Caption: Microtubules (blue) in a beating heart muscle cell, or cardiomyocyte. Credit: Lab of Ben Prosser, Ph.D., Perelman School of Medicine, University of Pennsylvania
You might expect that scientists already know everything there is to know about how a healthy heart beats. But researchers have only recently had the tools to observe some of the dynamic inner workings of heart cells as they beat. Now an NIH-funded team has captured video to show that a component of a heart muscle cell called microtubules—long thought to be very rigid—serve an unexpected role as molecular shock absorbers.
As described for the first time recently in the journal Science, the microtubules buckle under the force of each contraction of the muscle cell before springing back to their original length and form. The team also details a biochemical process that allows a cell to fine-tune the level of resistance that the microtubules provide. The findings have important implications for understanding not only the mechanics of a healthy beating heart, but how the abnormal stiffening of heart cells might play a role in various forms of cardiac disease.
Credit: Jessica Ryvlin, Stephanie Lindsey, and Jonathan Butcher, Cornell University, Ithaca, NY
What might appear in this picture to be an exotic, green glow worm served up on a collard leaf actually comes from something we all know well: an egg. It’s a 3-day-old chicken embryo that’s been carefully removed from its shell, placed in a special nutrient-rich bath to keep it alive, and then photographed through a customized stereo microscope. In the middle of the image, just above the blood vessels branching upward, you can see the outline of a transparent, developing eye. Directly to the left is the embryonic heart, which at this early stage is just a looped tube not yet with valves or pumping chambers.
Developing chicks are one of the most user-friendly models for studying normal and abnormal heart development. Human and chick hearts have a lot in common structurally, with four chambers and four valves pumping two circulations of blood in parallel. Unlike mammalian embryos tucked away in the womb, researchers have free range to study the chick heart in or out of the egg as it develops from a simple looped tube to a four-chambered organ.
Jonathan Butcher and his NIH-supported research group at Cornell University, Ithaca, NY, snapped this photo, a winner in the Federation of American Societies for Experimental Biology’s 2015 BioArt competition, to monitor differences in blood flow through the developing chick heart. You can get a sense of these differences by the varying intensities of green fluorescence in the blood vessels. The Butcher lab is interested in understanding how the force of the blood flow triggers the switching on and off of genes responsible for making functional heart valves. Although the four valves aren’t yet visible in this image, they will soon elongate into flap-like structures that open and close to begin regulating the normal flow of blood through the heart.
Caption: A bioprinted coronary artery. Credit: Carnegie Mellon University
When the heart or another part of the body fails, a transplant is sometimes the only option. Still, the demand for donated organs far outpaces supply, with thousands of people on waiting lists. Furthermore, transplants currently require long term immunosuppression to prevent rejection. Wouldn’t it be even better to create the needed body part from the individual’s own cells? While it may sound too good to be true, research is moving us closer to the day when it may be possible to use 3D printing technology to meet some of this demand, as well as address a variety of other biomedical challenges.
In a study published in the journal Science Advances , an NIH-funded team from Carnegie Mellon University, Pittsburgh, recently modified an off-the-shelf 3D printer to create gel-like scaffolds that could be seeded with living cells to produce coronary arteries, an embryonic heart, and a variety of other tissues and organs.These researchers, of course, aren’t the only ones making progress in the rapidly emerging field of bioprinting. Using more costly, highly specialized 3D printing systems, other groups have crafted customized joints, bones, and splints out of hard, synthetic materials , as well as produced tissues and miniature organs by printing and layering sheets of human cells . What distinguishes the new approach is its more affordable printer; its open-source software; and, perhaps most importantly, its ability to print soft, biological scaffolds that set the stage for the creation of custom-made tissues and organs with unprecedented anatomical detail.
Caption: Heart microchamber generated from human iPS cells; cardiomyocytes (red), myofibroblasts (green), cell nuclei (blue) Credit: Zhen Ma, University of California, Berkeley
The adult human heart is about the size of a large fist, divided into four chambers that beat in precise harmony about 100,000 times a day to circulate blood throughout the body. That’s a very dynamic system, and also a very challenging one to study in real-time in the lab. Understanding how the heart forms within developing human embryos is another formidable challenge. So, you can see why researchers are excited by the creation of tiny, 3D heart chambers with the ability to exist (see image above) and even beat (see video below) in a lab dish, or as scientists say “in vitro.”
Credit: Zhen Ma et al., Nature Communications
To achieve this feat, an NIH-funded team from University of California, Berkeley, and Gladstone Institute of Cardiovascular Disease, San Francisco turned to human induced pluripotent stem (iPS) cell technology. The resulting heart chambers may be miniscule—measuring no more than a couple of hair-widths across—but they hold huge potential for everything from improving understanding of cardiac development to speeding drug toxicity screening.
Caption: Healthy zebrafish (top) compared to zebrafish with arrhythmia-causing mutation (bottom). Their hearts are shown to the right, with enlargement indicating a weaker heart. The heart’s outflow tract is marked OFT; atrium, a; and ventricle, v. Credit: Asimaki et al. Science Translational Medicine
Arrhythmia is a condition in which the heart loses its regular rhythm, beating either too rapidly or too slowly. Occasional irregular heartbeats are harmless, but if sustained they can cause dizziness, fainting, and even sudden death. There are a number of drugs available that can prevent arrhythmias, but none are perfect. Implanted devices can help—pacemakers can keep the heart from beating too slowly, and defibrillators can reset the heart’s rhythm with an electrical shock if a dangerously rapid rhythm develops.
But new treatments are needed. Now, an NIH-funded research team has created an animal model that is advancing efforts to find new drugs to prevent arrhythmia. Led by Jeffrey Saffitz at Beth Israel Deaconess Medical Center, Boston, researchers used genetic engineering techniques to produce zebrafish with genetic mutations identical to those in some people who suffer from a rare inherited disease called arrhythmogenic cardiomyopathy (ACM). In humans, ACM leads to dangerous arrhythmias that can cause sudden cardiac death, usually in people under the age of 35.