Proceedings of the National Academy of Sciences

A new way to evade immune rejection in transplanting cells

/ Kevin McCormack / 2 Comments
Immune fluorescence of HIP cardiomyocytes in a dish; Photo courtesy of UCSF

Transplanting cells or an entire organ from one person to another can be lifesaving but it comes with a cost. To avoid the recipient’s body rejecting the cells or organ the patient has to be given powerful immunosuppressive medications. Those medications weaken the immune system and increase the risk of infections. But now a team at the University of California San Francisco (UCSF) have used a new kind of stem cell to find a way around that problem.

The cells are called HIP cells and they are a specially engineered form of induced pluripotent stem cell (iPSC). Those are cells that can be turned into any kind of cell in the body. These have been gene edited to make them a kind of “universal stem cell” meaning they are not recognized by the immune system and so won’t be rejected by the body.

The UCSF team tested these cells by transplanting them into three different kinds of mice that had a major disease; peripheral artery disease; chronic obstructive pulmonary disease; and heart failure.

The results, published in the journal Proceedings of the National Academy of Science, showed that the cells could help reduce the incidence of peripheral artery disease in the mice’s back legs, prevent the development of a specific form of lung disease, and reduce the risk of heart failure after a heart attack.

In a news release, Dr. Tobias Deuse, the first author of the study, says this has great potential for people. “We showed that immune-engineered HIP cells reliably evade immune rejection in mice with different tissue types, a situation similar to the transplantation between unrelated human individuals. This immune evasion was maintained in diseased tissue and tissue with poor blood supply without the use of any immunosuppressive drugs.”

Deuse says if this does work in people it may not only be of great medical value, it may also come with a decent price tag, which could be particularly important for diseases that affect millions worldwide.

“In order for a therapeutic to have a broad impact, it needs to be affordable. That’s why we focus so much on immune-engineering and the development of universal cells. Once the costs come down, the access for all patients in need increases.”

A guide to healing

/ Kevin McCormack / 3 Comments
Dr. Evan Snyder

Having grown up in an era where to find your way around you had to use paper maps, a compass and a knowledge of the stars (OK, I’m not actually that old!) I’m forever grateful to whoever invented the GPS. It’s a lifesaver, and I daresay has also saved more than a few marriages!

Having a way to guide people where they need to be is amazing. Now researchers at Sanford Burnham Prebys Medical Discovery Institute have come up with a similar tool for stem cells. It’s a drug that can help guide stem cells to go where they need to go, to repair damaged tissue and improve the healing process.

In a news release Evan Snyder, MD, PhD, the senior author of the study, explained in wonderfully simply terms what they have done:

“The ability to instruct a stem cell where to go in the body or to a particular region of a given organ is the Holy Grail for regenerative medicine. Now, for the first time ever, we can direct a stem cell to a desired location and focus its therapeutic impact.”

More than a decade ago Snyder and his team discovered that when our body suffers an injury the result is often inflammation and that this then sends out signals for stem cells to come and help repair the damage. This is fine when the problem is a cut or sprain, short term issues in need of a quick fix. But what happens if it’s something more complex, such as a heart attack or stroke where the need is more long term.

In the study, funded in part by CIRM, the team took a molecule, called CXCL12, known to help guide stem cells to damaged tissue, and used it to create a drug called SDV1a. Snyder says this new drug has several key properties.

“Since inflammation can be dangerous, we modified CXCL12 by stripping away the risky bit and maximizing the good bit. Now we have a drug that draws stem cells to a region of pathology, but without creating or worsening unwanted inflammation.”

To test the drug to see how well it worked the team implanted SDV1a and some human brain stem cells into mice with Sandhoff disease, a condition that progressively destroys cells in the brain and spinal cord. They were able to demonstrate that the drug helped the stem cells migrate to where they were needed and to help in repairing the damage. The treated mice had a longer lifespan and better motor function, as well as developing symptoms later than untreated mice.

The team is now testing this drug to see if it has any impact on ALS, also known as Lou Gehrig’s disease. And Snyder says there are other areas where it could prove effective.

“We are optimistic that this drug’s mechanism of action may potentially benefit a variety of neurodegenerative disorders, as well as non-neurological conditions such as heart disease, arthritis and even brain cancer. Interestingly, because CXCL12 and its receptor are implicated in the cytokine storm that characterizes severe COVID-19, some of our insights into how to selectively inhibit inflammation without suppressing other normal processes may be useful in that arena as well.”

