How MRSA infection compromises lymphatic function

Infections of the skin or other soft tissues with the hard-to-treat MRSA (methicillin-resistant Staphylococcus aureus) bacteria appear to permanently compromise the lymphatic system, which is crucial to immune system function. Massachusetts General Hospital (MGH) investigators describe finding that MRSA infection impairs the ability of lymphatic vessels to pump lymphatic fluid to lymph nodes in mouse models, which may contribute to the frequent recurrences of MRSA infection experienced by patients.

 MRSA produces toxins that kill the muscle cells critical to the pumping of lymph, MRSA with a genetic deficiency that lowers the amount of toxin produced does not kill lymphatic muscle cells, which both supports the role for bacterial toxins in the post-MRSA impairment of lymphatic function and may also suggest a possible treatment strategy. Patients with lymphedema - swelling and fluid buildup caused by damage to or blockage of the lymphatic system - are particularly prone to recurrent infections, which can exacerbate existing lymphedema.

In contrast to the cardiovascular system, in which blood is propelled through arteries and veins by the pumping of the heart, in the lymphatic system, lymphatic fluid - which carries immune cells and other important factors - is pumped along by the contraction of the lymphatic vessels , driven by lymphatic muscle cells. Experiments in mouse models of MRSA tissue infections - conducted by team members including lead author Dennis Jones, PhD - revealed that the infection itself cleared within 30 days and associated inflammation was gone within 60 days.

 The lymphatic vessels in MRSA-infected tissues showed abnormalities - including increased vessel diameter and weaker, less frequent contractions - that were still present 120 days after the induction of infection. Close examination revealed that the number of lymphatic muscle cells surrounding lymphatic vessels was depleted as late as 260 days after infection. Lymph pumping was restored after the resolution of sterile inflammation, MRSA-induced impairment persisted long after the infection was resolved and the inflammation had stopped. This persistence long after bacteria have been cleared can be explained by the loss of lymphatic muscle cells.

Exposure of cultured mouse and human lymphatic or smooth muscle cells to the proteins produced by MRSA led to the death of these cells, and detailed analysis of MRSA-produced proteins identified a significant number of known pathogenic toxins. Since expression of many MRSA toxins is controlled by a genetic element called the accessory gene regulator (agr), the team tested a mutant form of MRSA lacking the agr against several types of cultured cells and in their animal model.

The agr-mutant MRSA did not produce the muscle-cell-killing proteins, and lymphatic function - including the strength and frequency of vessel contraction - was significantly better in mice infected with the mutant strain than in animals infected with a non-mutated strain. Targeting the action of the agr during and after MRSA infection may preserve lymphatic muscle cells and, as a result, lymphatic function.
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Reversing damaged heart tissue

It is possible to change fibroblasts -scar tissue cells into cardiomyocytes -heart muscle cells. Researchers used single cell RNA sequencing technology in combination with mathematical modeling and genetic and chemical approaches to delineate the step-by-step molecular changes that occur during cell fate conversion from fibroblast to cardiomyocyte. They reconstructed the routes a single cell could take in this process but also identified underlying molecular pathways and key regulators important for the transformation from one cell type to another.

Embryonic stem cells throughout human body gradually changes into a variety of highly specialized cell types, such as neurons, blood cells, and heart muscle cells. New discovery showed that it is possible to revert terminally differentiated somatic cells to a pluripotent state- cell that can self-produce and potentially turn into any kind of cell in the body. Researchers have also figured out how to convert one kind of differentiated somatic cell type into another without detouring through the pluripotent stage or the original progenitor stage. Such findings shifted the paradigm of cellular hierarchy and revolutionized stem cell research and the field of regenerative medicine.


Direct cardiac reprogramming, a promising approach for cardiac regeneration and disease modeling that direct conversion of cardiac non-myocytes into induced cardiomyocytes (iCMs) that closely resemble endogenous CMs. Like any reprogramming process, the many cells that are being reprogrammed don't do so at the same time.

Cellular reprogramming is heterogeneous, which makes it difficult to study using traditional approaches.
Using microfluidic single-cell RNA sequencing techniques, addressed the two main issues of 'asynchronous' programming and heterogeneous cell populations. They analyzed global transcriptome changes during fate conversion from fibroblasts to iCMs.
Using mathematical algorithms, they identified molecularly distinct subpopulations of cells along the reprogramming pipeline.

After a heart attack, cardiac fibroblasts around the injured area are immediately activated and become highly proliferative but this proliferative capacity decreases over time. How to take advantage of the varied cell cycle status of fibroblasts over the progression of a heart attack and its aftermath would certainly broaden the application of cellular reprogramming for patients and optimize outcomes. The molecular features of subpopulations of fibroblasts were differentially suppressed during reprogramming, suggesting that the susceptibility of cells to be reprogrammed varies.

This susceptibility coincides with the timing of cardiomyocyte differentiation during heart development. The signatures in the intermediate populations that seem to appear earlier in heart development were more resistant to the alterations. This suggests that the recent epigenetic memories of cells might be more easily erased, and so the fibroblast subpopulations with such epigenetic features are more easily converted into cardiomyocytes. Adjusting epigenetic memories not just changing their current epigenetic status could be crucial for changing a cell fate for therapeutic value.
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Potassium regulates calcification of arteries

Foods rich in potassium like banana and avocado may protect against pathogenic vascular calcification.
Reduced dietary potassium promotes elevated aortic stiffness in a mouse model, as compared with normal-potassium-fed mice.

