HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals.

Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes.

Desmin enters the nucleus of cardiac stem cells and modulates Nkx2.5 expression by participating in transcription factor complexes that interact with the nkx2.5 gene.

The transcription factor Nkx2.5 and the intermediate filament protein desmin are simultaneously expressed in cardiac progenitor cells during commitment of primitive mesoderm to the cardiomyogenic lineage. Up-regulation of Nkx2.

VUT-MK142 : a new cardiomyogenic small molecule promoting the differentiation of pre-cardiac mesoderm into cardiomyocytes.

Intra-cardiac cell transplantation is a new therapy after myocardial infarction. Its success, however, is impeded by the limited capacity of donor cells to differentiate into functional cardiomyocytes in the heart. A strategy to overcome this problem is the induction of cardiomyogenic function in cells prior to transplantation.

Small molecule cardiogenol C upregulates cardiac markers and induces cardiac functional properties in lineage-committed progenitor cells.

Background/aims: Cell transplantation into the heart is a new therapy after myocardial infarction. Its success, however, is impeded by poor donor cell survival and by limited transdifferentiation of the transplanted cells into functional cardiomyocytes. A promising strategy to overcome these problems is the induction of cardiomyogenic properties in donor cells by small molecules.

Reconsidering pluripotency tests: do we still need teratoma assays?

The induction of teratoma in mice by the transplantation of stem cells into extra-uterine sites has been used as a read-out for cellular pluripotency since the initial description of this phenomenon in 1954. Since then, the teratoma assay has remained the assay of choice to demonstrate pluripotency, gaining prominence during the recent hype surrounding human stem cell research. However, the scientific significance of the teratoma assay has been debated due to the fact that transplanted cells are exposed to a non-physiological environment.

Embryonic stem cells facilitate the isolation of persistent clonal cardiovascular progenitor cell lines and leukemia inhibitor factor maintains their self-renewal and myocardial differentiation potential in vitro.

Compelling evidence for the existence of somatic stem cells in the heart of different mammalian species has been provided by numerous groups; however, so far it has not been possible to maintain these cells as self-renewing and phenotypically stable clonal cell lines in vitro. Thus, we sought to identify a surrogate stem cell niche for the isolation and persistent maintenance of stable clonal cardiovascular progenitor cell lines, enabling us to study the mechanism of self-renewal and differentiation in these cells. Using postnatal murine hearts with a selectable marker as the stem cell source and embryonic stem cells and leukemia inhibitory factor (LIF)-secreting fibroblasts as a surrogate niche, we succeeded in the isolation of stable clonal cardiovascular progenitor cell lines.

Mechanisms of cardiogenesis in cardiovascular progenitor cells.

Self-renewing cells of the vertebrate heart have become a major subject of interest in the past decade. However, many researchers had a hard time to argue against the orthodox textbook view that defines the heart as a postmitotic organ. Once the scientific community agreed on the existence of self-renewing cells in the vertebrate heart, their origin was again put on trial when transdifferentiation, dedifferentiation, and reprogramming could no longer be excluded as potential sources of self-renewal in the adult organ.

Self-organization phenomena in embryonic stem cell-derived embryoid bodies: axis formation and breaking of symmetry during cardiomyogenesis.

Aggregation of embryonic stem cells gives rise to embryoid bodies (EBs) which undergo developmental processes reminiscent of early eutherian embryonic development. Development of the three germ layers suggests that gastrulation takes place. In vivo, gastrulation is a highly ordered process but in EBs only few data support the hypothesis that self-organization of differentiating cells leads to morphology, reminiscent of the early gastrula.

Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans.

Histone deacetylase (HDAC) inhibitors induce cell cycle arrest, differentiation or apoptosis in tumour cells and are, therefore, promising anti-cancer reagents. However, the specific HDAC isoforms that mediate these effects are not yet identified. To explore the role of HDAC1 in tumourigenesis and tumour proliferation, we established an experimental teratoma model using wild-type and HDAC1-deficient embryonic stem cells.

