You can bank on CIRM

Way back in 2013, the CIRM Board invested $32 million in a project to create an iPSC Bank. The goal was simple;  to collect tissue samples from people who have different diseases, turn those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and create a facility where those lines can be stored and distributed to researchers who need them.

Fast forward almost seven years and that idea has now become the largest public iPSC bank in the world. The story of how that happened is the subject of a great article (by CIRM’s Dr. Stephen Lin) in the journal Science Direct.

Dr. Stephen Lin

In 2013 there was a real need for the bank. Scientists around the world were doing important research but many were creating the cells they used for that research in different ways. That made it hard to compare one study to another and come up with any kind of consistent finding. The iPSC Bank was designed to change that by creating one source for high quality cells, collected, processed and stored under a single, consistent method.

Tissue samples – either blood or skin – were collected from thousands of individuals around California. Each donor underwent a thorough consent process – including being shown a detailed brochure – to explain what iPS cells are and how the research would be done.

The diseases to be studied through this bank include:

  • Age-Related Macular Degeneration (AMD)
  • Alzheimer’s disease
  • Autism Spectrum Disorder (ASD)
  • Cardiomyopathies (heart conditions)
  • Cerebral Palsy
  • Diabetic Retinopathy
  • Epilepsy
  • Fatty Liver diseases
  • Hepatitis C (HCV)
  • Intellectual Disabilities
  • Primary Open Angle Glaucoma
  • Pulmonary Fibrosis

The samples were screened to make sure they were safe – for example the blood was tested for HBV and HIV – and then underwent rigorous quality control testing to make sure they met the highest standards.

Once approved the samples were then turned into iPSCs at a special facility at the Buck Institute in Novato and those lines were then made available to researchers around the world, both for-profit and non-profit entities.

Scientists are now able to use these cells for a wide variety of uses including disease modeling, drug discovery, drug development, and transplant studies in animal research models. It gives them a greater ability to study how a disease develops and progresses and to help discover and test new drugs or other therapies

The Bank, which is now run by FUJIFILM Cellular Dynamics, has become a powerful resource for studying genetic variation between individuals, helping scientists understand how disease and treatment vary in a diverse population. Both CIRM and Fuji Film are committed to making even more improvements and additions to the collection in the future to ensure this is a vital resource for researchers for years to come.

What to be thankful for this Thanksgiving: scientists hard at work

Biomedical technician Louis Pinedo feeds stem cells their special diet. Photo by Cedars-Sinai.

With Thanksgiving and Black Friday approaching in the next couple of days, we wanted to give thanks to all the scientists hard at work during this holiday weekend. Science does not sleep–the groundbreaking research and experiments that are being conducted do not take days off. There are tasks in the laboratory that need to be done daily otherwise months, even years, of important work can be lost in an instant.

Below is a story from Cedars-Sinai Medical Center that talks about one of these scientists, Louis Pinedo, that will be working during this holiday weekend.

Stem Cells Don’t Take the Day Off on Thanksgiving

Inside a Cedars-Sinai Laboratory, Where a Scientist Will be Busy Feeding Stem Cells During the Holiday

While most of us are stuffing ourselves with turkey and pumpkin pie at home on Thanksgiving Day, the staff at one Cedars-Sinai laboratory will be on the job, feeding stem cells.

“Stem cells do not observe national holidays,” says Loren Ornelas-Menendez, the manager of a lab that converts samples of adult skin and blood cells into stem cells—the amazing “factories” our bodies use to make our cells. These special cells help medical scientists learn how diseases develop and how they might be cured.

Stem cells are living creatures that must be hand-fed a special formula each day, monitored for defects and maintained at just the right temperature. And that means the cell lab is staffed every day, 52 weeks a year.

These cells are so needy that Ornelas-Menendez jokes: “Many people have dogs. We have stem cells.”

Millions of living stem cells are stored in the David and Janet Polak Foundation Stem Cell Core Laboratory at the Cedars-Sinai Board of Governors Regenerative Medicine Institute. Derived from hundreds of healthy donors and patients, they represent a catalogue of human ills, including diabetes, breast cancer, Alzheimer’s disease, Parkinson’s disease and Crohn’s disease.