CIRM’s President & CEO, Dr. Maria Millan, says this kind of work highlights the important role the stem cell agency plays, in providing long-term support for promising but early stage research.

“Thanks to decades of investment in stem cell science, we are making tremendous progress in our understanding of how these cells work and how they can be harnessed to help reverse injury or disease. Dr. Snyder’s group has identified a drug that could boost the ability of neural stem cells to home to sites of injury and initiate repair. This candidate could help speed the development of stem cell treatments for conditions such as spinal cord injury and Alzheimer’s disease.”

The discovery is published in the Proceedings of the National Academy of Sciences (PNAS)

Lab-grown human sperm cells could unlock treatments for infertility

/ Kevin McCormack / 1 Comment
Dr. Miles Wilkinson: Photo courtesy UCSD

Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.

The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.

In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”

Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.

So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.

This image has an empty alt attribute; its file name is wilkinson-ssc-graphic_450px.jpg
Illustrations by Vishaala Wilkinson

The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.

The study is published in the journal Proceedings of the National Academy of Science.

A recap on last week: two gut wrenching studies

/ Yimy Villa / Leave a comment
Fluorescent pictures of a human colon organoid
Image credit: Dr Thierry Jarde

With everyone stocking up on food essentials this past week, it brings to mind the vital role that our stomach plays in order to properly digest these foods. This week, we wanted to share two separate studies related to aspects of the gut.

Promising results for a gut-related condition

Gastroparesis is a painful condition in which the stomach is unable to empty itself of food. Symptoms include heartburn, abdominal cramps, nausea, vomiting, and feeling full quickly when eating. In extremely severe cases, patients can experience dehydration, malnutrition and bezoars, a small stone-like matter that forms when food hardens and can block the opening from the stomach into the pylorus (small intestine).

A new study, led by Dr. Prabhash Dadhich and Dr. Khalil N Bitar at Wake Forest School of Medicine showed how a stem cell-combo therapy could bring long-term relief to these patients.

The team of scientists used interstitial cells of Cajal (ICCs), a type of stem cell found in the gastrointestinal tract, in combination with neural stem cells. An animal model similar to gastroparesis was then made using tissue from the small intestine of rats. The combination of stem cells were then injected into the small intestine tissue, where the cells were able to survive and integrate with host muscle layers.

In a news release, Dr. Bitar explains how this approach could potentially restore stomach muscle function and enable normal food digestion.

“Our analysis also confirmed the reinstatement and restoration of the stomach muscles’ functionality, both of which are critical in the treatment of pylorus dysfunctionality. These findings are very promising. We hope this study opens avenues for future cell-based clinical applications.”

The full study was published in Stem Cells Journals.

Superbug can damage stem cells in the gut

Clostridioides difficile (C. diff)
Image courtesy of the Central for Disease Control (CDC) website

A collaboration by the Monash Biomedicine Discovery Institute (BDI) has revealed that a bacterial superbug can prevent stem cells in the gut from regenerating the inner lining of the intestine.

Clostridioides difficile (C. diff) is a bacterial germ that is responsible for more than half of all hospital infections related to the gut and causes severe diarrhea. It usually grows after antibiotic treatment is administered to a patient.

The team of scientists found that C. diff damages stem cells in the colon, which in turn can cause problems with tissue repair and recovery.

In a press release, Professor Helen Abud, an expert in stem cell biology and one of the authors of this study, explains how this discovery can have wider implications.

“Our study provides the first direct evidence that a microbial infection alters the functional capacity of gut stem cells. It adds a layer of understanding about how the gut repairs after infection and why this superbug can cause the severe damage that it does. The reason it’s important to have that understanding is that we’re rapidly running out of antibiotics – we need to find other ways to prevent and treat these infections.”

The full results to this study were published in Proceedings of the National Academy of Sciences (PNAS).

Stem cell stories that caught our eye: update on Capricor’s heart attack trial; lithium on the brain; and how stem cells do math

/ Kevin McCormack / Leave a comment

Capricor ALLSTARToday our partners Capricor Therapeutics announced that its stem cell therapy for patients who have experienced a large heart attack is unlikely to meet one of its key goals, namely reducing the scar size in the heart 12 months after treatment.

