Stem cell stories that caught our eye: developing the nervous system, aging stem cells and identical twins not so identical

Here are the stem cell stories that caught our eye this week. Enjoy!

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

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Have Scientists Found a Stem Cell-lution to Thyroid Disorders?

The thyroid gland is located in the neck. (WebMD)

The thyroid gland is located in the neck. (WebMD)

Have you thanked your thyroid today? If not, you should because your thyroid is essential for many of life’s daily activities and processes that you probably take for granted.

You can thank your thyroid for things like regulating your body temperature and appetite, and keeping you energetic, slim, and focused. That’s because these small glands in your neck are hormone-producing factories, and thyroid secreted hormones (TSH) control the growth and development of our organs and tissues and regulate important processes like your metabolism.

When your thyroid doesn’t work…

People who have thyroid disorders suffer from a number of uncomfortable or even nasty symptoms. Those with overactive thyroid glands (hyperthyroidism) produce too much thyroid hormone and have an overactive metabolism, which causes symptoms such as excessive sweating, weight loss, heart problems, and sensitivity to heat. Those with underactive thyroids (hypothyroidism) don’t produce enough hormone and have an impaired metabolism, which causes symptoms of tiredness, reduced heart rate, hair loss, feeling cold, and weight gain.

There are other types of thyroid problems (cancer and inflammation to name a few), but the bottom line is that, if your thyroid isn’t functioning properly, your quality of life will be negatively affected.

A stem cell-lution to hypothyroidism

However, there maybe a new “stem cell-lution” therapy for some forms of thyroid dysfunction. Scientists from the Boston University School of Medicine and the Beth Israel Deaconess Medical Center reported in Cell Stem Cell on Thursday that they can generate functional thyroid tissue from stem cells derived from different mammalian models. This is a huge deal because previously, scientists were unable to manipulate pluripotent stem cells into mature thyroid cells that had the correct thyroid identity (meaning they turned on the correct combination of thyroid-specific genes). This previous inability has made it very difficult for scientists to model thyroid diseases in a dish.

In this study, the authors used two factors, BMP and FGF, to directly differentiate mouse pluripotent stem cells into thyroid progenitor cells. These progenitors could be coaxed further into mature and properly functioning thyroid organoids (3D thyroid-like structures) that secreted thyroid hormone both in a dish and when transplanted back into mice.

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

Scientists generated thyroid tissue from pluripotent stem cells of frogs, mice and humans. (Cell Stem Cell)

What was truly exciting about their discovery, was that the same two factors could make functional thyroid tissue from mouse, frog, and human pluripotent stem cells, showing that the role of BMP4 and FGF2 in thyroid development is conserved across multiple species.

With the bases loaded, the authors hit a grand slam by using BMP4 and FGF2 to generate thyroid progenitor cells from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) derived from the skin cells of both healthy individuals and patients with hypothyroidism.

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Thyroid organoids generated from mouse embryonic stem cells. (Cell Stem Cell)

Big Picture

This study not only offers a new understanding of the early stages of thyroid development, but provides a potential source of transplantable stem-cell derived thyroid progenitor cells for cell-based therapies that could treat some forms of hypothyroidism.

In a press release from the Beth Israel Deaconess Medical Center, co-senior author of the study Anthony Hollenberg explained the significance of their findings:

This research represents an important step toward the goal of being able to better treat thyroid diseases and being able to permanently rescue thyroid function through the transplantation of a patient’s own engineered pluripotent stem cells.

 

Co-senior author Darrell Kotton went further to describe the novelty of their discovery:

Until now, we haven’t fully understood the natural process that underlies early thyroid development. With this paper, we’ve identified the signaling pathways in thyroid cells that regulate their differentiation, the process by which unspecialized stem cells give rise to specialized cells during early fetal development.”

 

Remembering Anita Kurmann

Anita Kurmann

Anita Kurmann

While this discovery is a major step forward in the field of thyroid disease and regenerative medicine, the victory is bittersweet in light of the recent passing of the study’s first author, Anita Kurmann. Anita was a Swiss surgeon and a talented scientist who was tragically killed while riding her bike in Boston’s Back Bay on August 7th, 2015. She had just heard that her publication would be accepted to Cell Stem Cell days before the accident and was planning to start her own lab at the end of the year in Switzerland.

Her colleagues, friends, and the science world will miss her dearly. As a tribute to Anita, her co-authors dedicated the Cell Stem Cell publication to her memory.

We dedicate this work to the memory of our co-first author, Dr. Anita Kurmann, who died in a tragic bicycle accident when this manuscript was in the final stages of formatting. She was intelligent, well read, kind, humble, and tirelessly committed to her patients, her thyroid research, her family, and her colleagues, who miss her dearly.


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Key stem cell gene controlled from afar, Canadian scientists discover

Embryonic stem cells can, by definition, mature into any cell type in the body. They are able to maintain this state of so-called pluripotency with the help of a gene called Sox2. And now, researchers at the University of Toronto (U of T) have discovered the unseen force that controls it. These findings, reported in the latest issue of Genes & Development, offer much-needed understanding of the steps a cell must take as it grows up.

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Mouse embryonic stem cells grown in a round colony of cells (A) and express Sox2 (B), shown in red. Sox2 control region (SCR)-deleted cells have lost the typical appearance of embryonic stem cells (C) and do not express Sox2 (D). [Credit: Jennifer Mitchell/University of Toronto]

Led by U of T Professor Jennifer Mitchell, the research team were, for the first time, able to identify the specific molecular regulator that switched the Sox2 gene on and off at specific times during an embryonic cell’s lifetime. As Mitchell explained:

“We studied how the Sox2 gene is turned on in mice, and found the region of the genome that is needed to turn the gene on in embryonic stem cells. Like the gene itself, this region of the genome enables these stem cells to maintain their ability to become any type of cell.”

The team named this region the Sox2 control region, or SCR.

For the last decade scientists have been using knowledge gleaned from the Human Genome Project to map how and when genes are switched on and off. Interestingly, the regions that control the gene in question aren’t always located close by.

This was the case with Sox2, said Mitchell. Early on, researchers had argued that Sox2 was regulated from nearby. But in this study, the team found the SCR, which controls Sox2, to be located more than 100,000 DNA base pairs away. According to Mitchell, the process by which the SCR activates Sox2 is fascinating:

“To contact the gene, the DNA makes a loop that brings the SCR close to the gene itself only in embryonic stem cells… It is possible that the formation of the loop needed to make contact with the Sox2 gene is an important final step in the process by which researchers practicing regenerative medicine can generate pluripotent cells from adult cells.”

Indeed, despite a flurry of research breakthroughs and a promising number of clinical trials moving forward, there are still some fundamental aspects of stem cell biology that remain unknown. This discovery, argues Mitchell, is an important step towards reaching toward improving the way in which scientists manipulate stem cells to treat disease.