Cedars-Sinai scientists rely on stem cells for many tasks: to make important discoveries about how our brains develop; to grow tiny versions of human tissues for research; and to create experimental treatments for blindness and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) that they are testing in clinical trials.

The lab’s main collection consists of induced pluripotent stem cells, or iPSCs, which mimic the all-powerful stem cells we all had as embryos. These ingenious cells, which Cedars-Sinai scientists genetically engineer from adult cells, can make any type of cell in the body—each one matching the DNA of the donor. Other types of stem cells in the lab make only one or two kinds of cells, such as brain or intestinal cells.

Handy and versatile as they are, stem cells are high-maintenance. A few types, such as those that make connective tissue cells for wound healing, can be fed as infrequently as every few days. But iPSCs require a daily meal to stay alive, plus daily culling to weed out cells that have started to turn into cells of the gut, brain, breast or other unwanted tissues.

So each day, lab staff suit up and remove trays of stem cells from incubators that are set at a cozy 98.6 degrees. Peering through microscopes, they carefully remove the “bad” cells to ensure the purity of the iPSCs they will provide to researchers at Cedars-Sinai and around the world.

While the cells get sorted, a special feeding formula is defrosting in a dozen bottles spread around a lab bench. The formula incudes sodium, glucose, vitamins and proteins. Using pipettes, employees squeeze the liquid into food wells inside little compartments that contain the iPSCs. Afterward, they return the cells to their incubators.

The lab’s 10 employees are on a rotating schedule that ensures the lab is staffed on weekends and holidays, not just weekdays. On Thanksgiving Day this year, biomedical technician Louis Pinedo expects to make a 100-mile round trip from his home in Oxnard, California, to spend several hours at work, filling nearly 600 feeding wells. On both Christmas and New Year’s Day, two employees are expected to staff the lab.

All this ceaseless effort helps make Cedars-Sinai one of the world’s top providers of iPSCs, renowned for consistency and quality. Among the lab’s many clients are major universities and the global Answer ALS project, which is using the cells in its search for a cure for this devastating disease.

That’s why the lab’s director, Dhruv Sareen, PhD, suggests that before you sit down to your Thanksgiving feast, why not lift a glass to these hard-working lab employees?

“One day the cells they tend could lead to treatments for diseases that have plagued humankind for centuries,” he says. “And that’s something to be truly thankful for.”

Blood-brain barrier chip created with stem cells expands potential for personalized medicine

An Organ-Chip used in the study to create a blood-brain barrier (BBB).

The brain is a complex part of the human body that allows for the formation of thoughts and consciousness. In many ways it is the essence of who we are as individuals. Because of its importance, our bodies have developed various layers of protection around this vital organ, one of which is called the blood-brain barrier (BBB).

The BBB is a thin border of various cell types around the brain that regulate what can enter the brain tissue through the bloodstream. Its primary purpose is to prevent toxins and other unwanted substances from entering the brain and damaging it. Unfortunately this barrier can also prevent helpful medications, designed to fix problems, from reaching the brain.

Several brain disorders, such as Amyotrophic Lateral Sclerosis (ALS – also known as Lou Gehrig’s disease), Parkinson’s Disease (PD), and Huntington’s Disease (HD) have been linked to defective BBBs that keep out critical biomolecules needed for healthy brain activity.

In a CIRM-funded study, a team at Cedars-Sinai Medical Center created a BBB through the use of stem cells and an Organ-Chip made from induced pluripotent stem cells (iPSCs). These are a specific type of stem cells that can turn into any type of cell in the body and can be generated from a person’s own cells. In this study, iPSCs were created from adult blood samples and used to make the neurons and other supporting cells that make up the BBB. These cells were then placed inside an Organ-Chip which recreates the environment that cells normally experience within the human body.

Inside the 3-D Organ-Chip, the cells were able to form a BBB that functions as it does in the body, with the ability to block entry of certain drugs. Most notably, when the BBB was generated from cell samples of patients with HD, the BBB malfunctioned in the same way that it does in patients with the disease.

