A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes.

Hypoxic metabolism in human hematopoietic stem cells.

Background: Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment, known as niche in the endosteal regions of the bone marrow. This stem cell niche with low oxygen tension requires HSCs to adopt a unique metabolic profile. We have recently demonstrated that mouse long-term hematopoietic stem cells (LT-HSCs) utilize glycolysis instead of mitochondrial oxidative phosphorylation as their main energy source.

Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart.

Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function.

Redox signaling in cardiac renewal.

Significance: Utilizing oxygen (O2) through mitochondrial oxidative phosphorylation enables organisms to generate adenosine triphosphate (ATP) with a higher efficiency than glycolysis, but it results in increased reactive oxygen species production from mitochondria, which can result in stem cell dysfunction and senescence.

Recent Advances: In the postnatal organism, the hematopoietic system represents a classic example of the role of stem cells in cellular turnover and regeneration. However, in other organs such as the heart, both the degree and source of cellular turnover have been heavily contested.

The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.

The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes.

Meis1 regulates postnatal cardiomyocyte cell cycle arrest.

The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown.

Harnessing the power of dividing cardiomyocytes.

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Recently, our group demonstrated that neonatal mammalian hearts have a remarkable regenerative potential in the first few days after birth. Although adult mammals lack this regenerative potential, it is now clear that there is measurable cardiomyocyte turnover that occurs in the adult mammalian heart.

Histone deacetylase 9 activates gamma-globin gene expression in primary erythroid cells.

Strategies to induce fetal hemoglobin (HbF) synthesis for the treatment of β-hemoglobinopathies probably involve protein modifications by histone deacetylases (HDACs) that mediate γ-globin gene regulation. However, the role of individual HDACs in globin gene expression is not very well understood; thus, the focus of our study was to identify HDACs involved in γ-globin activation. K562 erythroleukemia cells treated with the HbF inducers hemin, trichostatin A, and sodium butyrate had significantly reduced mRNA levels of HDAC9 and its splice variant histone deacetylase-related protein.

High-density SNP genotyping to define beta-globin locus haplotypes.

Five major beta-globin locus haplotypes have been established in individuals with sickle cell disease (SCD) from the Benin, Bantu, Senegal, Cameroon, and Arab-Indian populations. Historically, beta-haplotypes were established using restriction fragment length polymorphism (RFLP) analysis across the beta-locus, which consists of five functional beta-like globin genes located on chromosome 11. Previous attempts to correlate these haplotypes as robust predictors of clinical phenotypes observed in SCD have not been successful.