Stem Cell Roundup: New understanding of Huntington’s; how stem cells can double your DNA; and using “the Gary Oldman of cell types” to reverse aging

This week’s roundup highlights how we are constantly finding out new and exciting ways that stem cells could help change the way we treat disease.

Our Cool Stem Cell Image of the Week comes from our first story, about unlocking some of the secrets of Huntington’s disease. It comes from the Laboratory of Stem Cell Biology and Molecular Embryology at The Rockefeller University

Huntington's neurons

A new approach to studying and developing therapies for Huntington’s disease

Researchers at Rockefeller University report new findings that may upend the way scientists study and ultimately develop therapies for Huntington’s disease, a devastating, inherited neurodegenerative disorder that has no cure. Though mouse models of the disease are well-established, the team wanted to focus on human biology since our brains are more complex than those of mice. So, they used CRISPR gene editing technology in human embryonic stem cells to introduce the genetic mutations that cause HD.

Though symptoms typically do not appear until adulthood, the researchers were surprised to find that in their human cell-based model of HD, abnormalities in nerve cells occur at the earliest steps in brain development. These results suggest that HD therapies should focus on treatments much earlier in life.

The researchers observed another unexpected twist: cells that lack Huntingtin, the gene responsible for HD, are very similar to cells found in HD. This suggests that too little Huntingtin may be causing the disease. Up until now, the prevailing idea has been that Huntington’s symptoms are caused by the toxicity of too much mutant Huntingtin activity.

We’ll certainly be keeping an eye on how further studies using this new model affect our understanding of and therapy development for HD.

This study was published in Development and was picked by Science Daily.

How you can double your DNA

dna

As you can imagine we get lots of questions about stem cell research here at CIRM. Last week we got an email asking if a stem cell transplant could alter your DNA? The answer is, under certain circumstances, yes it could.

A fascinating article in the Herald Review explains how this can happen. In a bone marrow transplant bad blood stem cells are killed and replaced with healthy ones from a donor. As those cells multiply, creating a new blood supply, they also carry the DNA for the donor.

But that’s not the only way that people may end up with dual DNA. And the really fascinating part of the article is how this can cause all sorts of legal and criminal problems.

One researcher’s efforts to reverse aging

gary-oldman

Gary Oldman: Photo courtesy Variety

“Stem cells are the Gary Oldman of cell types.” As a fan of Gary Oldman (terrific as Winston Churchill in the movie “Darkest Hour”) that one line made me want to read on in a profile of Stanford University researcher Vittorio Sebastiano.

Sebastiano’s goal is, to say the least, rather ambitious. He wants to reverse aging in people. He believes that if you can induce a person’s stem cells to revert to a younger state, without changing their function, you can effectively turn back the clock.

Sebastiano says if you want to achieve big things you have to think big:

“Yes, the ambition is huge, the potential applications could be dramatic, but that doesn’t mean that we are going to become immortal in some problematic way. After all, one way or the other, we have to die. We will just understand aging in a better way, and develop better drugs, and keep people happier and healthier for a few more years.”

The profile is in the journal Nautilus.

Stem cell stories that caught our eye: heart muscle-on-a-chip, your own private microliver, the bloody holy grail and selfish sperm

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.

Two hearts beat as one, or not
Sorry for the pre-Valentine’s Day buzzkill but stem cell research published this past week points to a very unromantic discovery: two hearts do not beat as one. The study, out of Rockefeller University, and published in the Journal of Cell Biology, sought to understand the limited success of clinical trials in which stem cell-derived heart muscle cells, or cardiomyocytes, are transplanted into the heart to help repair tissue scarred by disease or a heart attack.

If you’re a regular at The Stem Cellar, you’ll recall that just last Friday we summarized published experiments that suggest the cardiomyocytes used in successful trials do not grow new tissue themselves but instead heal the heart indirectly by releasing proteins that stimulate repair.

The research team behind this week’s study instead reasoned that the transplanted cardiomyocytes do indeed integrate into the heart tissue, but they fail to contract properly with the undamaged heart cells. So, the thinking goes, the transplanted cells do nothing to restore the heart’s ability to beat at full strength.

Watch video here: http://medicalxpress.com/news/2016-02-muscles-on-a-chip-insight-cardiac-stem.html

A two-cell “microtissue” contains a mouse embryonic stem cell-derived cardiomyocyte and a mouse neonatal cardiomyocyte. The lower panel shows the traction forces generated as the two cells contract; the stronger, neonatal cardiomyocyte produces more force than the weaker, stem cell-derived cardiomyocyte. Credit: Aratyn-Schause, Y. et al. J Cell Biol. 2016 Watch video here: http://medicalxpress.com/news/2016-02-muscles-on-a-chip-insight-cardiac-stem.html

 

To test this hypothesis, the researchers devised a two-cell micro-tissue made up of a single mouse cardiomyocyte and a single cardiomyocyte derived from either mouse embryonic stem cells or induced pluripotent stem cells (iPS). This “muscle-on-a-chip” showed that the two cells are able to physically connect up and even beat in sync with each other. But, the embryonic and iPS-derived cardiomyocytes beat less strongly than the native cell. Based on computer simulations, this imbalance made the micro-tissue beat less efficiently. A university press release picked up by Newswise includes a short yet fascinating video of the differing strengths of the beating heart cells (click on image above).

