Aging

Can regenerative medicine turn back the clock on aging?

/ Kevin McCormack / Leave a comment

One of my favorite phrases is “standing room only”. I got a chance to use it last week when we held a panel discussion on whether regenerative medicine could turn back the clock on aging. The event was at the annual conference of the International Society for Stem Cell Research (ISSCR) and more than 150 people packed into a conference room to hear the debate (so far more than 800 also watched a live stream of the event.)

It’s not surprising the place was jammed. The speakers included:

  • Dr. Deepak Srivastava, the President of the Gladstone Institutes, an expert on heart disease and the former President of ISSCR.
  • Dr. Stanley “Tom” Carmichael, Chair of the Department of Neurology at UCLA and an expert on strokes and other forms of brain injury.
  • Adrienne Shapiro, the mother of a daughter with sickle cell disease, a tireless patient advocate and supporter of regenerative medicine research, and the co-founder of Axis Advocacy, a family support organization for people with sickle cell.
  • Jonathan Tomas, PhD, JD, the Chair of the CIRM Board.

And the topic is a timely one. It is estimated that as many as 90 percent of the people who die every day, die from diseases of aging such as heart disease, stroke, and cancer. So, what can be done to change that, to not just slow down or stop these diseases, but to turn back the clock, to repair the damage already done and replace cells and tissues already destroyed.

The conversation was enlightening, hopeful and encouraging, but also cautionary.

You can watch the whole event on our Youtube channel.

I think you are going to enjoy it.

Join us to hear how stem cell and gene therapy are taking on diseases of aging

/ Kevin McCormack / Leave a comment

It is estimated that as many as 90 percent of people in industrialized countries who die every day, die from diseases of aging such as heart disease, stroke, and cancer. Of those still alive the numbers aren’t much more reassuring. More than 80 percent of people over the age of 65 have a chronic medical condition, while 68 percent have two or more.

Current medications can help keep some of those conditions, such as high blood pressure, under control but regenerative medicine wants to do a lot more than that. We want to turn back the clock and restore function to damaged organs and tissues and limbs. That research is already underway and we are inviting you to a public event to hear all about that work and the promise it holds.

On June 16th from 3p – 4.30p PST we are holding a panel discussion exploring the impact of regenerative medicine on aging. We’ll hear from experts on heart disease and stroke; we will look at other ground breaking research into aging; and we’ll discuss the vital role patients and patient advocates play in helping advance this work.

The discussion is taking place in San Francisco at the annual conference of the International Society for Stem Cell Research. But you can watch it from the comfort of your own home. That’s because we are going to live stream the event.

Here’s where you can see the livestream: https://www.youtube.com/watch?v=CaUgsc5alDI

And if you have any questions you would like the panel to answer feel free to send them to us at info@cirm.ca.gov

Muscle stem cells provide insight into treatment of muscular dystrophies and aging muscles

/ Yimy Villa / 3 Comments
Dr. Alessandra Sacco, associate professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys.

Muscles are a vital part of the body that enable us to walk, run, lift, and do everyday activities. When muscles start to deteriorate, we start to have difficulty performing these activities, which severely limits quality of life and autonomy. Typically, this becomes more commonplace as we age and is known as sarcopenia, which affects nearly ten percent of adults over the age of 50 and nearly half of individuals in their 80s.

However, there are other instances where this happens much more rapidly and early on due to genetic disease. These are commonly known as muscular dystrophies, which consist of more than 30 genetic diseases characterized by progressive muscle weakness and degeneration. A cure does not currently exist.

Regardless of the cause of the muscle deterioration, scientists at Sanford Burnham Prebys have uncovered how to potentially promote growth inside stem cells found within the muscle, thereby promoting muscle growth. In a mouse model study funded in part by CIRM and published in Nature Communications, Dr. Alessandra Sacco, senior author of the paper, and her team describe how a signaling pathway, along with a specific protein, can help regulate what muscle stem cells do.

Muscle stem cells can do two things, they either become adult muscle cells or self-renew to replenish the stem cell population. The paper discusses how the signaling pathway and specific protein are crucial for muscle stem cell differentiation and muscle growth, both of which are needed to prevent deterioration. Their aim is to use this knowledge to develop therapeutic targets that can aid with muscle growth.

Dr. Alessandra Sacco is quoted in an article as saying,

“Muscle stem cells can ‘burn out’ trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to ‘make the right decision’ and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging.”