The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation.

Histone deacetylases (HDACs) are chromatin-modifying enzymes that are involved in the regulation of proliferation, differentiation and development. HDAC inhibitors induce cell cycle arrest, differentiation, or apoptosis in tumor cells and are therefore promising antitumor agents. Numerous genes were found to be deregulated upon HDAC inhibitor treatment; however, the relevant target enzymes are still unidentified.

Desmin stimulates differentiation of cardiomyocytes and up-regulation of brachyury and nkx2.5.

Desmin contributes to structural integrity and function of the myocardium but its function seems to be redundant in early cardiomyogenesis in the desmin null mouse model. To test the hypothesis that desmin also plays a supportive role in cardiomyogenic commitment and early differentiation of cardiomyocytes we investigated cardiomyogenesis in embryoid bodies expressing different desmin alleles. Constitutive expression of desmin and increased synthesis during mesoderm formation led to the up-regulation of brachyury and nkx2.

Differentiation of cardiomyocytes requires functional serine residues within the amino-terminal domain of desmin.

Desmin contributes to the stability of the myocardium and its amino-terminal domain influences intermediate filament formation and interacts with a variety of proteins and DNAs. Specific serine residues located in this domain are reversibly phosphorylated in a cell cycle and developmental stage-dependent manner as has been demonstrated also for other cytoplasmic type III intermediate filament proteins. Although absence of desmin apparently does not affect cardiomyogenesis, homozygous deletion of the amino-terminal domain of desmin severely inhibited in vitro cardiomyogenesis.

Parietal endoderm secreted S100A4 promotes early cardiomyogenesis in embryoid bodies.

Cardiomyogenesis is influenced by factors secreted by anterior-lateral and extra-embryonic endoderm. Differentiation of embryonic stem cells in embryoid bodies allows to study the influence of growth factors on cardiomyogenesis. By these means SPARC was identified as a new factor enhancing cardiomyogenesis [M.

Parietal endoderm secreted SPARC promotes early cardiomyogenesis in vitro.

Cardiomyogenesis proceeds in the presence of signals emanating from extra-embryonic lineages emerging before and during early eutherian gastrulation. In embryonic stem cell derived embryoid bodies, primitive endoderm gives rise to visceral and parietal endoderm. Parietal endoderm undergoes an epithelial to mesenchymal transition shortly before first cardiomyocytes start to contract rhythmically.

Single inner cell masses yield embryonic stem cell lines differing in lifr expression and their developmental potential.

The unique differentiation potential of inner cell mass derived embryonic stem cells together with their outstanding self-renewal capacity makes them a desirable source for somatic cell therapy of human diseases. Somatic cells are gained by in vitro differentiation of embryonic stem cells, however, the differentiation potential of embryonic stem cells varied even between isogenic cell lines. Variable differentiation potentials may either be a consequence of an inherent inhomogeneity of gene expression in the inner cell mass or may have technical reasons.

Amino-terminally truncated desmin rescues fusion of des(-/-) myoblasts but negatively affects cardiomyogenesis and smooth muscle development.

Desmin fulfils important functions in maintenance of muscle cells and mutations in the desmin gene have been linked to a variety of myopathies. To ascertain the role of desmin's amino-terminal domain in muscle cells we generated embryonic stem cells constitutively expressing desmin(Delta1-48) in a null background and investigated muscle cell development in vitro. Desmin(Delta1-48) lacking the first 48 amino acid residues promotes fusion of myoblasts, rescues myogenesis and down-regulates vimentin expression in embryoid bodies, but hampers cardiomyogenesis and blocks smooth muscle development.

Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression.

Histone deacetylases (HDACs) modulate chromatin structure and transcription, but little is known about their function in mammalian development. HDAC1 was implicated previously in the repression of genes required for cell proliferation and differentiation. Here we show that targeted disruption of both HDAC1 alleles results in embryonic lethality before E10.