The present and future of regenerative medicine

One of the great pleasures of my job is getting to meet the high school students who take part in our SPARK or Summer Internship to Accelerate Regenerative Medicine Knowledge program. It’s a summer internship for high school students where they get to spend a couple of months working in a world class stem cell and gene therapy research facility. The students, many of whom go into the program knowing very little about stem cells, blossom and produce work that is quite extraordinary.

One such student is Tan Ieng Huang, who came to the US from China for high school. During her internship at U.C. San Francisco she got to work in the lab of Dr. Arnold Kriegstein. He is the Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco. Not only did she work in his lab, she took the time to do an interview with him about his work and his thoughts on the field.

It’s a fascinating interview and shows the creativity of our SPARK students. You will be seeing many other examples of that creativity in the coming weeks. But for now, enjoy the interview with someone who is a huge presence in the field today, by someone who may well be a huge presence in the not too distant future.

‘a tête-à-tête with Prof. Arnold Kriegstein’

The Kriegstein lab team: Photo courtesy UCSF

Prof. Arnold Kriegstein is the Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco. Prof. Kriegstein is also the Co-Founder and Scientific Advisor of Neurona Therapeutics which seeks to provide effective and safe cell therapies for chronic brain disorder. A Clinician by training, Prof. Kriegstein has been fascinated by the intricate workings of the human brain. His laboratory focuses on understanding the transcriptional and signaling networks active during brain development, the diversity of neuronal cell types, and their fate potential. For a long time, he has been interested in harnessing this potential for translational and therapeutic intervention.

During my SEP internship I had the opportunity to work in the Kriegstein lab. I was in complete awe. I am fascinated by the brain. During the course of two months, I interacted with Prof. Kriegstein regularly, in lab meetings and found his ideas deeply insightful. Here’s presenting some excerpts from some of our discussions, so that it reaches many more people seeking inspiration!

Tan Ieng Huang (TH): Can you share a little bit about your career journey as a scientist?

Prof. Arnold Kriegstein (AK): I wanted to be a doctor when I was very young, but in high school I started having some hands-on research experience. I just loved working in the lab. From then on, I was thinking of combining those interests and an MD/PhD turned out to be an ideal course for me. That was how I started, and then I became interested in the nervous system. Also, when I was in high school, I spent some time one summer at Rockefeller University working on a project that involved operant conditioning in rodents and I was fascinated by behavior and the role of the brain in learning and memory. That happened early on, and turned into an interest in cortical development and with time, that became my career.

TH: What was your inspiration growing up, what made you take up medicine as a career?

AK: That is a little hard to say, I have an identical twin brother. He and I used to always share activities, do things together. And early on we actually became eagle scouts, sort of a boy scout activity in a way. In order to become an eagle scout without having to go through prior steps, we applied to a special program that the scouts had, which allowed us to shadow physicians in a local hospital. I remember doing that at a very young age. It was a bit ironic, because one of the evenings, they showed us films of eye surgery, and my brother actually fainted when they made an incision in the eye. The reason it makes me laugh now is because my brother became an eye surgeon many years later. But I remember our early experience, we both became very fascinated by medicine and medical research.

Tan Ieng and Dr. Arnold Kriegstein at UCSF

TH: What inspired you to start the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Institute?

AK: My interest in brain development over the years became focused on earlier stages of development and eventually Neurogenesis, you know, how neurons are actually generated during early stages of in utero brain development. In the course of doing that we discovered that the radial glial cells, which have been thought for decades to simply guide neurons as they migrate, turned out to actually be the neural stem cells, they were making the neurons and also guiding them toward the cortex. So, they were really these master cells that had huge importance and are now referred to as neural stem cells. But at that time, it was really before the stem cell field took off. But because we studied neurogenesis, because I made some contributions to understanding how the brain develops from those precursors or progenitor cells, when the field of stem cells developed, it was very simple for me to identify as someone who studied neural stem cells. I became a neural stem cell scientist. I started a neural stem cell program at Columbia University when I was a Professor there and raised 15 million dollars to seed the program and hired new scientists. It was shortly after that I was approached to join UCSF as the founder of a new stem cell program. And it was much broader than the nervous system; it was a program that covered all the different tissues and organ systems.