Arterial stiffness in humans is predictive of heart disease and death from heart disease, increased dietary potassium levels lessened vascular calcification and aortic stiffness. The different levels of dietary potassium were monitored by different blood levels of potassium in the three groups of mice.

When researchers looked at arterial cross-sections in cultures that were exposed to three different concentrations of potassium, based on normal physiological levels of potassium in the blood, they found a direct effect for the potassium on arterial calcification within arterial rings.

Arterial rings in low-potassium had markedly enhanced calcification, while high-potassium inhibited aortic calcification. In cell culture, low potassium levels in the culture media markedly enhanced calcification of vascular smooth muscle cells.

They discovered that the low-potassium conditions promoted the expression of several gene markers that are hallmarks of bone cells, but decreased the expression of vascular smooth muscle cell markers, suggesting the transformation of the vascular smooth muscle cells into bone-like cells under low-potassium conditions. They found that low-potassium increased intracellular calcium in the vascular smooth muscle cells, through a potassium transport channel called the inward rectifier potassium channel.
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How to turn scar tissue into healthy tissue

Limited therapeutic options and the heart's inability to regenerate healthy cells after heart attacks are parts of factors that cause sudden death in heart attack patients. Scientists are exploring ways to reprogram scar tissue cells into healthy heart muscle cells to reduce death.

Creation of cardiomyocytes with genetic signatures that closely mimic those found in healthy adult heart muscle cells can solve the problem. The other reprogramming approach leads to the creation of cardiomyocytes with more embryonic cell signatures.

The differences in the cardiomyocytes generated using these two methods are
Cardiomyocytes, the cells responsible for the beating of the heart, are essential to repairing the heart after injury. But after injury, such as a heart attack, many of these cells are irreversibly lost; they've been turned into scar tissue cells.

The replacement of these lost cells with patient-specific cardiomyocytes has gained attention as a potential therapy because existing healthy heart tissue better accepts these cells and because of increased recovery rates. Patient-specific cardiomyocytes also offer unique advantages for drug screens to help doctors identify each patient's drug type and dosage.

There are presently two widely practiced approaches to generate patient-specific cardiomyocytes.
In the first approach, an adult connective cell called a fibroblast is reprogrammed back into a naïve embryonic stem cell-like state. Once in this naïve state, the cell has the potential to develop into any cell type in the body, but scientists direct it to develop into a cardiomyocyte. These newly created cardiomyocytes are called induced pluripotent stem cell cardiomyocytes iPSC-CM.

In the second approach called direct cardiac reprogramming, a fibroblast is directly converted into a cardiomyocyte, without having to first be reprogrammed into a naïve embryonic stem cell. These new cardiomyocytes are called induced cardiomyocytes iCM. The researchers found that both methods resulted in cells with classic cardiomyocyte molecular features. However, by comparing the unique set of genes activated or not activated in each group of cells, the researchers found that iPSC-CMs more closely resembled embryonic cardiomyocytes, while iCMs more closely resembled adult cardiomyocytes.

Researchers also found that iPSC-CMs feature more active genes and a higher number of genes poised to be either activated or repressed a trait more commonly found in potent cells.
Metabolically, iPSC-CMs had a higher expression of glycolytic genes while iCMs had a higher expression of genes involved in fatty acid oxidation, the primary means of energy production in adult hearts.

In iPSC-CMs, heart muscle cells called sarcomeres, which give the heart a striated look, were less organized than in iCMs. The contractibility of cardiomyocytes as measured by the intake and removal of calcium was also greater in iCMs, suggesting that iCM cells are more mature than iPSC-CM cells.
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How to fight inflammation with exercise

Inflammation is the body's way of healing itself after an injury and protecting itself from infection; but chronic inflammation is associated with different kinds of diseases.

During exercise like running, jumping, jogging, swimming and walking muscle cells release a small protein known as Interleukin 6, IL-6, which fights an inflammation. Any forms of exercise that you can think of will produce the same Interleukin 6. It has several anti-inflammatory effects; it lowers levels of a protein called TNF alpha, which triggers inflammation in the body.

It prevents the effects of a protein known as interleukin 1 beta, which triggers inflammation that can damage the cells in the pancreas. The quantity of IL-6 release by muscles is determined by quality of time spent during exercise, the longer you engage in exercise, the more IL-6 will be released into your body.

Regular exercise induces a strong anti-inflammatory effect on the body and it prevents an inflammation. It also increases levels of protein, known as Interleukin-15 (IL-15), in muscle cells. IL-15 regulates the accumulation of abdominal fat, with higher levels of IL-15 providing protection against abdominal fat buildup.

Regular exercise should be used as part of the treatment for chronic inflammatory diseases. Exercise serves as natural, anti-inflammatory and metabolism-improving 'drug'. It can be useful for treating type 2 diabetes and cardiovascular disease.
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