Biology subjects

Hofbauer, P.

Publications and source records attributed to Hofbauer, P..

3 recordsLinked to original sources

bioRxiv2022

Multi-chamber cardioids unravel human heart development and cardiac defects

The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible, and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining the underlying causes is difficult. Here, we established a human cardioid platform that recapitulates the development of all major embryonic heart compartments, including right and left ventricles, atria, outflow tract, and atrioventricular canal. By leveraging both 2D and 3D differentiation, we efficiently generated progenitor subsets with distinct first, anterior, and posterior second heart field identities. This advance enabled the reproducible generation of cardioids with compartment-specific in vivo-like gene expression profiles, morphologies, and functions. We used this platform to unravel the ontogeny of signal and contraction propagation between interacting heart chambers and dissect how genetic and environmental factors cause region-specific defects in the developing human heart. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/499699v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@c9c629org.highwire.dtl.DTLVardef@f0d521org.highwire.dtl.DTLVardef@1389411org.highwire.dtl.DTLVardef@181098a_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTS- Mesoderm induction and patterning signals specify aSHF, pSHF, and FHF progenitors - Cardiac progenitors sort, co-develop and functionally connect in multi-chamber cardioids - Multi-chamber cardioids coordinate contraction propagation and share a lumen - Multi-chamber platform dissects genetic (ISL1, TBX5, FOXF1) and teratogenic defects

developmental biology↗

bioRxiv2021

ZFP462 targets heterochromatin to transposon-derived enhancers restricting transcription factor binding and expression of lineage-specifying genes

ZNF462 haploinsufficiency is linked to Weiss-Kruszka Syndrome, a genetic disorder characterized by a range of neurodevelopmental defects including Autism. Though it is highly conserved in vertebrates and essential for embryonic development the molecular functions of ZNF462 are unclear. We identified its murine homolog ZFP462 in a screen for epigenetic gene silencing in mouse embryonic stem cells (mESCs). Here, we show ZFP462 safeguards neural lineage specification by targeting the H3K9-specific histone methyltransferase complex G9A/GLP to mediate epigenetic silencing of endodermal genes. ZFP462 binds to thousands of transposable elements (TEs) that harbor ESC- and endoderm-specific transcription factor (TF) binding sites and act as enhancers. Through physical interaction with G9A/GLP, ZFP462 seeds heterochromatin at TE-derived enhancers restricting the binding of core pluripotency TFs OCT4 and SOX2. Loss of ZFP462 in ESCs results in increased chromatin accessibility at target sites and ectopic expression of endodermal genes. Taken together, ZFP462 restricts TF binding and subsequent endodermspecific gene activation by conferring lineage and locus-specificity to the broadly expressed epigenetic regulator G9A/GLP. Our results suggest that aberrant activation of endodermal genes in the neuronal lineage underlies ZNF462-associated neurodevelopmental pathology.

genetics↗

bioRxiv2020

Cardioids reveal self-organizing principles of human cardiogenesis

Organoids that self-organize into tissue-like structures have transformed our ability to model human development and disease. To date, all major organs can be mimicked using self-organizing organoids with the notable exception of the human heart. Here, we established self-organizing cardioids from human pluripotent stem cells that intrinsically specify, pattern and morph into chamber-like structures containing a cavity. Cardioid complexity can be controlled by signaling that instructs the separation of cardiomyocyte and endothelial layers, and by directing epicardial spreading, inward migration and differentiation. We find that cavity morphogenesis is governed by a mesodermal WNT-BMP signaling axis and requires its target HAND1, a transcription factor linked to human heart chamber cavity defects. In parallel, a WNT-VEGF axis coordinates myocardial self-organization with endothelial patterning and specification. Human cardioids represent a powerful platform to mechanistically dissect self-organization and congenital heart defects, serving as a foundation for future translational research. Highlights- Cardioids form cardiac-like chambers with inner endothelial lining and interact with epicardium - Cardioid self-organization and lineage complexity can be controlled by signaling - WNT-BMP signaling directs cavity formation in self-organized cardioids via HAND1 - WNT-VEGF coordinate endothelial patterning with myocardial cavity morphogenesis

developmental biology↗