With this micro-tissue in hand, the team aims to find a way to fix this imbalance, which hopefully would make cell therapies for heart disease more potent.

Your Own Private Micro-liver
Enough about micro-hearts, let’s talk micro-livers.

In a report published on Monday in PNAS, a multidisciplinary UCSD team of engineers and biomedical researchers described the creation of a bioprinted 3D liver model made from human iPS-derived liver cells, or hepatocytes. The hepatocytes are imprinted on a surface in hexagonal shapes, the kind seen in the complex microarchitecture of the human liver. These structures were also seeded with two other cell types: endothelial cells, which form blood vessels, and fat cells, which support the health of hepatocytes. Including these relevant cell types in the “micro-liver” design resulted in a 3D cell culture that not only mimics structures but also replicates functions found in a natural liver.

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The 3-D-printed parts of the biomimetic liver tissue include: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right). — Chen Laboratory, UC San Diego

This is a really exciting development for improving drug safety. A big concern of any new drug coming on the market is its potential liver toxicity, formally known as DILI (drug induced liver injury), the most common cause of liver failure in the U.S. Although animal studies and clinical trials carefully test for the potential of DILI, that doesn’t guarantee the drug will be safe in all individuals. And because this liver model was designed using human iPS cells – which can be derived from anyone with a simple skin biopsy – it has the potential to serve as a personalized drug screening device as well as a disease-in-a-dish model for studying inherited forms of liver disease.

As Bradley Fikes, San Diego Union Tribune’s biotechnology writer, mentions in an excellent summary of the publication, beyond drug screening and disease-in-dish modeling, this bioprinting process could also one day make it possible for researchers to reach the “holy grail” of tissue engineering: building an entire organ.

Finally! The Bloody Holy Grail
While that holy grail remains on the horizon, Stanford researchers are nearly holding the goblet in their hands. Based on a Nature report published yesterday, a team led by CIRM grantee Irv Weissman have found a long sought after cellular tag that can fish out a very specific type of hematopoietic stem cell (HSC), or blood-forming stem cell, from bone marrow.

Almost thirty years ago, Weissman identified HSCs, which have the ability to form all the cell types of the blood. Since that time, scientists have struggled with fully understanding how HSCs are maintained in the body and, in turn, how to grow them in the laboratory.

The source of this problem is due to the fact that most HSCs are so-called short term HSCs because they eventually lose their “stemness”; that is, their ability to divide indefinitely. Only a small fraction of HSCs are of the long-term variety. To really understand how the body sustains a life-long supply of HSCs, it’s necessary to have a method to pick out just the long term HSCs.

So scientists in Weissman’s lab set out to do just that. Starting with a list of 100 genes that are known to be active in the bone marrow, they looked for genes that are turned on only in long term HSCs. After a painstaking, systematic method that took two years, the team narrowed down the list to just one gene that was unique to long term HSCs.

Co-lead author James Y. Chen, a MD/PHD candidate at Stanford, described the significance of this effort in a university press release:

chen

James Y. Chen

“For nearly 30 years, people have been trying to grow HSCs outside the body and have not been able to do it — it’s arguably the ‘holy grail’ in this field. Now that we have an anchor, a way to look at long-term HSCs, we can look at the cells around them to understand and, ideally, recreate the niche.”

 

 

 

Older Dads and The Selfish Sperm

We wrap up the week with a PNAS publication that got a wide range of coverage by the likes of BBC News, Gizmodo and Cosmos in addition to the usual suspects like Health Canal. Not too surprising given the topic including selfish sperm and chopped up testicles.

Research over the past decade or so has made it increasingly clear that biological clocks not only tick for would-be moms but also dads. At first glance, it makes sense: older fathers have had more time to accumulate random DNA mutations in their spermatogonia, the stem cells that produce sperm. But studies of Apert syndrome, a rare disease causing defects in the skull, fingers and toes, has put this hypothesis in question.

Back in 2003, a research team at Oxford University found the mutation in spermatogonia that causes Apert syndrome occurs 100 to 1000 times more frequently than would be expected if it were merely due to a random mutation (the Apert syndrome is not inherited because males with the disease rarely go on to have children).

So what’s going on? To answer that question the Oxford scientists collaborated with a USC research team who (men: you may not want to read the rest of this sentence, this is your only warning) chopped up human testicles – ones that had been removed for unrelated medical reasons and donated – in order to reconstruct a three-dimensional map of where these Apert syndrome mutations were occurring. If the mutations were merely random, the affected spermatogonia would have been evenly distributed throughout the testicle. Instead, the team found clusters of cells carrying the mutation.