TH: Can you tell us a little bit about how stem cell research is contributing to the treatment of diseases? How far along are we in terms of treatments?

AK: It’s taken decades, but things are really starting to reach the clinic now. The original work was basic discovery done in research laboratories, now things are moving towards the clinic. It’s a really very exciting time. Initially the promise of stem cell science was called Regenerative medicine, the idea of replacing injured or worn-out tissues or structures with new cells and new tissues, new organs, the form of regeneration was made possible by understanding that there are stem cells that can be tweaked to actually help make new cells and tissues. Very exciting process, but in fact the main progress so far hasn’t been replacing worn out tissues and injured cells, but rather understanding diseases using human based model of disease. That’s largely because of the advent of induced pluripotent stem cells, a way of using stem cells to make neurons or heart cells or liver cells in the laboratory, and study them both in normal conditions during development and in disease states. Those platforms which are relatively easy to make now and are pretty common all over the world allow us to study human cells rather than animal cells, and the hope is that by doing that we will be able to produce conventional drugs and treatments that work much better than ones we had in the past, because they will be tested in actual human cells rather than animal cells.

TH: That is a great progress and we have started using human models because even though there are similarities with animal models, there are still many species-specific differences, right?

AK: Absolutely, in fact, one of the big problems now in Big Pharma, you know the drug companies, is that they invest millions and sometimes hundreds of millions of dollars in research programs that are based on successes in treating mice, but patients don’t respond the same way. So the hope is that by starting with a treatment that works on human cells it might be more likely that the treatment will work on human patients.

TH: What are your thoughts on the current challenges and future of stem cell research?

AK: I think this is an absolute revolution in modern medicine, the advent of two things that are happening right now, first the use of induced pluripotent stem cells, the ability to make pluripotent cells from adult tissue or cells from an individual allows us to use models of diseases that I mentioned earlier from actual patients. That’s one major advance. And the other is gene editing, and the combination of gene editing and cell-based discovery science allows us to think of engineering cells in ways that can make them much more effective as a form of cell therapy and those cell therapies have enormous promise. Right now, they are being used to treat cancer, but in the future, they might be able to treat heart attack, dementia, neurodegenerative diseases, ALS, Parkinson’s disease, a huge list of disorders that are untreatable right now or incurable. They might be approached by the combination of cell-based models, cell therapies, and gene editing.

TH: I know there are still some challenges right now, like gene editing has some ethical issues because people don’t know if there can be side effects after the gene editing, what are your thoughts?

AK: You know, like many other technologies there are uncertainties, and there are some issues. Some of the problems are off-target effects, that is you try to make a change in one particular gene, and while doing that you might change other genes in unexpected ways and cause complications. But we are understanding that more and more now and can make much more precise gene editing changes in just individual genes without affecting unanticipated areas of the genome. And then there are also the problems of how to gene-edit cells in a safe way. There are certain viral factors that can be used to introduce the gene editing apparatus into a cell, and sometimes if you are doing that in a patient, you can also have unwanted side effects from the vectors that you are using, often they are modified viral vectors. So, things get complicated very quickly when you start trying to treat patients, but I think these are all tractable problems and I think in time they will all be solved. It will be a terrific, very promising future when it comes to treating patients who are currently untreatable.

TH: Do you have any advice for students who want to get into this field?

AK: Yes, I think it’s actually never been a better time and I am amazed by the technologies that are available now. Gene editing that I mentioned before but also single cell approaches, the use of single cell multiomics revealing gene expression in individual cells, the molecular understanding of how individual cells are formed, how they are shaped, how they change from one stage to another, how they can be forced into different fates. It allows you to envision true Regenerative medicine, improving health by healing or replacing injured or diseased tissues. I think this is becoming possible now, so it’s a very exciting time. Anyone who has an interest in stem cell biology or new ways of treating diseases, should think about getting into a laboratory or a clinical setting. I think this time is more exciting than it’s ever been.

TH: So excited to hear that, because in school we have limited access to the current knowledge, the state-of-art. I want to know what motivates you every day to do Research and contribute to this field?