These findings expand the potential for personalized medicine for various brain disorders linked to problems in the BBB. In a press release, Dr. Clive Svendsen, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and senior author of the study, was quoted as saying,

“The study’s findings open a promising pathway for precision medicine. The possibility of using a patient-specific, multicellular model of a blood barrier on a chip represents a new standard for developing predictive, personalized medicine.”

The full results of the study were published in the scientific journal Cell Stem Cell.

First patient treated for colon cancer using reprogrammed adult cells

Dr. Sandip Patel (left) and Dr. Dan Kaufman (center) of UC San Diego School of Medicine enjoy a light-hearted moment before Derek Ruff (right) receives the first treatment for cancer using human-induced pluripotent stem cells (hiPSCs). Photo courtesy of UC San Diego Health.

For patients battling cancer for the first time, it can be quite a draining and grueling process. Many treatments are successful and patients go into remission. However, there are instances where the cancer returns in a much more aggressive form. Unfortunately, this was the case for Derek Ruff.

After being in remission for ten years, Derek’s cancer returned as Stage IV colon cancer, meaning that the cancer has spread from the colon to distant organs and tissues. According to statistics from Fight Colorectal Cancer, colorectal cancer is the 2nd leading cause of cancer death among men and women combined in the United States. 1 in 20 people will be diagnosed with colorectal cancer in their lifetime and it is estimated that there will be 140,250 new cases in 2019 alone. Fortunately, Derek was able to enroll in a groundbreaking clinical trial to combat his cancer.

In February 2019, as part of a clinical trial at the Moores Cancer Center at UC San Diego Health in collaboration with Fate Therapeutics, Derek became the first patient in the world to be treated for cancer with human-induced pluripotent stem cells (hiPSCs). hiPSCs are human adult cells, such as those found on the skin, that are reprogrammed into stem cells with the ability to turn into virtually any kind of cell. In this trial, hiPSCs were reprogrammed into natural killer (NK) cells, which are specialized immune cells that are very effective at killing cancer cells, and are aimed at treating Derek’s colon cancer.

A video clip from ABC 10 News San Diego features an interview with Derek and the groundbreaking work being done.

In a public release, Dr. Dan Kaufman, one of the lead investigators of this trial at UC San Diego School of Medicine, was quoted as saying,

“This is a landmark accomplishment for the field of stem cell-based medicine and cancer immunotherapy. This clinical trial represents the first use of cells produced from human induced pluripotent stem cells to better treat and fight cancer.”

In the past, CIRM has given Dr. Kaufman funding related to the development of NK cells. One was a $1.9 million grant for developing a different type of NK cell from hiPSCs, which could also potentially treat patients with lethal cancers. The second grant was a $4.7 million grant for developing NK cells from human embryonic stem cells (hESCs) to potentially treat patients with acute myelogenous leukemia (AML).

In the public release, Dr. Kaufman is also quoted as saying,

“This is a culmination of 15 years of work. My lab was the first to produce natural killer cells from human pluripotent stem cells. Together with Fate Therapeutics, we’ve been able to show in preclinical research that this new strategy to produce pluripotent stem cell-derived natural killer cells can effectively kill cancer cells in cell culture and in mouse models.”

A new stem cell derived tool for studying brain diseases

Sergiu Pasca’s three-dimensional culture makes it possible to watch how three different brain-cell types – oligodendrocytes (green), neurons (magenta) and astrocytes (blue) – interact in a dish as they do in a developing human  brain.
Courtesy of the Pasca lab

Neurological diseases are among the most daunting diagnoses for a patient to receive, because they impact how the individual interacts with their surroundings. Central to our ability to provide better treatment options for these patients, is scientists’ capability to understand the biological factors that influence disease development and progression. Researchers at the Stanford University School of Medicine have made an important step in providing neuroscientists a better tool to understand the brain.

While animal models are excellent systems to study the intricacies of different diseases, the ability to translate any findings to humans is relatively limited. The next best option is to study human stem cell derived tissues in the laboratory. The problem with the currently available laboratory-derived systems for studying the brain, however, is the limited longevity and diversity of neuronal cell types. Dr. Sergiu Pasca’s team was able to overcome these hurdles, as detailed in their study, published in the journal Nature Neuroscience.