This results confirms a “selfish sperm” hypothesis in which the mutation provides a selective advantage to the affected sperm cells allowing them to out compete other nearby sperm cells, much like a cancer cell that multiples and gradually forms a tumor. The study serves as more sobering news to otherwise healthy older dads that they may have a higher risk of passing on harmful mutations to their offspring.

Like I said, sorry for the buzzkill. Happy Valentine’s Day weekend!

Confining Cells within Geometric Structures Key to Replicating Embryonic Development

It’s like trying to capture, and then recreate, a moment in time: the exact instant after fertilization when a small group of dividing cells begin to organize themselves into the various cellular layers that will one day make up the skin, the heart, the liver and the brain. But for all the advances in our understanding of how an embryonic stem cell grows, matures and differentiates—scientists still can’t replicate that very important process in the lab.

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

But now, scientists at The Rockefeller University have tried something new, and in so doing have finally found a way to stimulate this organization, thus mimicking in a petri dish what happens in the human embryo. The missing ingredient, the researchers found, wasn’t a molecule or chemical compound. Rather, the team just had to use a bit of geometry.

Reporting in the June 29 issue of the journal Nature Methods, the Rockefeller team—led by Dr. Ali Brivanlou—describes how they constructed microscopic circular patterns on glass plates that confined embryonic stem cells inside, similar to a hedge maze.

To their amazement, the cells confined within these patterns soon began to go through gastrulation, the process by which embryonic stem cells begin to form highly organized layers that eventually mature into the body’s various organs and tissues. A second group of cells not confined within these patterns, however, did not.

The next question they had to figure out, according to the researchers, was why.

To solve this mystery, Brivanlou and his team next monitored specific chemical signals between the cells as they matured. In so doing they uncovered a delicate arrangement of chemical cues—molecular ‘on-and-off-switches’—that guided each cell down one developmental path as opposed to another. What were crucial to these cues going off without a hitch, the researchers found, were the geometric patterns.

As Dr. Aryeh Warmflash, one of the paper’s lead authors, stated in this week’s news release:

“At the fundamental level, what we have developed is a new model to explore how human embryonic stem cells first differentiate into separate populations with a very reproducible spatial order just as in an embryo. We can now follow individual cells in real time in order to find out what makes them specialize, and we can begin to ask questions about the underlying genetics of the process.”

Added Brivanlou:

“Understanding what happens in this moment, when individual members of this mass of embryonic stem cells begin to specialize for the very first time and organize themselves into layers, will be key to harnessing the promise of regenerative medicine.”

Confining Cells within Geometric Structures Key to Replicating Embryonic Development

It’s like trying to capture, and then recreate, a moment in time: the exact instant after fertilization when a small group of dividing cells begin to organize themselves into the various cellular layers that will one day make up the skin, the heart, the liver and the brain. But for all the advances in our understanding of how an embryonic stem cell grows, matures and differentiates—scientists still can’t replicate that very important process in the lab.

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

Forty-two hours after they began to differentiate, embryonic cells are clearly segregating into the various layers that will one day become specific tissues and organs. Researchers say the key to achieving this patterning in culture is confining the colonies geometrically. [Credit: The Rockefeller University]

But now, scientists at The Rockefeller University have tried something new, and in so doing have finally found a way to stimulate this organization, thus mimicking in a petri dish what happens in the human embryo. The missing ingredient, the researchers found, wasn’t a molecule or chemical compound. Rather, the team just had to use a bit of geometry.

Reporting in the June 29 issue of the journal Nature Methods, the Rockefeller team—led by Dr. Ali Brivanlou—describes how they constructed microscopic circular patterns on glass plates that confined embryonic stem cells inside, similar to a hedge maze.

To their amazement, the cells confined within these patterns soon began to go through gastrulation, the process by which embryonic stem cells begin to form highly organized layers that eventually mature into the body’s various organs and tissues. A second group of cells not confined within these patterns, however, did not.

The next question they had to figure out, according to the researchers, was why.

To solve this mystery, Brivanlou and his team next monitored specific chemical signals between the cells as they matured. In so doing they uncovered a delicate arrangement of chemical cues—molecular ‘on-and-off-switches’—that guided each cell down one developmental path as opposed to another. What were crucial to these cues going off without a hitch, the researchers found, were the geometric patterns.

As Dr. Aryeh Warmflash, one of the paper’s lead authors, stated in this week’s news release:

“At the fundamental level, what we have developed is a new model to explore how human embryonic stem cells first differentiate into separate populations with a very reproducible spatial order just as in an embryo. We can now follow individual cells in real time in order to find out what makes them specialize, and we can begin to ask questions about the underlying genetics of the process.”

Added Brivanlou:

“Understanding what happens in this moment, when individual members of this mass of embryonic stem cells begin to specialize for the very first time and organize themselves into layers, will be key to harnessing the promise of regenerative medicine.”