Stem cell stories that caught our eye: regenerating limbs on scaffolds, self regeneration via a drug, mood stem cells, CRISPR

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Regenerating a limb, or at least part of it. Many teams have generated organs or parts of organs in animals by starting with a dead one. They literally wash away all the cells from the donor organ using a detergent so that they are left with a framework of the cells’ connective tissue. Then they seed that scaffold with stem cells or other cells to grow a new organ. A team at Massachusetts General Hospital has now used the same process to generate at least part of a rat limb.

The news cells growing on the donor limb scaffold in a bioreactor

The news cells growing on the donor limb scaffold in a bioreactor

It took a week to get the tiny little leg fully cleaned up and then another two weeks for the seeded cells to repopulate the scaffold left behind. That cellular matrix seems to send signals to the seeded cells on what type of tissue to become and how to arrange themselves. The team succeeded in creating an artificial limb with muscle cells aligned into appropriate fibers and blood vessels in the right places to keep them nourished. The researchers published their work in the journal Biomaterials and the website Next Big Future wrote up the procedure and provided some context on the limitations of current prosthetic limbs. The author also notes that the researchers have a lot more work to do, notably to prove they can get nerves to grow and connect at the point of transplantation to the “patient” animal. Discover also wrote a version of the story.

Getting the body to regenerate itself. A strain of mice discovered 20 years ago has led a multi-institution team to a possible way to get the body to regenerate damaged tissue, something the mouse discovered two decades ago can do and other mammals cannot. The researchers found that those mice have one chemical pathway, HIF-1a, that is active in the adult mice but is normally only active in the developing embryo. When they pushed that chemical path to work in normal mice those mice, too, gained the power to regenerate tissue. Ellen Heber-Katz from the Lankenau Institute for Medical Research outside of Philadelphia was quoted in the institute’s press release on Health Medicine Network.

“We discovered that the HIF-1a pathway–an oxygen regulatory pathway predominantly used early in evolution but still used during embryonic development–can act to trigger healthy regrowth of lost or damaged tissue in mice, opening up new possibilities for mammalian tissue regeneration.”

Heber-Katz led the team that included researchers from the company Allergan and the University of California, Berkeley. In order to activate the HIF-1a pathway they basically took the natural brakes off it. Another cellular chemical, PHD normally inhibits the action of HIF-1a in adults. The researcher turned the table on PHD and inhibited it instead. The result, after three injections of the PHD inhibitor over five days the mice who had a hole punched in their ear healed over the hole complete with cartilage and new hair.

Regulating memory and mood. It turns out your brain’s hippocampus, the section responsible for both memory and mood, has not one type of stem cell replenishing nerves, but two. And those two types of stem cells give rise to different types of nerves, which may account for the highly varied function of this part of the brain. Researchers at the University of Queensland in Australia isolated the two types of stem cells and then let them grow into nerves but the nerves from each expressed different genes, which means they have different functions. The lead researcher on the study, Dhanisha Jhaveri, discussed the findings in a press release picked up by Science Daily:

“The two cell groups are located in different regions of the hippocampus, which suggests that distinct areas within the hippocampus control spatial learning versus mood.”

The research provides fodder for future work looking into the treatment of learning and mood disorders. Review of the now celebrity tool, CRISPR. I don’t think I have ever seen so much ink and so many electrons spilled over a science tool as I have seen for CRISPR, particularly for one few scientists can tell you what the acronym stands for: Clustered Regularly Interspaced Short Palindromic Repeats. It is basically a fluke in the genes of several bacteria in which some of the base pairs that make up their DNA get repeated at regular intervals. Their configuration confers the ability for CRISPR segments to be used to disrupt or change specific genes in other organisms. Heidi Ledford writing for Nature in the journal’s news section provides a great wrap-up of what the technology is and what it can do, but also provides some caveats about its efficiency, accuracy, ethical concerns, and occasionally just not understanding how it works. The Nature team provides some valuable infographics showing the history of the science and on the rapid adoption of the technology as shown in publications, patents and funding. They also published an infographic on using CRISPR for “gene drive,” a way to push a modified trait through a population quickly, such as a mutation that could stop mosquitos from transmitting malaria. This potential drives much of the concern about misuse of the tool. But scientists quoted in the piece also provide more mundane reasons for moving slowly in thinking about using the therapy for patients. One of those is that it can sometime cause a high rate of “off-target” gene edits; simply put, cutting DNA in the wrong place. But as a research tool, there is no doubt it has revolutionized the field of gene modification. It is so much faster and so much cheaper than earlier gene editing tools; it is now possible for almost any lab to do this work. The piece starts out with an anecdote from CIRM-grantee Bruce Conklin of the Gladstone Institutes, talking about how it completely changed the way his lab works.

“It was a student’s entire thesis to change one gene,” Conklin said, adding “CRISPR is turning everything on its head.”

CIRM-Funded Scientists Test Recipe for Building New Muscles

When muscles get damaged due to disease or injury, the body activates its reserves—muscle stem cells that head to the injury site and mature into fully functioning muscle cells. But when the reserves are all used up, things get tricky.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

This is especially the case for people living with muscle diseases, such as muscular dystrophy, in which the muscle degrades at a far faster rate than average and the body’s reserve stem cell supply becomes exhausted. With no more supply from which to draw new muscle cells, the muscles degrade further, resulting in the disease’s debilitating symptoms, such as progressive difficulty walking, running or speaking.

So, scientists have long tried to find a way to replenish the dwindling supply of muscle stem cells (called ‘satellite cells’), thus slowing—or even halting—muscle decay.

And now, researchers at the Sanford-Burnham Medical Research Institute have found a way to tweak the normal cycle, and boost the production of muscle cells even when supplies appear to be diminished. These findings, reported in the latest issue of Nature Medicine, offer an alternative treatment for the millions of people suffering not only from muscular dystrophy, but also other diseases that result in muscle decay—such as some forms of cancer and age-related diseases.

In this study, Sanford-Burnham researchers found that introducing a particular protein, called a STAT3 inhibitor, into the cycle of muscle-cell regeneration could boost the production of muscle cells—even after multiple rounds of repair that would otherwise render regeneration virtually impossible.

The STAT3 inhibitor, as its name suggests, works by ‘inhibiting,’ or effectively neutralizing, another protein called STAT3. Normally, STAT3 gets switched on in response to muscle injury, setting in motion a series of steps that replenishes muscle cells.

In experiments first in animal models of muscular dystrophy—and next in human cells in a petri dish—the team decided to modify how STAT3 functions. Instead of keeping STAT3 active, as would normally occur, the team introduced the STAT3 inhibitor at specific times during the muscle regeneration process. And in so doing, noticed a significant boost in muscle cell production. As Dr. Alessandra Sacco, the study’s senior author, stated in a news release:

“We’ve discovered that by timing the inhibition of STAT3—like an ‘on/off’ light switch—we can transiently expand the satellite cell population followed by their differentiation into mature cells.”

This approach to spurring muscle regeneration, which was funded in part by a CIRM training grant, is not only innovative, but offers new hope to a disease for which treatments have offered little. As Dr. Vittorio Sartorelli, deputy scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), stated:

“Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process. A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”

Sacco and her colleagues are encouraged by these results, and plan to explore their findings in greater detail—hopefully moving towards clinical trials:

“Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans.”