Snapshots of Life: Tales from the (Intestinal) Crypt!

Caption: This “spooky” video ends with a scientific image of intestinal crypts (blue and green) plus organoids made from cultured crypt stem cells (pink). 

As Halloween approaches, some of you might be thinking about cueing up the old TV series “Tales from the Crypt” and diving into its Vault of Horror for a few hours. But today I’d like to share the story of a quite different and not nearly so scary kind of crypt: the crypts of Lieberkühn, more commonly called intestinal crypts.

This confocal micrograph depicts a row of such crypts (marked in blue and green) lining a mouse colon. In mice, as well as in humans, the intestines contain millions of crypts, each of which has about a half-dozen stem cells at its base that are capable of regenerating the various types of tissues that make up these tiny glands. What makes my tale of the crypt particularly interesting are the oval structures (pink), which are organoids that have been engineered from cultured crypt stem cells and then transplanted into a mouse model. If you look at the organoids closely, you’ll see Paneth cells (aqua blue), which are immune cells that support the stem cells and protect the intestines from bacterial invasion.

A winner in the 2016 “Image Awards” at the Koch Institute Public Galleries, Massachusetts Institute of Technology (MIT), Cambridge, this image was snapped by Jatin Roper, a physician-scientist in the lab of Omer Yilmaz, with the help of his MIT collaborator Tuomas Tammela. Roper and his colleagues have been making crypt organoids for a few years by placing the stem cells in a special 3D chamber, where they are bathed with the right protein growth factors at the right time to spur them to differentiate into the various types of cells found in a crypt.

Once the organoids are developmentally complete, Roper can inject them into mice and watch them take up residence. Then he can begin planning experiments.

For example, Roper’s group is now considering using the organoids to examine how high-fat and low-calorie diets affect intestinal function in mice. Another possibility is to use similar organoids to monitor the effect of aging on the colon or to test which of a wide array of targeted therapies might work best for a particular individual with colon cancer.

Links:

Video: Gut Reaction (Jatin Roper)

Jatin Roper (Tufts Medical Center, Boston)

Omer Yilmaz (Massachusetts Institute of Technology, Cambridge)

The Koch Institute Galleries (MIT)

NIH Support: National Cancer Institute; National Institute on Aging

Cool Videos: Regenerating Nerve Fibers

If you enjoy action movies, you can probably think of a superhero—maybe Wolverine?—who can lose a limb in battle, yet grow it right back and keep on going. But could regenerating a lost limb ever happen in real life? Some scientists are working hard to understand how other organisms do this.

As shown in this video of a regenerating fish fin, biology can sometimes be stranger than fiction. The zebrafish (Danio rerio), which is a species of tropical freshwater fish that’s an increasingly popular model organism for biological research, is among the few vertebrates that can regrow body parts after they’ve been badly damaged or even lost. Using time-lapse photography over a period of about 12 hours, NIH grantee Sandra Rieger, now at MDI Biological Laboratory, Bar Harbor, ME, used a fluorescent marker (green) to track a nerve fiber spreading through the skin of a zebrafish tail fin (gray). The nerve regeneration was occurring in tissue being spontaneously formed to replace a section of a young zebrafish’s tail fin that had been lopped off 3 days earlier.

Along with other tools, Rieger is using such imaging to explore how the processes of nerve regeneration and wound healing are coordinated. The researcher started out by using a laser to sever nerves in a zebrafish’s original tail fin, assuming that the nerves would regenerate—but they did not! So, she went back to the drawing board and discovered that if she also used the laser to damage some skin cells in the tail fin, the nerves regenerated. Rieger suspects the answer to the differing outcomes lies in the fact that the fish’s damaged skin cells release hydrogen peroxide, which may serve as a critical prompt for the regenerative process [1]. Rieger and colleagues went on discover that the opposite is also true: when they used a cancer chemotherapy drug to damage skin cells in a zebrafish tail fin, it contributed to the degeneration of the fin’s nerve fibers [2].

Based on these findings, Rieger wants to see whether similar processes may be going on in the hands and feet of cancer patients who struggle with painful nerve damage, called peripheral neuropathy, caused by certain chemotherapy drugs, including taxanes and platinum compounds. For some people, the pain and tingling can be so severe that doctors must postpone or even halt cancer treatment. Rieger is currently working with a collaborator to see if two protective molecules found in the zebrafish might be used to reduce or prevent chemotherapy-induced peripheral neuropathy in humans.

In recent years, a great deal of regenerative medicine has focused on learning to use stem cell technologies to make different kinds of replacement tissue. Still, as Rieger’s work demonstrates, there remains much to be gained from studying model organisms, such as the zebrafish and axolotl salamander, that possess the natural ability to regenerate limbs, tissues, and even internal organs. Now, that’s a super power we’d all like to have.

Reference:

[1] Hydrogen peroxide promotes injury-induced peripheral sensory axon regeneration in the zebrafish skin. Rieger S, Sagasti A. PLoS Biol. 2011 May;9(5):e1000621

[2] Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Lisse TS, Middleton LJ, Pellegrini AD, Martin PB, Spaulding EL, Lopes O, Brochu EA, Carter EV, Waldron A, Rieger S. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):E2189-E2198.

Links:

Chemotherapy-Induced Peripheral Neuropathy (National Cancer Institute/NIH)

Learning About Human Biology From a Fish (National Institute of General Medical Sciences/NIH)

Sandra Rieger (MDI Biological Laboratory, Bar Harbor, ME)

NIH Support: National Institute of Dental and Craniofacial Research; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke

Cool Videos: Fireworks under a Microscope

This Fourth of July, many of you will spread out a blanket and enjoy an evening display of fireworks with their dramatic, colorful bursts. But here’s one pyrotechnic pattern that you’ve probably never seen. In this real-time video, researchers set off some fluorescent fireworks under their microscope lens while making an important basic discovery about how microtubules, the hollow filaments that act as the supportive skeleton of the cell, dynamically assemble during cell division.

The video starts with a few individual microtubule filaments (red) growing linearly at one end (green). Notice the green “comets” that quickly appear, followed by a red trail. Those are new microtubules branching off. This continuous branching is interesting because microtubules were generally thought to grow linearly in animal cells (although branching had been observed a few years earlier in fission yeast and plant cells). The researchers, led by Sabine Petry, now at Princeton University, Princeton, NJ, showed for the first time that not only do new microtubules branch during cell division, but they do so very rapidly, going from a few branches to hundreds in a matter of minutes [1].

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Cool Videos: Another Kind of Art Colony

BioArt-Berkmen and PenilAs long as researchers have been growing bacteria on Petri dishes using a jelly-like growth medium called agar, they have been struck by the interesting colors and growth patterns that microbes can produce from one experiment to the next. In the 1920s, Sir Alexander Fleming, the Scottish biologist who discovered penicillin, was so taken by this phenomenon that he developed his own palette of bacterial “paints” that he used in his spare time to create colorful pictures of houses, ballerinas, and other figures on the agar [1].

Fleming’s enthusiasm for agar art lives on among the current generation of microbiologists. In this short video, the agar (yellow) is seeded with bacterial colonies and, through the magic of time-lapse photography, you can see the growth of the colonies into what appears to be a lovely bouquet of delicate flowers. This piece of living art, developing naturally by bacterial colony expansion over the course of a week or two, features members of three bacterial genera: Serratia (red), Bacillus (white), and Nesterenkonia (light yellow).

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A Look Inside a Beating Heart Cell

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.

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