Stem Cell Stories that Caught Our Eye: GPS for Skin & Different Therapies for Aging vs. Injured Muscles?

/ Todd Dubnicoff / Leave a comment

Skin stem cells specialize into new skin by sensing neighborhood crowding
When embarking on a road trip, the GPS technology inside our smartphones helps us know where we are and how to get where we’re going. The stem cells buried in the deepest layers of our skin don’t have a GPS and yet, they do just fine determining their location, finding their correct destination and becoming the appropriate type of skin cell. And as a single organ, all the skin covering your body maintains the right density and just the right balance of skin stem cells versus mature skin cells as we grow from a newborn into adult.

crowdinginth

Skin cells growing in a petri dish (green: cytoskeleton, red: cell-cell junction protein).
Credit: MPI for Biology of Aging

This easily overlooked but amazing feat is accomplished as skin cells are continually born and die about every 30 days over your lifetime. How does this happen? It’s an important question to answer considering the skin is our first line of defense against germs, toxins and other harmful substances.

This week, researchers at the Max Planck Institute for Biology of Aging in Cologne, Germany reported a new insight into this poorly understood topic. The team showed that it all comes down to the skin cells sensing the level of crowding in their local environment. As skin stem cells divide, it puts the squeeze on neighboring stem cells. This physical change in tension on these cells “next door” triggers signals that cause them to move upward toward the skin surface and to begin maturing into skin cells.

Lead author Yekaterina Miroshnikova explained in a press release the beauty of this mechanism:

“The fact that cells sense what their neighbors are doing and do the exact opposite provides a very efficient and simple way to maintain tissue size, architecture and function.”

The research was picked up by Phys.Org on Tuesday and was published in Nature Cell Biology.

Stem cells respond differently to aging vs. injured muscle
From aging skin, we now move on to our aging and injured muscles, two topics I know oh too well as a late-to-the-game runner. Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla report a surprising discovery that muscle stem cells respond differently to aging versus injury. This important new insight could help guide future therapeutic strategies for repairing muscle injuries or disorders.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber.
Image: Michael Rudnicki/OIRM

Muscle stem cells, also called satellite cells, make a small, dormant population of cells in muscle tissue that springs to life when muscle is in need of repair. It turns out that these stem cells are not identical clones of each other but instead are a diverse pool of cells.  To understand how the assortment of muscle stem cells might respond differently to the normal wear and tear of aging, versus damage due to injury or disease, the research team used a technology that tracks the fate of individual muscle stem cells within living mice.

The analysis showed a clear but unexpected result. In aging muscle, the muscle stem cells maintained their diversity but their ability to divide and grow declined. However, the opposite result was observed in injured muscle: the muscle stem cell diversity became limited but the capacity to divide was not affected. In a press release, team leader Alessandra Sacco explains the implications of these findings for therapy development:

sacco

Alessandra Sacco, PhD

“This study has shown clear-cut differences in the dynamics of muscle stem cell pools during the aging process compared to a sudden injury. This means that there probably isn’t a ‘one size fits all’ approach to prevent the decline of muscle stem cells. Therapeutic strategies to maintain muscle mass and strength in seniors will most likely need to differ from those for patients with degenerative diseases.”

This report was picked up yesterday by Eureka Alert and published in Cell Stem Cell.

Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics

/ Karen Ring / 1 Comment

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

Scientists claim first CRISPR editing of human embryos in the US.

Here’s the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.

A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).

Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused “off-target” effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell’s DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren’t genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren’t accurate enough to safely modify human embryos.

But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM’s Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and “off-target” effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.

The MIT piece quoted a scientist who knows of Mitalipov’s work,

“It is proof of principle that it can work. They significantly reduced mosaicism. I don’t think it’s the start of clinical trials yet, but it does take it further than anyone has before.”

Does this discovery, if it’s true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler’s blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg’s article in The Conversation.

Brain stem cells slow aging in mice

The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.

The hypothalamus is located smack in the center of your brain near the brain stem. It’s responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body’s metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.

The mouse hypothalamus. (NIH, Wikimedia).

In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.

They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more “youthful” qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.

So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.

They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.

In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, “Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person’s muscles and metabolism have degenerated beyond a point that could be reversed.”

This study and its “Fountain of Youth” implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.

BrainStorm ALS trial joins the CIRM Alpha Clinics

Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic’s Phase 3 trial that’s testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig’s disease).