AK: Well, you know that I have been an MD/PhD, as I mentioned before, in a way, there are two different reward systems at play. In terms of the PhD and the science, it’s the discovery part that is so exciting. Going in every day and thinking that you might learn something that no one has ever known before and have a new insight into a mechanism of how something happens, why it happens. Those kinds of new insights are terrifically satisfying, very exciting. On the MD side, the ability to help patients and improve peoples’ lives is a terrific motivator. I always wanted to do that, was very driven to become a Neurologist and treat both adult and pediatric patients with neurological problems. In the last decade or so, I’ve not been treating patients so much, and have focused on the lab, but we have been moving some of our discoveries from the laboratory into the clinic. We have just started a clinical trial, of a new cell-based therapy for epilepsy in Neurona Therapeutics, which is really exciting. I am hoping it will help the patients but it’s also a chance to actually see something that started out as a project in the laboratory become translated into a therapy for patients, so that’s an achievement that has really combined my two interests, basic science, and clinical medicine. It’s a little late in life but not too late, so I’m very excited about that.

Tan Ieng Huang, Kriegstein Lab, SEP Intern, CIRM Spark Program 2022

Stem cells help researchers map out glaucoma in search for new treatments

Glaucoma is the world’s leading cause of irreversible blindness. There is no cure and current treatments are only able to slow down the progression of the disease. Now research using stem cells to create a genetic blueprint of glaucoma is giving scientist a powerful new tool to combat the disease.

Glaucoma occurs when healthy retinal ganglion cells, which relay information from the eyes to the brain, are damaged and die. However, researchers were unable to really understand what was happening because the only way to look at retinal ganglion cells was through very invasive procedures.

So, researchers in Australia took skin cells from people with glaucoma and people with healthy eyes and, using the iPSC method, turned them into retinal ganglion cells. They were then able to map the genetic expression of these cells and compare the healthy cells with the diseased ones.

In an interview with Science Daily, Professor Joseph Powell , who led the team, says they were able to identify more than 300 unique genetic features which could provide clues as to what is causing the vision loss.

“The sequencing identifies which genes are turned on in a cell, their level of activation and where they are turned on and off like a road network with traffic lights. This research gives us a genetic roadmap of glaucoma and identifies 312 sites in the genome where these lights are blinking. Understanding which of these traffic lights should be turned off or on will be the next step in developing new therapies to prevent glaucoma.”

Powell says by identifying underlying causes for glaucoma researchers may be able to develop new, more effective therapies.

The study is published in Cell Genomics.

Replacement brain cells offer hope for Parkinson’s treatment

A colony of iPSCs from a Parkinson’s patient (left) and dopaminergic neurons made from these iPSCs (right) to model PD. (Image credit: Jeanne Loring)

A new study that used adult blood stem cells to create replacement brain nerve cells appears to help rats with Parkinson’s.

In Parkinson’s, the disease attacks brain nerve cells that produce a chemical called dopamine. The lack of dopamine produces a variety of symptoms including physical tremors, depression, anxiety, insomnia and memory problems. There is no cure and while there are some effective treatments they tend to wear off over time.

In this study, researchers at Arizona State University took blood cells from humans and, using the iPSC method, changed those into dopamine-producing neurons. They then cultured those cells in the lab before implanting them in the brains of rats which had Parkinson’s-like symptoms.

They found that rats given cells that had been cultured in the lab for 17 days survived in greater numbers and seemed to be better at growing new connections in their brains, compared to rats given cells that had been cultured for 24 or 37 days.

In addition, those rats given larger doses of the cells experienced a complete reversal of their symptoms, compared to rats given smaller doses.

In a news release, study co-author Dr. Jeffrey Kordower, said: “We cannot be more excited by the opportunity to help individuals who suffer from [a] genetic form of Parkinson’s disease, but the lessons learned from this trial will also directly impact patients who suffer from sporadic, or non-genetic forms of this disease.”

The study, published in the journal npj Regenerative Medicine, says this approach might also help people suffering from other neurological diseases like Alzheimer’s or Huntington’s disease.

COVID is a real pain in the ear

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The more you learn about COVID-19 the more there is to dislike about it. The global death toll from the virus is now more than five million and for those who survive there can be long-term health consequences. We know COVID can attack the lungs, heart and brain. Now we are learning it can also mess up your ears causing hearing problems, ringing in the ear (tinnitus) and leave you dizzy.

