Circulation Research Journal Club

For the Feb 17, 2012 Circulation Research Journal Club, we look at an article by Chen et al who show that given a choice of direction, vascular mesenchymal cells turn right and reveal an inherent asymmetry.

 Although animals might appear to be symmetrical on the outside, their innards reveal a striking left-right asymmetry in both the positioning of organs and the structure of the organs themselves. In the early embryo, the beating of cilia on the surface of certain cells sets up left-right asymmetry by washing molecules in one direction over neighboring cells. This model implies that cells themselves have an inherent left-right asymmetry, but the random orientation of cells in culture makes testing that theory rather difficult. Chen et al noticed that vascular mesenchymal cells (VMCs) form distinct patterns when grown on plates striped with adherent and nonadherent surfaces. Closer inspection revealed that as proliferating VMCs filled the adherent stripes and were forced to venture toward nonadherent stripes, they instinctively turned right, eventually leading to the observed patterns. This preference was dependent on intracellular stress fiber formation and was not unique to VMCs; 1 other cell type, ST2, showed a left turn preference, whereas 2 other cell types showed no preference. These findings could be important not only in studies of development but also in tissue engineering, say the team. [More] [Novelty & Significance]

Complete PDF: Left-Right Symmetry Breaking in Tissue Morphogenesis via Cytoskeletal Mechanics  [Online Data Supplement]

Journal Club Pack [Abstract, Novelty & Significance section, and all figures]

As suggested by the authors, the findings by Chen et al  “offer novel mechanisms of cellular self-organization and may guide cell-based therapy for tissue repair.” Some areas to consider when discussing this article include suggestions for alternate interpretations of the data or the novelty of the discoveries; the strengths/weaknesses of the methodology; the significance for the broader community of cardiovascular scientists; and the potential clinical or translational implications and directions/areas that need to be addressed in future studies.

Download the Journal Club Pack for offline discussion or start/join the discussion in the Comments section.

For the Feb 3 2012 Circulation Research Journal Club, we look at two related articles by Hanna et al & Hamers et al that both examine the role of the nuclear receptor Nur77 in atherosclerosis.

First, Hanna et al report that Nur77 prevents atherosclerotic lesion formation by discouraging monocytes from becoming pro-inflammatory macrophages. Nur77 belongs to a small family of orphan nuclear receptors. It is expressed in and drives the differentiation of a subset of monocytes called Ly6C^-. Although these cells can give rise to both classical pro-inflammatory (M1) macrophages, and alternative anti-inflammatory (M2) cells, they tend to favor the latter. Mice lacking Nur77 also lack Ly6C^- cells, leaving Hanna et al to wonder how this monocyte imbalance might affect the outcome of inflammatory disorders. Because Nur77 is known to be expressed in atherosclerotic lesions, they focused their study specifically on atherosclerosis. In two different mouse models of the disease, they found that the absence of Nur77 exacerbated symptoms—the size, macrophage content, and lipid content of plaques. Consistent with these results, macrophages in Nur77-lacking mice were preferentially pro-inflammatory, expressing inflammatory factors such as TNF-a and nitric oxide. The authors also found that a newly-identified subset of human monocytes thought to be equivalent to Ly6C^- cells expressed Nur77 as well. Together these findings suggest that boosting Nur77 in humans might be an effective means to suppress atherosclerosis. [More]

Then, Hamers et al find that Nur77 dampens the fire of atherosclerosis. In an independent research study, a group from the Netherlands also investigated the effect of Nur77 deletion on inflammation. Their focus, however, was more specifically centered on the question of macrophage phenotype. They found that in addition to an increase in inflammatory factors such as nitric oxide, cells lacking Nur77 had increased expression of the chemokine stromal cell–derived factor 1a (SDF1a). In vitro, SDF1a promoted macrophage migration, while in vivo, Nur77^-/- mice exhibited increased inflammatory cell migration towards a site of irritation when compared with wild-type mice. The team also found that in a mouse model of atherosclerois, animals transplanted with Nur77^-/- bone marrow cells had larger lesions containing a greater number of macrophages, T cells, and smooth muscle cells than those given wild-type bone marrow cells. Plaques in the animals with Nur77^-/- bone marrow cells also had high levels of SDF1a expression. The team concluded that deletion of Nur77, by increasing in SDF1a, attracted inflammatory cells to plaques. Thus both Nur77 and SDF1a may be good targets for atherosclerosis therapies. [More]

 Hanna et al [Complete PDF]: NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis  [Online Data Supplement]
Journal Club Pack [Abstract, Novelty & Significance section, and all figures]

Hamers et al [Complete PDF]: Bone Marrow–Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis  [Online Data Supplement]
Journal Club Pack [Abstract, Novelty & Significance section, and all figures]

Editorial on both by Lefebvre, Chinetti, & Staels [PDF]: Nur77turing Macrophages in Atherosclerosis

As discussed in the editorial, these articles suggest a number of exciting possibilities in the field of atherosclerosis research. Some areas to consider when discussing these articles include suggestions for alternate interpretations of the data or the novelty of the discoveries; the strengths/weaknesses of the methodologies; the significance for the broader community of cardiovascular scientists; and the potential clinical or translational implications and directions/areas that need to be addressed in future studies.

