained cis-regulatory elements.  During early stages of human cardiogenesis, these cis-regulatory elements are also gained within genomic loci of transcriptional regulators, potentially expanding their role in human heart development.  In particular, we discovered that gained enhancers in the locus of the early developmental regulator ZIC3 are selectively accessible within a subpopulation of mesoderm cells which exhibits cardiogenic potential, thus possibly extending the function of ZIC3 beyond its conserved left-right asymmetry role.  Genetic deletion of these enhancers resulted in not only reduced early cardiac gene expression but also decreased cardiomyocyte differentiation.  Overall, our results illuminate how human gained cis-regulatory elements may contribute to human-specific cardiac attributes, and provide insight into how transcriptional regulators may gain developmental roles through the evolutionary acquisition of enhancers.