Viral infections are a known cause of hearing loss and other kinds of infection. That’s why, before the pandemic started, Dr. Konstantina Stantovic at Massachusetts Eye and Ear and Dr. Lee Gherke at MIT had been studying how and why things like measles, mumps and hepatitis affected people’s hearing. After COVID hit they heard reports of patients experiencing sudden hearing loss and other problems, so they decided to take a closer look.

They took cells from ten patients who had all experienced some hearing or ear-related problems after testing positive for COVID and, using the iPSC method, turned those cells into the kind found in the inner ear including hair cells, supporting cells, nerve fibers, and Schwann cells.  

They then compared those to cells from patients who had similar hearing issues but who had not been infected with COVID. They found that the hair and Schwann cells both had proteins the virus can use to infect cells. That’s important because hair cells help with balance and the Schwann cells play a protective role for neuronal axons, which help different nerve cells in the brain communicate with each other.

In contrast, some of the other cells in the inner ear didn’t have those proteins and so were protected from COVID.

In a news release Dr. Stankovic says it’s not known how many people infected with COVID experienced hearing issues. “Initially this was because routine testing was not readily available for patients who were diagnosed with COVID, and also, when patients were having more life-threatening complications, they weren’t paying much attention to whether their hearing was reduced or whether they had tinnitus. We still don’t know what the incidence is, but our findings really call for increased attention to audio vestibular symptoms in people with Covid exposure.”

The doctors are not sure how the virus gets into the inner ear but speculate that it may enter through the Eustachian tube, that’s a small passageway that connects your throat to your middle ear. When you sneeze, swallow, or yawn, your Eustachian tubes open, preventing air pressure and fluid from building up inside your ear. They think that might allow particles from the nose to spread to the ear.

The study is published in the journal Communications Medicine.

CIRM has funded 17 different projects targeting COVID-19, several of which are still active.

A step forward in finding a treatment for a deadly neurological disorder

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MRI section of a brain affected by ALS with the front section of the brain highlighted

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a nasty disease that steadily attacks nerve cells in the brain and spinal cord. It’s pretty much always fatal within a few years. As if that wasn’t bad enough, ALS also can overlap with a condition called frontotemporal dementia (ALS/FTD). Together these conditions cause devastating symptoms of muscle weakness along with changes in memory, behavior and personality.

Now researchers at Cambridge University in the UK have managed to grow groups of cells called “mini-brains” that mimic ALS/FTD and could lead to new approaches to treating this deadly combination.

We have written about these mini-brains before. Basically, they are created, using the iPSC method, that takes skin or blood cells from a patient with a particular condition, in this case ALS/FTD, and turns them into the kind of nerve cells in the brain affected by the disease. Because they came from someone who had ALS/FTD they display many of the characteristics of the disease and this gives researchers a great tool to study the condition.

This kind of approach has been done before and given researchers a glimpse into what is happening in the brains of people with ALS/FTD. But in the past those cells were in a kind of clump, and it wasn’t possible to get enough nutrients to the cells in the middle of the clump for the mini-brain to survive for long.

What is different about the Cambridge team is that they were able to create these mini-brains using thin, slices of cells. That meant all the cells could get enough nutrients to survive a long time, giving the team a better model to understand what is happening in ALS/FTD.

In a news release, Dr András Lakatos, the senior author of the study, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

Thanks to these longer-lived cells the team were able to see changes in the mini-brains at a very early stage, including damage to DNA and cell stress, changes that affected other cells which play a role in muscle movements and behavior.

Because the cells developed using the iPSC method are from a patient with ALS/FTD, the researchers were able to use them to screen many different medications to see if any had potential as a therapy. They identified one, GSK2606414, that seemed to help in reducing the build-up of toxic proteins, reduced cell stress and the loss of nerve cells.

The team acknowledge that these results are promising but also preliminary and will require much more research to verify them.

CIRM has funded three clinical trials targeting ALS. You can read about that work here.

Building a better brain (model) in the lab

Leica Picture of a brain organoid: courtesy National Institute of Allergy and Infectious Diseases, NIH

One of the biggest problems with trying to understand what is happening in a disease that affects the brain is that it’s really difficult to see what is going on inside someone’s head. People tend to object to you trying to open their noggin while they are still using it.

New technologies can help, devices such as MRI’s – which chart activity and function by measuring blood flow – or brain scans using electroencephalograms (EEGs), which measure activity by tracking electrical signaling and brain waves. But these are still limited in what they can tell us.