Download the Journal Club Packs for offline discussion or start/join the discussion in the Comments section.

Want to comment on or discuss an article from the January 20th issue that wasn’t selected for Journal Club? Then head to the Comments section of this Open Thread post.

Circulation Research January 20, 2012

For the Jan 20 2012 Circulation Research Journal Club, we look at an article by Yin et al who suggest that using induced vascular progenitor cells rather than other stem cells could be a better strategy for fixing damaged hearts.

A variety of stem and progenitor cell types have been suggested, and assessed, for their potential to repair damaged heart tissue, but it is not clear which cells will ultimately yield the most successful clinical outcomes. Part of the problem, suggest Yin and colleagues, is that replacing all the damaged tissues—muscle, connective tissue, blood vessels—is a tall order for any cell. The team, therefore, investigated whether replacing blood vessels alone would be enough to improve heart function. They created induced vascular progenitor cells (iVPCs), which differentiated only into vessel cell types—smooth muscle and endothelial cells. When injected into rat hearts, these iVPCs integrated into coronary vessels, improved vessel growth and blood flow, and led to better cardiac function. The iVPCs were derived from fully differentiated endothelial cells by a similar protocol to that used for making induced pluripotent stem cells (iPSCs). Unlike iPSCs or other pluripotent stem cells, however, iVPCs had a considerably lower likelihood of forming tumors in rats. Reprogramming cells to a partially differentiated state rather than full pluripotency may be an effective strategy for replacing specific tissues while avoiding the risk of tumors, say the authors. [More] [Novelty & Significance]

Complete PDF: Induction of Vascular Progenitor Cells From Endothelial Cells Stimulates Coronary Collateral Growth [Online Data Supplement]

Journal Club Pack [Abstract, Novelty & Significance section, and all figures]

Editorial by James Faber [PDF]: Reprogrammed Endothelial Cells: Cell Therapy for Coronary Collateral Growth?

As discussed in the editorial, this “study by Yin et al offers a new approach in regenerative therapy—partial reprogramming of endothelial cells ‘back’ to a progenitor cell that remains committed to the vascular lineage.” Some areas to consider when discussing this article include suggestions for alternate interpretations of the data or the novelty of the discoveries; the strengths/weaknesses of the methodology; the significance for the broader community of cardiovascular scientists; and the potential clinical or translational implications and directions/areas that need to be addressed in future studies.

Download the Journal Club Pack for offline discussion or start/join the discussion in the Comments section.

Want to comment on or discuss an article from the January 6th issue that wasn’t selected for Journal Club? Then head to the Comments section of this Open Thread post.

Circulation Research January 6, 2012

For the Jan 6 2012 Circulation Research Journal Club, we look at an article by Kara et al exploring how placentas could be a source of heart-repairing cells through fetal cell microchimerism.

Pregnant women with cardiomyopathy are known to have a higher recovery rate than other individuals with the disease. It is also known that during pregnancy, fetal cells can pass to the mother and incorporate into her tissues, sometimes remaining there for years. Kara et al suspected that fetal cells might be contributing to the repair process in mothers with cardiomyopathy. To test this, they induced myocardial infarction in pregnant mice and studied what the fetal cells were doing. They discovered that these cells homed to the injured heart, and once there, they differentiated into cardiomyocytes, smooth muscle cells, and endothelial cells. In fact, the fetal cells could form entirely new blood vessels. Approximately 40% of the fetal cells in the mothers’ hearts expressed a transcription factor, called Cdx2, which is a marker of trophoblast stem cells—the cells that give rise to the placenta during embryogenesis. Until now, trophoblast stem cells had been thought only to contribute to the formation of the placenta. Thus, the new work suggests that placentas, which are routinely discarded in hospital maternity wards, could be a valuable source of multipotent stem cells. [Novelty & Significance section]

Complete PDF: Fetal Cells Traffic to Injured Maternal Myocardium and Undergo Cardiac Differentiation

Journal Club Pack [Abstract, Novelty & Significance section, and all figures]

Editorial by Pritchard & Bianchi [PDF]: Fetal Cell Microchimerism in the Maternal Heart: Baby Gives Back

The article by Kara et al contributes toward to the increasing number of studies exploring fetal cell microchimerism. This is an intriguing area of research and this article and others have generated a lot of discussion online (you can find some here & here).

Some areas to consider when discussing this article include suggestions for alternate interpretations of the data or the novelty of the discoveries; the strengths/weaknesses of the methodology; the significance for the broader community of cardiovascular scientists; and the potential clinical or translational implications and directions/areas that need to be addressed in future studies.

Download the Journal Club Pack for offline discussion or start/join the discussion in the Comments section.