Scientists tackle aging by stabilizing defective blood stem cells in mice

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.”

While You Were Away: Gene Editing Treats Mice with Duchenne Muscular Dystrophy

Welcome back everyone! I hope you enjoyed your holiday and are looking forward to an exciting new year. My favorite thing about coming back from vacation is to see what cool new science was published. Because as you know, science doesn’t take a vacation!

As I was reading over the news for this past week, one particular story stood out. On New Year’s Eve, Science magazine published three articles (here, here, here) simultaneously that successfully used CRISPR/Cas9 gene editing to treat mice that have Duchenne muscular dystrophy (DMD).

DMD is a rare, genetic disease that affects approximately 1 in 3,600 boys in the US. It’s caused by a mutation in the dystrophin gene, which generates a protein that is essential for normal muscle function. DMD causes the body’s muscles to weaken and degenerate, leaving patients deformed and unable to move. It’s a progressive disease, and the average life expectancy is around 25 years. Though there are treatments that help prolong or control the onset of symptoms, there is no cure for DMD.

Three studies use CRISPR to treat DMD in mice

For those suffering from this debilitating disease, there is hope for a new therapy – a gene therapy that is. Three groups from UT Southwestern, Harvard, and Duke, used the CRISPR gene editing method to remove and correct the mutation in the dystrophin gene in mice with DMD. All three used a safe viral delivery method to transport the CRISPR/Cas9 gene editing complex to the proper location on the dystrophin gene in the mouse genome. There, the complex was able to cut out the mutated section of DNA and paste together a version of the gene that could produce a functional dystrophin protein.

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

This technique was tested in newly born mice as well as in adult mice by injecting the virus into the mouse circulatory system (so that the gene editing could happen everywhere) or into specific areas like the leg muscle to target muscle cells and stem cells. After the gene editing treatment, all three studies found restored expression of the dystrophin protein in heart and skeletal muscle tissue, which are the main tissues affected in DMD. They were also able to measure improved muscle function and strength in the animals.

This is really exciting news for the DMD field, which has been waiting patiently for an approved therapy. Currently, two clinical trials are underway by BioMarin and Sarepta Therapeutics, but the future of these drugs is uncertain. A gene therapy that could offer a “one-time cure” would certainly be a more attractive option for these patients.

Charles Gersbach, Duke University

Charles Gersbach, Duke University

It’s important to note that none of these gene editing studies reported a complete cure. However, the results are still very promising. Charles Gersbach, senior author on the Duke study, commented, “There’s a ton of room for optimization of these approaches.”

Strong media coverage of DMD studies

The implications of these studies are potentially huge and suitably, these studies were covered by prominent news outlets like Science News, STAT News, The Scientist, and The New York Times.

What I like about the news coverage on the DMD studies is that the results and implications aren’t over hyped. All of the articles mention the promise of this research, but also mention that more work needs to be done in mice and larger animals before gene therapy can be applied to human DMD patients. The words “safe” or “safety” was used in each article, which signals to me that both the science and media worlds understand the importance of testing promising therapies rigorously before attempting in humans on a larger scale.

However, it does seem that CRISPR gene editing for DMD could reach clinical trials in the next few years. Charles Gersbach told STATnews that he could see human clinical trials using this technology in a few years after scientists properly test its safety. He also mentioned that they first will need to understand “how the human immune system will react to delivery of  the CRISPR complex within the body.” He went on, “The hope for gene editing is that if we do this right, we will only need to do one treatment. This method, if proven safe, could be applied to patients in the foreseeable future.”

Eric Olson, UT Southwestern

Eric Olson, UT Southwestern

Eric Olson, senior author on the UT Southwestern study, had a similar opinion, “To launch a clinical trial, we need to scale up, improve efficiency and assess safety. I think within a few years, those issues can be addressed.”

 


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Could We Reverse Alzheimer’s Disease with Stem Cells?