Enter brain organoids. These are three dimensional models made from clusters of human stem cells grown in the lab. They aren’t “brains in a dish” – they can’t function or think independently – but they can help us develop a deeper understanding of how the brain works and even why it doesn’t always work as well as we’d like.

Now researchers at UCLA’s Broad Center of Regenerative Medicine have created brain organoids that demonstrate brain wave activity similar to that found in humans, and even brain waves found in particular neurological disease.

The team – with CIRM funding – took skin tissue from healthy individuals and, using the iPSC method – which enables you to turn these cells into any other kind of cell in the body – they created brain organoids. They then studied both the physical structure of the organoids by examining them under a microscope, and how they were functioning by using a probe to measure brain wave activity.

In a news release Dr. Ranmal Samarasinghe, the first author of the study in the journal Nature Neuroscience, says they wanted to do this double test for a very good reason: “With many neurological diseases, you can have terrible symptoms but the brain physically looks fine. So, to be able to seek answers to questions about these diseases, it’s very important that with organoids we can model not just the structure of the brain but the function as well.”

Next, they took skin cells from people with a condition called Rhett syndrome. This is a rare genetic disorder that affects mostly girls and strikes in the first 18 months of life, having a severe impact on the individual’s ability to speak, walk, eat or even breathe easily. When the researchers created brain organoids with these cells the structure of the organoids looked similar to the non-Rhett syndrome ones, but the brain wave activity was very different. The Rhett syndrome organoids showed very erratic, disorganized brain waves.

When the team tested an experimental medication called Pifithrin-alpha on the Rhett organoids, the brain waves became less erratic and more like the brain waves from the normal organoids.

“This is one of the first tangible examples of drug testing in action in a brain organoid,” said Samarasinghe. “We hope it serves as a stepping stone toward a better understanding of human brain biology and brain disease.”

Paving the way for a treatment for dementia

What happens in a stroke

When someone has a stroke, the blood flow to the brain is blocked. This kills some nerve cells and injures others. The damaged nerve cells are unable to communicate with other cells, which often results in people having impaired speech or movement.

While ischemic and hemorrhagic strokes affect large blood vessels and usually produce recognizable symptoms there’s another kind of stroke that is virtually silent. A ‘white’ stroke occurs in blood vessels so tiny that the impact may not be noticed. But over time that damage can accumulate and lead to a form of dementia and even speed up the progression of Alzheimer’s disease.

Now Dr. Tom Carmichael and his team at the David Geffen School of Medicine at UCLA have developed a potential treatment for this, using stem cells that may help repair the damage caused by a white stroke. This was part of a CIRM-funded study (DISC2-12169 – $250,000).

Instead of trying to directly repair the damaged neurons, the brain nerve cells affected by a stroke, they are creating support cells called astrocytes, to help stimulate the body’s own repair mechanisms.

In a news release, Dr. Irene Llorente, the study’s first author, says these astrocytes play an important role in the brain.

“These cells accomplish many tasks in repairing the brain. We wanted to replace the cells that we knew were lost, but along the way, we learned that these astrocytes also help in other ways.”

The researchers took skin tissue and, using the iPSC method (which enables researchers to turn cells into any other kind of cell in the body) turned it into astrocytes. They then boosted the ability of these astrocytes to produce chemical signals that can stimulate healing among the cells damaged by the stroke.

These astrocytes were then not only able to help repair some of the damaged neurons, enabling them to once again communicate with other neurons, but they also helped another kind of brain cell called oligodendrocyte progenitor cells or OPCs. These cells help make a protective sheath around axons, which transmit electrical signals between brain cells. The new astrocytes stimulated the OPCs into repairing the protective sheath around the axons.

Mice who had these astrocytes implanted in them showed improved memory and motor skills within four months of the treatment.  

And now the team have taken this approach one step further. They have developed a method of growing these astrocytes in large amounts, at very high quality, in a relatively short time. The importance of that is it means they can produce the number of cells needed to treat a person.

“We can produce the astrocytes in 35 days,” Llorente says. “This process allows rapid, efficient, reliable and clinically viable production of our therapeutic product.”

The next step is to chat with the Food and Drug Administration (FDA) to see what else they’ll need to do to show they are ready for a clinical trial.