A new approach

Specifically, Dr. Pasca’s group developed a method to differentiate or transform skin derived human induced pluripotent stem cells (iPSCs – which are capable of becoming any cell type) into brain-like structures that mimic how oligodendrocytes mature during brain development. Oligodendrocytes are most well known for their role in myelinating neurons, in effect creating a protective sheath around the cell to protect its ability to communicate with other brain cells. Studying oligodendrocytes in culture systems is challenging because they arise later in brain development, and it is difficult to generate and maintain them with other cell types found in the brain.

These scientists circumvented this problem by using a unique combination of growth factors and nutrients to culture the oligodendrocytes, and found that they behaved very similarly to oligodendrocytes isolated from humans. Most excitingly, they observed that the stem cell-derived oligodendrocytes were able to myelinate other neurons in the culture system. Therefore they were both physically and functionally similar to human oligodendrocytes.

Importantly, the scientists were also able to generate astrocytes alongside the oligodendrocytes. Astrocytes perform many important functions such as providing essential nutrients and directing the electrical signals that help cells in the brain communicate with each other. In a press release, Dr. Pasca explains the importance of generating multiple cell types in this in vitro system:

“We now have multiple cell types interacting in one single culture. This permits us to look close-up at how the main cellular players in the human brain are talking to each other.”

This in vitro or laboratory-developed system has the potential to help scientists better understand oligodendrocytes in the context of diseases such as multiple sclerosis and cerebral palsy, both of which stem from improper myelination of brain nerve cells.

This work was partially supported by a CIRM grant.

Midwest universities are making important tools to advance stem cell research

580b4-ipscell

iPSCs are not just pretty, they’re also pretty remarkable

Two Midwest universities are making headlines for their contributions to stem cell research. Both are developing important tools to advance this field of study, but in two unique ways.

Scientists at the University of Michigan (UM), have compiled an impressive repository of disease-specific stem cell lines. Cell lines are crucial tools for scientists to study the mechanics of different diseases and allows them to do so without animal models. While animal models have important benefits, such as the ability to study a disease within the context of a living mammal, insights gained from such models can be difficult to translate to humans and many diseases do not even have good models to use.

The stem cell lines generated at the Reproductive Sciences Program at UM, are thanks to numerous individuals who donated extra embryos they did not use for in vitro fertilization (IVF). Researchers at UM then screened these embryos for abnormalities associated with different types of disease and generated some 36 different stem cell lines. These have been donated to the National Institute of Health’s (NIH) Human Embryonic Stem Cell Registry, and include cell lines for diseases such as cystic fibrosis, Huntington’s Disease and hemophilia.

Using one such cell line, Dr. Peter Todd at UM, found that the genetic abnormality associated with Fragile X Syndrome, a genetic mutation that results in developmental delays and learning disabilities, can be corrected by using a novel biological tool. Because Fragile X Syndrome does not have a good animal model, this stem cell line was critical for improving our understanding of this disease.

In the next state over, at the University of Wisconsin-Madison (UWM), researchers are doing similar work but using induced pluripotent stem cells (iPSCs) for their work.

The Human Stem Cell Gene Editing Service has proved to be an important resource in expediting research projects across campus. They use CRISPR-Cas9 technology (an efficient method to mutate or edit the DNA of any organism), to generate human stem cell lines that contain disease specific mutations. Researchers use these cell lines to determine how the mutation affects cells and/or how to correct the cellular abnormality the mutation causes. Unlike the work at UM, these stem cell lines are derived from iPSCs  which can be generated from easy to obtain human samples, such as skin cells.

The gene editing services at UWM have already proved to be so popular in their short existence that they are considering expanding to be able to accommodate off-campus requests. This highlights the extent to which both CRISPR technology and stem cell research are being used to answer important scientific questions to advance our understanding of disease.

CIRM also created an iPSC bank that researchers can use to study different diseases. The  Induced Pluripotent Stem Cell (iPSC) Repository is  the largest repository of its kind in the world and is used by researchers across the globe.

