Research Report 2010 - MDC

standing of the molecular and cellular mechanismsunderlying a solid myocardial regeneration. In thisregard, the embryonic heart is a perfect model to studythese processes as key events like cardiomyocyte proliferation,differentiation as well as regional and functionalspecification occur physiologically in the developingheart.Our recent findings have shown that the embryonicmurine heart has a remarkable regenerative capacity.We have inactivated the X-linked gene encodingHolocytochrome c synthase (Hccs), an enzyme essentialfor normal function of the mitochondrial electrontransport chain, specifically in the developing mouseheart. Loss of Hccs activity results in cellular energystarvation causing disturbed cardiomyocyte differentiationand ultimately cellular degeneration. In contrast tothe observed mid-gestational lethality of hemizygousHccs knock-out (KO) males, heterozygous femalesappeared normal during the first months of life withsurprisingly few clusters of affected cardiomyocytes,considering an expected mosaic of affected and normalcardiomyocytes as a result of random X chromosomalinactivation. However, analyses of heterozygous femaleembryos revealed the expected 50:50 ratio of Hccs deficientto normal cardiac cells at mid-gestation with aprogressive reduction in disease tissue to 10% prior tobirth. We could show that this significant change isaccounted for by increased proliferation of remaininghealthy cardiac cells. These data reveal a previouslyunrecognised but impressive regenerative capacity ofthe mid-gestational heart that can compensate for aneffective loss of at least 50% of cardiac tissue to enableformation of a functional heart at birth. Yet despite thisregeneration, hearts of neonatal heterozygous Hccs KOfemales do not appear completely normal but showmorphological, cellular as well as molecular signs ofimmaturity. These changes, however, normalize untiladulthood suggesting activation of compensatory cardiacgrowth mechanisms in the postnatal heart afterdisturbed heart development.The detailed characterisation of molecular signalingpathways as well as cell types involved in embryonicheart regeneration is currently underway and shouldprovide major new insights into heart developmentand cardiac organ size control. Furthermore, the identificationof regenerative factors and stimuli within theembryonic heart might potentially enable the developmentof new therapeutic strategies for cardiac repair inthe adult. Finally, this model might provide a useful toolto study the impact of disturbed heart development onthe incidence of postnatal cardiac disease in the contextof fetal programming.Nuclear Receptors as Potential Target for theTreatment and Prevention of Metabolic,Inflammatory and Cardiovascular DiseaseFlorian BlaschkeMembers of the nuclear receptor superfamily of liganddependenttranscription factors play essential roles indevelopment, homeostasis, reproduction and immunefunction. Several members of this family, including theestrogen receptor (ER) and peroxisome proliferator-acti-Figure 3. β-Galactosidase staining of 19.5 dpc (days postcoitum) fetal hearts prior to birth (counterstained with Eosin).The control heart (♀ +lacZ /+, heterozygous for an X-linked lacZreporter gene) shows large patches of β-Gal positive and negativecells due to random X chromosome inactivation. In theheterozygous Hccs-knock-out heart (♀ -lacZ /+) the lacZ reportergene is linked to the X chromosome carrying the defective Hccsgene allowing the detection of Hccs deficient cells by β-Galstaining. Due to cardiac regeneration during embryonic developmentthe proportion of Hccs deficient cells is minimizeduntil birth. Very few isolated Hccs deficient cardiomyocytes canbe detected within the ventricular and atrial myocardium withonly the basal region of the interventricular septum showing alarger cluster of β-Gal positive cells (see arrow). RA = right atrium,LA = left atrium, RV = right ventricle, LV = left ventricle.44 Cardiovascular and Metabolic Disease Research