Cardiometabolic Disease: Big Data Tackles a Big Health Problem

Cardiometabolic risk lociMore and more studies are popping up that demonstrate the power of Big Data analyses to get at the underlying molecular pathology of some of our most common diseases. A great example, which may have flown a bit under the radar during the summer holidays, involves cardiometabolic disease. It’s an umbrella term for common vascular and metabolic conditions, including hypertension, impaired glucose and lipid metabolism, excess belly fat, and inflammation. All of these components of cardiometabolic disease can increase a person’s risk for a heart attack or stroke.

In the study, an international research team tapped into the power of genomic data to develop clearer pictures of the complex biocircuitry in seven types of vascular and metabolic tissue known to be affected by cardiometabolic disease: the liver, the heart’s aortic root, visceral abdominal fat, subcutaneous fat, internal mammary artery, skeletal muscle, and blood. The researchers found that while some circuits might regulate the level of gene expression in just one tissue, that’s often not the case. In fact, the researchers’ computational models show that such genetic circuitry can be organized into super networks that work together to influence how multiple tissues carry out fundamental life processes, such as metabolizing glucose or regulating lipid levels. When these networks are perturbed, perhaps by things like inherited variants that affect gene expression, or environmental influences such as a high-carb diet, sedentary lifestyle, the aging process, or infectious disease, the researchers’ modeling work suggests that multiple tissues can be affected, resulting in chronic, systemic disorders including cardiometabolic disease.

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Snapshots of Life: The Hard Working Hepatocyte

Human hepatocyte

Caption: Magnified image of a hepatocyte: nuclei in blue; actin fibers in red, yellow, orange, and green.
Credit: Donna Beer Stolz, University of Pittsburgh

The humble hepatocyte handles a lot of the body’s maintenance and clean up work. It detoxifies the blood, metabolizing medications and alcohol. It secretes important proteins that regulate carbohydrates and fats—including both the good and bad kinds of cholesterol. It’s also the most common cell in one of the few human organs that regenerate: the liver. When this organ is damaged, hepatocytes begin dividing to repair the tissue.

Its regenerative ability is just one reason that Donna Beer Stolz, a microscopist and cell biologist at the University of Pittsburgh, in Pennsylvania, has been studying the hepatocyte for more than 20 years. She captured this image while conducting one of her experiments. As she was carefully scanning a dish of cells, one particular hepatocyte caught her eye. It was perfectly round. Struck by its symmetry and beauty, Stolz snapped pictures of the cell at different layers and then used software to reconstruct and color the image.

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iMPCs: Cell Reprogrammers Take Aim at Liver Disease

Cross-section of mouse liver

Caption: Cross-section of mouse liver containing iMPC-derived human liver cells (red), some of which are proliferating (green). All cell nuclei appear blue.
Credit: Milad Rezvani, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco

Over the past few years, researchers have learned how to reprogram skin or blood cells into induced pluripotent stem cells (iPSCs), which have the ability to differentiate into heart, nerve, muscle, and many other kinds of cells. But it’s proven a lot more tricky to coax iPSCs (as well as human embryonic stem cells) to differentiate into mature, fully functional liver cells.

Now, NIH-funded researchers at the University of California, San Francisco (UCSF) and the Gladstone Institutes appear to have overcome this problem. They have developed a protocol that transforms human skin cells into mature liver cells that not only function normally in a lab dish, but proliferate after they’ve been transplanted into mice that model human liver failure [1]. This ability to proliferate is a hallmark of normal liver cells—and the secret to the liver’s astounding capacity to regenerate after infection or injury.

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Put This Liver To The Test

A photo of a petri dish holding a piece of tissue.

Artificial Liver
Source: NIBIB, NIH

Growth of blood vessels (red) enables implanted human ectopic artificial livers (HEALs) to grow and function in the mouse. This miniature human liver was removed from a HEAL-humanized mouse. Mice implanted with these organs are particularly useful for monitoring drug metabolism, drug-drug interactions, and predicting how certain drugs can damage and destroy the human liver.