INT'L GUEST SPEAKER - Professor Thomas Braun MD, Director, Max Planck Inst for Heart & Lung Research : ‘Pathways controlling cardiac morphogenesis and skeletal muscle regeneration’

Thomas Braun, Max-Planck-Institute for Heart and Lung Research. Ludwigstr. 43, 61231 Bad Nauheim, Germany
Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases is attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. We found that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing ISL1 in the secondary heart field are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating Nkx2.5, resulting in decreased cell proliferation and enhanced cardiomyocyte specification leading to CHD. Mechanistically, hypoxia-induced arrest of Isl1+ CPC proliferation is due to complex formation of HIF1α with the Notch effector HES1 and the protein deacetylase SIRT1 at the Isl1 gene. Our results indicate that spatial differences in oxygenation of the developing heart serve as signals to control CPC expansion and cardiac morphogenesis. We propose that physiological hypoxia coordinates homeostasis of CPCs, providing mechanistic explanations for some nongenetic causes of CHD.
Cardiomyocytes in the adult heart show a decline of differentiated functions and acquisition of immature, “embryonic” properties under various disease processes, which seems to protect cells from hypoxia by reduction of ATP consumption. Cardiomyocyte dedifferentiation in mice depends on the OSM receptor leading to the release of multiple cytokines including Reg3b, which is required for efficient homing of macrophages to the damaged myocardium. In a search for posttranscriptional regulatory processes controlling cardiomyocyte dedifferentiation, we identified miRNAs that suppress the FGFR and OSMR pathways, which are instrumental for the control of postnatal cardiomyocyte proliferation and dedifferentiation.
In contrast to the heart muscle, skeletal muscles contain dedicated stem cells enabling muscle regeneration throughout adult life. We have conducted a large high-resolution mass spectrometry-based analysis of proteins expressed in satellite cells combined with a non-biased high-throughput lentiviral RNAi screen to analyze the function of chromatin-modifying enzymes in muscle stem cells. We discovered that skeletal muscle stem cells primarily carry facultative heterochromatin, which, after differentiation of satellite cells to myofibers, switches to a combination of euchromatin and constitutive heterochromatin. Inactivation of the chromatin modifier Suv4-20h1 in muscle stem cells results in widespread chromatin rearrangements and loss of PCR-dependent H3K27me3 modifications, which causes relocation of the MyoD locus from the nuclear periphery and precocious MyoD expression. Other epigenetic modifiers repress expression of components of the necroptosis pathway in muscle stem cells. Reduced expression of such modifiers under inflammatory conditions increases necroptosis of muscle stem cells and compromises skeletal muscle regeneration.