The news came after analyzing results from patients at the halfway point of the trial, six months after their treatment in the Phase 2 ALLSTAR clinical trial which CIRM was funding. They found that there was no significant difference in the reduction in scarring on the heart for patients treated with donor heart-derived stem cells, compared to patients given a placebo.

Obviously this is disappointing news for everyone involved, but we know that not all clinical trials are going to be successful. CIRM supported this research because it clearly addressed an unmet medical need and because an earlier Phase 1 study had showed promise in helping prevent decline in heart function after a heart attack.

Yet even with this failure to repeat that promise in this trial,  we learned valuable lessons.

In a news release, Dr. Tim Henry, Director of the Division of Interventional Technologies in the Heart Institute at Cedars-Sinai Medical Center and a Co-Principal Investigator on the trial said:

“We are encouraged to see reductions in left ventricular volume measures in the CAP-1002 treated patients, an important indicator of reverse remodeling of the heart. These findings support the biological activity of CAP-1002.”

Capricor still has a clinical trial using CAP-1002 to treat boys and young men developing heart failure due to Duchenne Muscular Dystrophy (DMD).

Lithium gives up its mood stabilizing secrets

As far back as the late 1800s, doctors have recognized that lithium can help people with mood disorders. For decades, this inexpensive drug has been an effective first line of treatment for bipolar disorder, a condition that causes extreme mood swings. And yet, scientists have never had a good handle on how it works. That is, until this week.

evan snyder

Evan Snyder

Reporting in the Proceedings of the National Academy of Sciences (PNAS), a research team at Sanford Burnham Prebys Medical Discovery Institute have identified the molecular basis of the lithium’s benefit to bipolar patients.  Team lead Dr. Evan Snyder explained in a press release why his group’s discovery is so important for patients:

“Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks.”

The study, funded in part by CIRM, attempted to understand lithium’s beneficial effects by comparing cells from patient who respond to those who don’t (only about a third of patients are responders). Induced pluripotent stem cells (iPSCs) were generated from both groups of patients and then the cells were specialized into nerve cells that play a role in bipolar disorder. The team took an unbiased approach by looking for differences in proteins between the two sets of cells.

The team zeroed in on a protein called CRMP2 that was much less functional in the cells from the lithium-responsive patients. When lithium was added to these cells the disruption in CRMP2’s activity was fixed. Now that the team has identified the molecular location of lithium’s effects, they can now search for new drugs that do the same thing more effectively and with fewer side effects.

The stem cell: a biological calculator?

math

Can stem cells do math?

Stem cells are pretty amazing critters but can they do math? The answer appears to be yes according to a fascinating study published this week in PNAS Proceedings of the National Academy of Sciences.

Stem cells, like all cells, process information from the outside through different receptors that stick out from the cells’ outer membranes like a satellite TV dish. Protein growth factors bind those receptors which trigger a domino effect of protein activity inside the cell, called cell signaling, that transfers the initial receptor signal from one protein to another. Ultimately that cascade leads to the accumulation of specific proteins in the nucleus where they either turn on or off specific genes.

Intuition would tell you that the amount of gene activity in response to the cell signaling should correspond to the amount of protein that gets into the nucleus. And that’s been the prevailing view of scientists. But the current study by a Caltech research team debunks this idea. Using real-time video microscopy filming, the team captured cell signaling in individual cells; in this case they used an immature muscle cell called a myoblast.

goentoro20170508

Behavior of cells over time after they have received a Tgf-beta signal. The brightness of the nuclei (circled in red) indicates how much Smad protein is present. This brightness varies from cell to cell, but the ratio of brightness after the signal to before the signal is about the same. Image: Goentoro lab, CalTech.

To their surprise the same amount of growth factor given to different myoblasts cells led to the accumulation of very different amounts of a protein called Smad3 in the cells’ nuclei, as much as a 40-fold difference across the cells. But after some number crunching, they discovered that dividing the amount of Smad3 after growth factor stimulation by the Smad3 amount before growth stimulation was similar in all the cells.

As team lead Dr. Lea Goentoro mentions in a press release, this result has some very important implications for studying human disease:

“Prior to this work, researchers trying to characterize the properties of a tumor might take a slice from it and measure the total amount of Smad in cells. Our results show that to understand these cells one must instead measure the change in Smad over time.”