The iPSC Repository was created by CIRM to house a collection of stem cells from thousands of individuals, some healthy, but some with diseases such as heart, lung or liver disease, or disorders such as autism. The goal is for scientists to use these cells to better understand diseases and develop and test new therapies to combat them. This provides an unprecedented opportunity to study the cell types from patients that are affected in disease, but for which cells cannot otherwise be easily obtained in large quantities.

Sequencing data helps us understand the genes involved in heart cell development

skin cells to beating heart

Human heart cells generated in the laboratory. Image courtesy of Nathan Palapant at the University of Queensland

Heart disease is the leading cause of death for both men and women in the United States and is estimated to be responsible for 31% of all deaths globally. This disease encompasses a wide variety of conditions that all effect how well your heart is able to pump blood to the rest of your body. One of the reasons that heart disease is so devastating is because, unlike many other organs in our bodies, heart tissue is not able to repair itself once it is damaged. Now scientists at the Institute for Molecular Bioscience at the University of Queensland and the Garvan Institute for Medical Research in Australia have conducted a tour de force study to exquisitely understand the genes involved in heart development.

The findings of the study are published in the journal Cell Stem Cell. in a press release, Dr. Nathan Palapant, one of the the lead authors, says this type of research could pay dividends for heart disease treatment because:

“We think the answers to heart repair almost certainly lie in understanding heart development. If we can get to grips with the complex choreography of how the heart builds itself in the first place, we’re well placed to find new approaches to helping it rebuild after damage.”

To determine which genes are involved in heart cell development, the investigators use a method called single cell RNA sequencing. This technique allowed them to measure how 17,000 genes (almost every gene that is active in the heart) were being turned on and off during various stages of heart cell development in 40,000 human pluripotent stem cells (stem cells that are capable of becoming any other cell type) experimentally induced to turn into heart cells.  This data set, the first of its kind, is a critical new resource for all scientists studying heart development and disease.

Interestingly, this study also addressed a commonly present, but rarely discussed issue with scientific studies: how applicable are results generated in vitro (in the lab) rather than the body, in the context of human health and disease? It is well known that heart cells generated in the lab do not have the exact same characteristics as mature heart cells found in our bodies, but the extent and precise nature of those discrepancies is not well understood. These scientists find that a gene called HOPX, which is one of earliest markers of heart cell development, is not always expressed when it should be during in vitro cardiac cell development, which, in turn, affects expression of other genes that are downstream of HOPX later on in development. Therefore, these scientists suggest that mis-expression of HOPX  might be one reason why in vitro heart cells express different genes and are distinct from heart cells in humans.

The scientists also learned that HOPX is responsible for controlling whether the developing heart cell moves past the “immature” dividing phase to the mature phase where cells grow bigger, but do not divide. This finding shows that this data set is powerful both for determining differences between laboratory grown cells versus mature human cells, but also provides critical biological information about heart cell development.

Joseph Powell, another lead author of this research, further explains how this work contributes to the important fundamentals of heart cell development:

“Each cell goes through its own series of complex, nuanced changes. They are all different, and changes in one cell affect the activity of other cells. By tracking those changes across the different stages of development, we can learn a huge amount about how different sub-types of heart cells are controlled, and how they work together to build the heart.”

Coming up with a stem cell FIX for a life-threatening blood disorder

Hemophilia

A promising new treatment option for hemophiliacs is in the works at the Salk Institute for Biological Sciences. Patients with Hemophilia B experience uncontrolled, and sometimes life threatening, bleeding due to loss or improper function of Factor IX (FIX), a protein involved in blood clotting. There is no cure for the disease and patients rely on routine infusions of FIX to prevent excessive blood loss. As you can imagine, this treatment regimen is both time consuming and expensive, while also becoming less effective over time.

Salk researchers, partially funded by CIRM, aimed to develop a more long-term solution for this devastating disease by using the body’s own cells to fix the problem.