The study is published in the journal Stem Cell Research.

City of Hope scientists use stem cells to develop ‘mini-brains’ to study Alzheimer’s and to test drugs in development

Alzheimer’s is a progressive disease that destroys memory and other important mental functions. According to the non-profit HFC, co-founded by CIRM Board member Lauren Miller Rogen and her husband Seth Rogen, more than 5 million Americans are living with Alzheimer’s. It is the 6th leading cause of death in the U.S and it is estimated that by 2050 as many as 16 million Americans will have the disease. Alzheimer’s is the only cause of death among the top 10 in the U.S. without a way to prevent, cure, or even slow its progression, which is it is crucial to better understand the disease and to develop and test potential treatments.

It is precisely for this reason that researchers led by Yanhong Shi, Ph.D. at City of Hope have developed a ‘mini-brain’ model using stem cells in order to study Alzheimer’s and to test drugs in development.

The team was able to model sporadic Alzheimer’s, the most common form of the disease, by using human induced pluripotent stem cells (iPSCs), a kind of stem cell that can be created from skin or blood cells of people through reprogramming and has the ability to turn into virtually any other kind of cell. The researchers used these iPSCs to create ‘mini-brains’, also known as brain organoids, which are 3D models that can be used to analyze certain features of the human brain. Although they are far from perfect replicas, they can be used to study physical structure and other characteristics. 

The scientists exposed the ‘mini-brains’ to serum that mimics age-associated blood-brain barrier (BBB) breakdown. The BBB is a protective barrier that surrounds the brain and its breakdown has been associated with Alzheimer’s and other age-related neurodegenerative diseases . After exposure, the team tested the ‘mini-brains’ for various Alzheimer’s biomarkers. These markers included elevated levels of proteins known as amyloid and tau that are associated with the disease and synaptic breaks linked to cognitive decline.

Research using brain organoids has shown that exposure to serum from blood could induce multiple Alzheimer’s symptoms. This suggests that combination therapies targeting multiple areas would be more effective than single-target therapies currently in development.

The team found that attempting a single therapy, such as inhibiting only amyloid or tau proteins, did not reduce the levels of tau or amyloid, respectively. These findings suggest that amyloid and tau likely cause disease progression independently. Furthermore, exposure to serum from blood, which mimics BBB breakdown, could cause breaks in synaptic connections that help brains remember things and function properly.

Image Description: Yanhong Shi, Ph.D.

In a press release from the Associated Press, Dr. Shi elaborated on the importance of their model for studying Alzheimer’s.

“Drug development for Alzheimer’s disease has run into challenges due to incomplete understanding of the disease’s pathological mechanisms. Preclinical research in this arena predominantly uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to brain architecture. We, at City of Hope, have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find treatments for this devastating illness.”

The full results of this study were published in Advance Science.

Dr. Shi has previously worked on several CIRM-funded research projects, such as looking at a potential link between COVID-19 and a gene for Alzheimer’s as well as the development of a therapy for Canavan disease.

UCSD researchers use stem cell model to better understand pregnancy complication

A team of UC San Diego researchers recently published novel preeclampsia models to aid in understanding this pregnancy complication that occurs in one of 25 U.S. pregnancies. Researchers include (left to right): Ojeni Touma, Mariko Horii, Robert Morey and Tony Bui. Credit: UC San Diego

Pregnant women often tread uncertain waters in regards to their health and well-being as well as that of their babies. Many conditions can arise and one of these is preeclampsia, a type of pregnancy complication that occurs in approximately one in 25 pregnancies in the United States according to the Center for Disease Control (CDC). It occurs when expecting mothers develop high blood pressure, typically after 20 weeks of pregnancy, and that in turn reduces the blood supply to the baby. This can lead to serious, even fatal, complications for both the mother and baby.

A CIRM supported study using induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any cell type, was able to create a “disease in a dish” model in order to better understand preeclampsia.

Credit: UC San Diego

For this study, Mariko Horii, M.D., and her team of researchers at the UC San Diego School of Medicine obtained cells from the placenta of babies born under preeclampsia conditions. These cells were then “reprogrammed” into a stem cell-like state, otherwise known as iPSCs. The iPSCs were then turned into cells resembling placental cells in early pregnancy. This enabled the team to create the preeclampsia “disease in the dish” model. Using this model, they were then able to study the processes that cause, result from, or are otherwise associated with preeclampsia.