The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient’s bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.

BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was “safe and well tolerated” and that “NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit.  Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks.”

This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.

Along with UCI, BrainStorm’s Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,

“We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution.”

Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.

With promising data from their Phase 1 and 2 trials, BrainStorm’s Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:

“NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm.”

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

/ Karen Ring / Leave a comment

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.

Telomere length matters: scientists find shorter telomeres may cause aging-related disease

/ Karen Ring / Leave a comment

Aging is inevitable no matter how much you exercise, sleep or eat healthy. There is no magic pill or supplement that can thwart growing older. However, preventing certain age-related diseases is a different story. Genetic mutations can raise the risk of acquiring age-related diseases like heart disease, diabetes, cancer and dementia. And scientists are on the hunt for treatments that target these mutations in hopes of preventing these diseases from happening.

Telomeres shown in white act as protective caps at the ends of chromosomes.

Another genetic component that can accelerate diseases of aging are telomeres. These are caps made up of repeat sequences of DNA that sit at the ends of chromosomes and prevent the loss of important genetic material housed within chromosomes. Healthy cells have long telomeres, and ascells divide these telomeres begin to shorten. If telomere shortening is left unchecked, cells become unhealthy and either stop growing or self-destruct.

Cells have machinery to regrow their telomeres, but in most cases, the machinery isn’t activated and over time, the resulting shortened telomeres can lead to problems like an impaired immune system and organ degeneration. Shortened telomeres are associated with age-related diseases, but the reasons why have remained elusive until recently.

Scientists from the Gladstone Institutes have found a clue to this telomere puzzle that they shared in a study published yesterday in the Journal of Clinical Investigation. This research was funded in part by a CIRM Discovery stage award.

In their study, the team found that mice with a mutation that causes a heart condition known as calcific aortic valve disease (CAVD) were more likely to get the disease if they had short telomeres. CAVD causes the heart valves and vessels to turn hard as rock due to a buildup of calcium. It’s the third leading cause of heart disease and the only effective treatment requires surgery to replace the calcified parts of the heart.

Old age and mutations in one of the copies of the NOTCH1 gene can cause CAVD in humans. However, attempts to model CAVD in mice using the same NOTCH1 mutation have failed to produce symptoms of the disease. The team at Gladstone knew that mice inherently have longer telomeres than humans and hypothesized that these longer telomeres could protect mice with the NOTCH1 mutation from getting CAVD.

They decided to study NOTCH1 mutant mice that had short telomeres and found that these mice had symptoms of CAVD including hardened arteries. Furthermore, mice that had the shortest telomeres had the most severe heart-related symptoms.

First author on the study Christina Theodoris, explained in a Gladstone news release how telomere length matters in animal models of age-related diseases:

“Our findings reveal a critical role for telomere length in a mouse model of age-dependent human disease. This model provides a unique opportunity to dissect the mechanisms by which telomeres affect age-dependent disease and also a system to test novel therapeutics for aortic valve disease.”

Deepak Srivastava and Christina Theodoris created mouse models of CAVD that may be used to test drug therapies for the disease. (Photo: Chris Goodfellow, Gladstone Institutes)

The team believes that there is a direct relationship between short telomeres and CAVD, likely through alterations in the activity of gene networks related to CAVD. They also propose that telomere length could influence how severe the symptoms of this disease manifest in humans.

This study is important to the field because it offers a new strategy to study age-related diseases in animal models. Senior author on the study, Dr. Deepak Srivastava, elaborated on this concept:

Deepak Srivastava, Gladstone Institutes

“Historically, we have had trouble modeling human diseases caused by mutation of just one copy of a gene in mice, which impedes research on complex conditions and limits our discovery of therapeutics. Progressive shortening of longer telomeres that are protective in mice not only reproduced the clinical disease caused by NOTCH1 mutation, it also recapitulated the spectrum of disease severity we see in humans.”

Going forward, the Gladstone team will use their new mouse model of CAVD to test drug candidates that have the potential to treat CAVD in humans. If you want to learn more about this study, watch this Gladstone video featuring an interview of Dr. Srivastava about this publication.

Stem Cell Stories that caught our eye: a womb with a view, reversing aging and stabilizing stem cells

/ Karen Ring / Leave a comment

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.

Today we bring you a trifecta of stem cell stories that were partially funded by grants from CIRM.