In the study, published in the journal Cell Reports, They harvested blood cells from hemophiliacs and turned them into iPSCs (induced pluripotent stem cells), which are able to turn into any cell type. Using gene editing, they repaired the iPSCs so they could produce FIX and then turned the iPSCs into liver cells, the cell type that naturally produces FIX in healthy individuals.

One step therapy

To test whether these FIX-producing liver cells were able to reduce excess blood loss, the scientists injected the repaired human cells into a hemophiliac mouse. The results were very encouraging; they saw a greater than two-fold increase in clotting efficiency in the mice, reaching about a quarter of normal activity. This is particularly promising because other studies showed that increasing FIX activity to this level in hemophiliac humans significantly reduces bleeding rates. On top of that they also observed that these cells were able to survive and produce FIX for up to a year in the mice.

In a news release Suvasini Ramaswamy, the first author of the paper, said this method could eliminate the need for multiple treatments, as well as avoiding the immunosuppressive therapy that would be required for a whole liver transplant.

“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs. Rather than constant injections, you can do this in one shot.”

While these results provide an exciting new avenue in hemophilia treatment, there is still much more work that needs to be done before this type of treatment can be used in humans. This approach, however, is particularly exciting because it provides an important proof of principle that combining stem cell reprogramming with genetic engineering can lead to life-changing breakthroughs for treating genetic diseases that are not currently curable.

 

 

Celebrating Exciting CIRM-Funded Discovery Research on World Parkinson’s Day

April 11th is World Parkinson’s Disease Awareness Day. To mark the occasion, we’re featuring the work of CIRM-funded researchers who are pursuing new, promising ideas to treat patients with this debilitating neurodegenerative disease.


Birgitt Schuele, Parkinson’s Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Birgitt and her team at the Parkinson’s Institute in Sunnyvale, California, are using CRISPR gene editing technology to reduce the levels of a toxic protein called alpha synuclein, which builds up in the dopaminergic brain cells affected by Parkinson’s disease.

Birgitt Schuele

“My hope is that I can contribute to stopping disease progression in Parkinson’s. If we can develop a drug that can get rid of accumulated protein in someone’s brain that should stop the cells from dying. If someone has early onset PD and a slight tremor and minor walking problems, stopping the disease and having a low dose of dopamine therapy to control symptoms is almost a cure.”

Parkinson’s disease in a dish. Dopaminergic neurons made from Parkinson’s patient induced pluripotent stem cells. (Image credit: Birgitt Schuele)


Jeanne Loring, Scripps Research Institute

CIRM Grant: Quest Award – Discovery Stage Research

Research: Jeanne Loring and her team at the Scripps Research Institute in La Jolla, California, are deriving dopaminergic neurons from the iPSCs of Parkinson’s patients. Their goal is to develop a personalized, stem cell-based therapy for PD.

Jeanne Loring

“We are working toward a patient-specific neuron replacement therapy for Parkinson’s disease.  By the time PD is diagnosed, people have lost more than half of their dopamine neurons in a specific part of the brain, and loss continues over time.  No drug can stop the loss or restore the neurons’ function, so the best possible option for long term relief of symptoms is to replace the dopamine neurons that have died.  We do this by making induced pluripotent stem cells from individual PD patients and turning them into the exact type of dopamine neuron that has been lost.  By transplanting a patient’s own cells, we will not need to use potentially dangerous immunosuppressive drugs.  We plan to begin treating patients in a year to two years, after we are granted FDA approval for the clinical therapy.”

Skin cells from a Parkinson’s patient (left) were reprogrammed into induced pluripotent stem cells (center) that were matured into dopaminergic neurons (right) to model Parkinson’s disease. (Image credit: Jeanne Loring)


Justin Cooper-White, Scaled BioLabs Inc.

CIRM Grant: Quest Award – Discovery Stage Research

Research: Justin Cooper-White and his team at Scaled Biolabs in San Francisco are developing a tool that will make clinical-grade dopaminergic neurons from the iPSCs of PD patients in a rapid and cost-effective manner.