What if you could give people whose memories have been stolen the ability to remember again? I’m talking about curing a population of more than 5 million Americans living with Alzheimer’s disease (AD) – not a small task. Unfortunately, this number is predicted to more than triple by 2050, and with it so will healthcare costs and other burdens to society. The situation is dire enough that president Barack Obama signed a law last year that increased the amount of money to fund AD research, education, outreach, and caregiver support.

This weekend, a story was picked up in the news that brings hope for AD research. South China Morning Post covered a scientific study that claims it can reverse memory loss in mice with Alzheimer’s using a cell-based therapy. The study was published in Stem Cell Reports in mid October by a group of Chinese scientists.

Although the study is still in its early stages and the results are preliminary, what I like about it is its simplicity and logic. The authors decided to generate a type of nerve cell that is typically lost (or dysfunctional) in the brains of AD patients and some mouse models of AD. It’s called a basal forebrain cholinergic neuron, and it lives in an area near the bottom of our brains that’s responsible for processing certain functions such as learning and attention. The scientists proposed that they would replace these lost nerve cells in AD mice with healthy nerve cells derived from stem cells in hopes of restoring memory function.

How they did it

The authors first devised methods to make these specific nerve cells from both mouse and human embryonic stem cells in a dish. They were successful in making nerve cells that expressed the correct markers for cholinergic neurons and functioned properly, meaning they could send the correct electrical signals to other nerve cells.

The next step was to test the functionality of the nerve cells in mouse models of AD. Instead of transplanting adult nerve cells into the brain (which don’t survive very well), the authors transplanted progenitor cells, which developmentally, are more specialized than stem cells and eventually become adult nerve cells.

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Brain section from an Alzheimer’s mouse that received a transplant of progenitor cells (green) into the basal forebrain. (Yue et al., 2015)

When the mouse progenitor cells were transplanted into the basal forebrain of AD mice, most of them survived and matured into adult cholinergic nerve cells that were able to function in tandem with the original mouse nerve cells. When they transplanted human progenitor cells into the same area, a majority of the transplanted human cells did not survive (likely due to the mouse immune system rejecting them), however, the ones that did were able to turn into functioning cholinergic neurons.

Then came the final question, could the mouse and human progenitors improve the memory of these forgetful mice? The scientists compared the memories of AD mice that had received mouse or human cholinergic progenitor cells to AD mice that received no treatment and to healthy normal mice. The groups were put through a memory test where they were trained to find a hidden platform in a circular pool of water. Untreated AD mice had trouble finding the platform and couldn’t remember where it was in subsequent trials. However, the AD mice that received either mouse or human progenitor cell transplants six to eight weeks before were able to find the platform more quickly and remember where it was in multiple trials. This suggested that the transplanted nerve cells improved their ability to learn tasks and recall memories.

The water maze tests a mouse's ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

The water maze tests a mouse’s ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

Hold on: Primates before humans

So it seems from this study that replacing cholinergic nerve cells in the basal forebrain area of the brain is a potential approach to reversing memory loss in Alzheimer’s disease. However, the study’s senior author, Naihe Jing, cautioned everyone to not get ahead of themselves.

Dr. Naihe Jing, Shanghai Institutes of Biological Science

Dr. Naihe Jing

Mice are still very different from humans, so the results on mice do not guarantee the same success on human patients. Our next step is to test the method on primates. It will probably be a long time before clinical trials can be carried out on human volunteers.

 

But he also explained that his group is thoroughly testing the safety of their embryonic stem cell based therapy.

We used human embryonic stem cells because this method will eventually be used on humans. If the human neurons can get a footing and grow in the brain of a mouse, the chance is high the effect will be even better on a human host. The biggest concern of this development is safety. We were afraid that the transplanted cells would mutate to other types of neurons or even cause brain tumours. We have been improving the technology and making close observation of the mice for more than seven years. So far no mutation or cancerous development has been detected.

So while we might not have a cell therapy to treat Alzheimer’s in the near future, we can be comforted by the fact that groups like this one are taking all the precautions to develop safe and effective treatments.


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