The findings revealed that cellular defects observed are related to an abnormal response in the environment in the womb. Specifically, they found that preeclampsia was associated with a low-oxygen environment in the uterus. The researchers used a computer modeling system at UC San Diego known as Comet to detail the differences between normal and preeclampsia placental tissue.

Horii and her team hope that these findings not only shed more light on the environment in the womb observed in preeclampsia, but also provided insight for future development of diagnostic tools and identification of potential medications. Furthermore, they hope that their iPSC disease model can be used to study other placenta-associated pregnancy disorders such as fetal growth restriction, miscarriage, and preterm birth.

The team’s next steps are to develop a 3D model to better study the relationship between environment and development of placental disease.

In a news release from UC San Diego, Horri elaborates more on these future goals.

“Currently, model systems are in two-dimensional cultures with single-cell types, which are hard to study as the placenta consists of maternal and fetal cells with multiple cell types, such as placental cells (fetal origin), maternal immune cells and maternal endometrial cells. Combining these cell types together into a three-dimensional structure will lead to a better understanding of the more complex interactions and cell-to-cell signaling, which can then be applied to the disease setting to further understand pathophysiology.”

The full study was published in Scientific Reports.

Stem cell treatment improves motor function in monkeys modeling Parkinson’s Disease

Neurodegenerative diseases impact millions of people worldwide with the risk of being affected by one of these diseases increasing as you get older. For many of these diseases, there are very few treatments available to patients. As life expectancy increases and the population continues to age, it is crucial to try and find treatments that can potentially slow the progression of these diseases or cure them entirely. This is one of the reasons why CIRM has committed directing around $1.5 billion in funding over the next few years to research related to neurological disorders.

One of the most common neurodegenerative diseases is Parkinson’s Disease (PD), a movement disorder that affects one million people in the U.S alone and leads to shaking, stiffness, insomnia, fatigue, and problems with walking, balance, and coordination.  It is caused by the breakdown and death of dopaminergic neurons, special nerve cells in the brain responsible for the production of dopamine, a chemical messenger that is crucial for normal brain activity.

A recent study published in Nature Medicine has shown improved motor function and growth of neurons over a two year period in monkeys modeling PD. The study was conducted by Su-Chun Zhang, M.D., Ph.D. and his team at the University of Wisconsin using induced pluripotent stem cells (iPSCs), a kind of stem cell that can become virtually any type of cell that can be made from skin cells. The hope is that these results can pave the way for starting human clinical trials.

In order to replicate PD in humans, the team injected 10 adult monkeys with a neurotoxin that produces PD like symptoms. As a result of this, all 10 monkeys developed slow movements, imbalances, tremors, and impaired coordination in the hand on the opposite side of the injection. Additionally, scans revealed that on the injected side, monkeys lost most brain activity involving dopamine in two key brain areas. The team then waited three years after injecting the neurotoxin before administering the therapy, during which time the monkeys’ symptoms persisted.

To generate iPSC lines, the team obtained skin cells from five of the monkeys. The iPSCs were then turned into dopamine neural progenitor cells, which have the ability to create dopamine. These newly created cells were then administered into the brains of the five monkeys, with each monkey receiving a treatment derived from their own skin cells. A sixth iPSC line from a donor monkey was used for the remaining five monkeys to see how the treatment would work if it was not derived from their own skin cells.

The results showed that the monkeys that received the treatment derived from their own skin cells recovered. These animals moved more, moved faster, and were nimbler than before the treatment. They gained the ability to grasp treats, use all four limbs for walking, and climb their cages with ease and increased agility. However, the monkeys that received iPSCs derived from a donor did not recover. Their symptoms remained unchanged or worsened compared to before the treatment.

In a news article, Zhang emphasizes how he and his team are proceeding with a treatment derived from one’s own cells (autologous) vs. one from a donor (allogeneic).

“I initially wanted to do allogeneic transplants in patients because the autologous approach is too expensive. However, after seeing [our] data, I changed my mind. I want to go with the autologous first… because I feel the chance of success is really, really high.”

CIRM is currently funding a human clinical trial ($5.5 million) that is using a gene therapy approach for PD.