A womb with a view: using 3D imaging to observe embryo implantation. Scientists have a good understanding of how the beginning stages of pregnancy happen. An egg cell from a woman is fertilized by a sperm cell from a man and the result is a single cell called a zygote. Over the next week, the zygote divides into multiple cells that form the developing embryo. At the end of that period, the embryo hatches out of its protective membrane and begins implanting itself into the lining of the mother’s uterus.

It’s possible to visualize the early stages of embryo development in culture dishes, which has helped scientists understand the biological steps required for an embryo to survive and develop into a healthy fetus. However, something that is not easy to observe is the implantation stage of the embryo in the uterus. This process is complex and involves a restructuring of the uterine wall to accommodate the developing embryo. As you can imagine, replicating these events would be extremely complicated and difficult to do in a culture dish, and current imaging techniques aren’t adequate either.

That’s where new CIRM-funded research from a team at UCSF comes to the rescue. They developed a 3D imaging technology and combined it with a previously developed “tissue clearing” method, which uses chemicals to turn tissues translucent, to provide clear images of the uterine wall during embryo implantation in mice. Their work was published this week in the journal Development.

According to a UCSF news release,

“Using their new approach, the team observed that the uterine lining becomes extensively folded as it approaches its window of receptivity for an embryo to implant. The geometry of the folds in which the incoming embryos dwell is important, the team found, as genetic mutants with defects in implantation have improper patterns of folding.”

Ultimately, the team aims to use their new imaging technology to get an inside scoop on how to prevent or treat pregnancy disorders and also how to improve the outcome of pregnancies by in vitro fertilization.

Senior author on the study, UCSF professor Diana Laird concluded:

“This new view of early pregnancy lets us ask fundamentally new questions about how the embryo finds its home within the uterus and what factors are needed for it to implant successfully. Once we can understand how these processes happen normally, we can also ask why certain genetic mutations cause pregnancies to fail, to study the potential dangers of environmental toxins such as the chemicals in common household products, and even why metabolic disease and obesity appears to compromise implantation.”

If you want to see this womb with a view, check out the video below.

Watch these two videos for more information:

Salk scientists reverse signs of aging in mice. For our next scintillating stem cell story, we’re turning back the clock – the aging clock that is. Scientists from the Salk Institute in La Jolla, reported an interesting method in the journal Cell  that reverses some signs of aging in mice. They found that periodic expression of embryonic stem cell genes in skin cells and mice could reverse some signs of aging.

The Salk team made use of cellular reprogramming tools developed by the Nobel Prize winning scientist Shinya Yamanaka. He found that four genes normally expressed in embryonic stem cells could revert adult cells back to a pluripotent stem cell state – a process called cellular reprogramming. Instead of turning adult cells back into stem cells, the Salk scientists asked whether the Yamanaka factors could instead turn back the clock on older, aging cells – making them healthier without turning them back into stem cells or cancer-forming cells.

The team found that they could rejuvenate skin cells from mice without turning them back into stem cells if they turned on the Yamanaka genes on for a short period of time. These skin cells were taken from mice that had progeria – a disease that causes them to age rapidly. Not only did their skin cells look and act younger after the treatment, but when the scientists used a similar technique to turn on the Yamanaka genes in progeria mice, they saw rejuvenating effects in the mice including a more rapid healing and regeneration of muscle and pancreas tissue.

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

(Left) impaired muscle repair in aged mice; (right) improved muscle regeneration in aged mice subjected to reprogramming. (Salk Institute)

The senior author on the study, Salk Professor Juan Carlos Izpisua Belmonte, acknowledged in a Salk news release that this is early stage work that focuses on animal models, not humans:

“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person. But this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought.”

This story was very popular, which is not surprising as aging research is particularly fascinating to people who want to live longer lives. It was covered by many news outlets including STATnews, Scientific American and Science Magazine. I also recommend reading Paul Knoepfler’s journal club-style blog on the study for an objective take on the findings and implications of the study. Lastly, you can learn more about the science of this work by watching the movie below by the Salk.

Movie:

Stabilizing unstable stem cells. Our final stem cell story is brought to you by scientists from the UCLA Broad Stem Cell Research Center. They found that embryonic stem cells can harbor genetic instabilities that can be passed on to their offspring and cause complications, or even disease, later in life. Their work was published in two separate studies in Cell Stem Cell and Cell Reports.

