Pericyte Progenitor Coupling to the Emerging Endothelium During Vasculogenesis via Connexin 43.

Background: Vascular pericytes stabilize blood vessels and contribute to their maturation, while playing other key roles in microvascular function. Nevertheless, relatively little is known about involvement of their precursors in the earliest stages of vascular development, specifically during vasculogenesis.

Methods: We combined high-power, time-lapse imaging with transcriptional profiling of emerging pericytes and endothelial cells in reporter mouse and cell lines.

Induced cardiomyocyte maturation: Cardiac transcription factors are necessary but not sufficient.

The process by which fibroblasts are directly reprogrammed into cardiomyocytes involves two stages; initiation and maturation. Initiation represents the initial expression of factors that induce fibroblasts to transdifferentiate into cardiomyocytes. Following initiation, the cell undergoes a period of maturation before becoming a mature cardiomyocyte.

Cardiomyocyte Maturation Requires TLR3 Activated Nuclear Factor Kappa B.

The process by which committed precursors mature into cardiomyocytes is poorly understood. We found that TLR3 inhibition blocked cardiomyocyte maturation; precursor cells committed to the cardiomyocyte lineage failed to express maturation genes and sarcomeres did not develop. Using various approaches, we found that the effects of TLR3 upon cardiomyocyte maturation were dependent upon the RelA subunit of nuclear factor kappa B (NFκB).

Demethylation of H3K27 Is Essential for the Induction of Direct Cardiac Reprogramming by miR Combo.

Rationale: Direct reprogramming of cardiac fibroblasts to cardiomyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo using a combination of 4 microRNAs (miR-1, miR-133, miR-208, and miR-499) that we named miR combo. However, the mechanism of miR combo mediated direct cardiac reprogramming is currently unknown.

Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs.

We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. Reprogramming of cardiac fibroblasts by miR combo in vivo is associated with improved cardiac function following myocardial infarction. However, the efficiency of direct reprogramming in vitro is relatively modest and new strategies beyond the traditional two-dimensional (2D) culture should be identified to improve reprogramming process.

MicroRNAs and Cardiac Regeneration.

The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes.

Abi3bp regulates cardiac progenitor cell proliferation and differentiation.

Rationale: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as a protein important for mesenchymal stem cell biology. Because CPCs share several characteristics with mesenchymal stem cells, we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation.

Reprogramming approaches in cardiovascular regeneration.

Reconstitution of cardiac muscle as well as blood vessels to provide sufficient oxygenation and nutrients to the myocardium is an important component of any therapeutic approach for cardiac repair after injury. Recent reports of reprogramming somatic cells directly to cells of another lineage raised the possibility of using cell reprogramming for cardiac regenerative therapy. Here, we provide an overview of the current reprogramming strategies to generate cardiomyocytes (CMs), endothelial cells (ECs) and smooth muscle cells (SMCs), and the implications of these methods for cardiac regeneration.

FoxA transcription factors are essential for the development of dorsal axial structures.

In vertebrates, embryonic structures present at the dorsal midline, prechordal plate, notochord, hypochord and floor plate share a common embryonic origin. In zebrafish, they derive from a pool of progenitors located within the embryonic shield at the onset of gastrulation. The molecular mechanisms responsible for the common development of these structures remain unknown.

Noggin1 and Follistatin-like2 function redundantly to Chordin to antagonize BMP activity.

In Xenopus, the dorso-ventral (D/V) axis is thought to be specified by the bone morphogenetic proteins (Bmp) activity arising through interaction with antagonists such as Noggin, Chordin and Follistatin. We report here, through inactivation of noggin1 (nog1) that this gene is not essential by itself to establish the D/V patterning. However, at blastula stage, inactivation of nog1 strongly amplifies chordin (chd) phenotype, revealing redundant functions of these two genes on D/V axis formation.