The science behind the genetic instabilities is too complicated to explain in this blog, so I’ll refer you to the UCLA news release for more details. In brief, the UCLA team found a way to reverse the genetic instability in the stem cells such that the mature cells that they developed into turned out healthy.

As for the future impact of this research, “The research team, led by Kathrin Plath, found a way to correct the instability by resetting the stem cells from a later stage of development to an earlier stage of development. This fundamental discovery could have great impact on the creation of healthy tissues to cure disease.”

Trash talking and creating a stem cell community

/ Kevin McCormack / Leave a comment

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Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.

Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.

The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.

One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.

Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.

Unlocking the secrets of premature aging

Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.

Creating a Community

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Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it’s 4th annual conference and the theme was “Culturing a Stem Cell Community.”

The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.

What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.

Bridging the divide

But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.

All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.

 

Scientists tackle aging by stabilizing defective blood stem cells in mice

/ Karen Ring / Leave a comment

Aging is an inevitable process that effects every cell, tissue, and organ in your body. You can live longer by maintaining a healthy, active lifestyle, but there is no magic pill that can prevent your body’s natural processes from slowly breaking down and becoming less efficient. As author Chinua Achebe would say, “Things Fall Apart”.

Adult stem cells are an unfortunate victim of the aging process. They have the important job of replenishing the cells in your body throughout your lifetime. However, as you grow older, adult stem cells lose their regenerative ability and fail to maintain the integrity and function of their tissues and organs. This can happen for a number of reasons, but no matter the cause, dysfunctional stem cells can accelerate aging and contribute to a shortened lifespan.

So to put it simply, aging adult stem cells = decline in stem cell function = shortened lifespan.

Dysfunctional blood stem cells make an unhappy immune system

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

A good example of this process is hematopoietic stem cells (HSCs), which are adult stem cells found in bone marrow that make all the cells in our blood and immune system. When HSCs get old, they lose their edge and fail to generate some of the important blood cell types that are crucial for a healthy immune system. This can be life-threatening for elderly people who are at higher risk for infections and disease.

So how can we improve the function of aging HSCs to boost the immune system in older people and potentially extend their healthy years of life? A team of researchers from Germany might have an answer. They’ve identified a genetic switch that revitalizes aged, defective HSCs in mice and prolongs their lifespan. They published their findings this week in Nature Cell Biology.

Identifying the Per-petrator for aging HSCs

The perpetrator in this story is a gene called Per2. The team identified Per2 through a genetic screen of hundreds of potential tumor suppressor genes that could potentially impair the regenerative abilities of HSCs in response to DNA damage caused by aging.

It turns out that the Per2 gene is turned on in a subset of HSCs, called lymphoid-HSCs, that preferentially generate blood cells in the lymphatic system. These include B and T cells, both important parts of our immune system. When Per2 is turned on in lymphoid-HSCs, it activates the DNA damage response pathway. While responding to DNA damage may sound like a good thing, it also slows down the cell division process and prevents lymphoid-HSCs from producing their normal amount of lymphoid cells. Adding insult to injury, Per2 also activates the p53-dependent apoptosis pathway, which causes programmed cell death and further reduces the number of HSCs in reserve.

To address these problems, the team decided to delete the Per2 gene in mice and study the function of their HSCs as they aged. They found that removing Per2 stabilized lymphoid-HSCs and rescued their ability to generate the appropriate number of lymphoid cells. Per2 deletion also boosted their immune system, making the mice less susceptible to infection, and extended their lifespan by as much as 15 percent.

A key finding was that deleting Per2 did not increase the incidence of tumors in the aging mice – a logical concern as Per2 mutations in humans are link to increased cancer risk.

Per2 might not be a Per-fect solution for healthy aging

In summary, getting rid of Per2 in the HSCs of older mice improves their function and the function of their immune system while also extending their lifespan.

Senior author on the study, Karl Lenhard Rudolph, commented about their findings in a news release:

Karl Lenhard Rudolph. Photo: Anne Günther/FSU

Karl Lenhard Rudolph.

“All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly.”

 

 

So Per2 may be a good healthy aging target in mice, but the real question is whether these results will translate to humans. Per2 is a circadian rhythm gene and is important for regulating the sleep-wake cycle. Deleting this gene in humans could cause sleep disorders and other unwanted side effects.

Rudolph acknowledges that his team needs to move their focus from mouse to humans.

“It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging — it is of great interest for us to further investigate this question.”