Justin Cooper-White

“Treating Parkinson’s disease with iPSC-derived dopaminergic neuron transplantation has a strong scientific and clinical rationale. Even the best protocols are long and complex and generally have highly variable quality and yield of dopaminergic neurons. Scaled Biolabs has developed a technology platform based on high throughput microfluidics, automation, and deep data which can optimize and simplify the road from iPSC to dopaminergic neuron, making it more efficient and allowing a rapid transition to GMP-grade derivation of these cells.  In our first 6 months of CIRM-funded work, we believe we have already accelerated and simplified the production of a key intermediate progenitor population, increasing the purity from the currently reported 40-60% to more than 90%. The ultimate goal of this work is to get dopaminergic neurons to the clinic in a robust and economical manner and accelerate treatment for Parkinson’s patients.”

High throughput differentiation of dopaminergic neuron progenitors in  microbioreactor chambers in Scaled Biolabs’ cell optimization platform. Different chambers receive different differentiation factors, so that optimal treatments for conversion to dual-positive cells can be determined (blue: nuclei, red: FOXA2, green: LMX1A).


Xinnan Wang, Stanford University

CIRM Grant: Basic Biology V

Research: Xinnan Wang and her team at Stanford University are studying the role of mitochondrial dysfunction in the brain cells affected in Parkinson’s disease.

Xinnan Wang

“Mitochondria are a cell’s power plants that provide almost all the energy a cell needs. When these cellular power plants are damaged by stressful factors present in aging neurons, they release toxins (reactive oxygen species) to the rest of the neuron that can cause neuronal cell death (neurodegeneration).  We hypothesized that in Parkinson’s mutant neurons, mitochondrial quality control is impaired thereby leading to neurodegeneration. We aimed to test this hypothesis using neurons directly derived from Parkinson’s patients (induced pluripotent stem cell-derived neurons).”

Dopaminergic neurons derived from human iPSCs shown in green, yellow and red. (Image credit: Atossa Shaltouki, Stanford)


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Stem Cell Roundup: watching brain cells in real time, building better heart cells, and the plot thickens on the adult neurogenesis debate

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

Watching brain cells in real time

This illustration depicts a new method that enables scientists to see an astrocyte (green) physically interacting with a neuronal synapse (red) in real time, and producing an optical signal (yellow). (Khakh Lab, UCLA Health)

Our stem cell photo of the week is brought to you by the Khakh lab at UCLA Health. The lab developed a new method that allows scientists to watch brain cells interact in real time. Using a technique called fluorescence resonance energy-transfer (FRET) microscopy, the team can visualize how astrocytes (key support cells in our central nervous system) and brain cells called neurons form connections in the mouse brain and how these connections are affected by diseases like Alzheimer’s and ALS.

Baljit Khakh, the study’s first author, explained the importance of their findings in a news release:

“This new tool makes possible experiments that we have been wanting to perform for many years. For example, we can now observe how brain damage alters the way that astrocytes interact with neurons and develop strategies to address these changes.”

The study was published this week in the journal Neuron.


Turn up the power: How to build a better heart cell (Todd Dubnicoff)

For years now, researchers have had the know-how to reprogram a donor’s skin cells into induced pluripotent stem cells (iPSCs) and then specialize them into heart muscle cells called cardiomyocytes. The intervening years have focused on optimizing this method to accurately model the biology of the adult human heart as a means to test drug toxicity and ultimately develop therapies for heart disease. Reporting this week in Nature, scientists at Columbia University report an important step toward those goals.

The muscle contractions of a beating heart occur through natural electrical impulses generated by pacemaker cells. In the case of lab-grown cardiomyocytes, introducing mechanical and electrical stimulation is required to reliably generate these cells. In the current study, the research team showed that the timing and amount of stimulation is a critical aspect to the procedure.

The iPS-derived cardiomyocytes have formed heart tissue that closely mimics human heart functionality at over four weeks of maturation. Credit: Gordana Vunjak-Novakovic/Columbia University.

The team tested three scenarios on iPSC-derived cardiomyocytes (iPSC-CMs): no electrical stimulation for 3 weeks, constant stimulation for 3 weeks, and finally, two weeks of increasingly higher stimulation followed by a week of constant stimulation. This third setup mimics the changes that occur in a baby’s heart just before and just after birth.

These scenarios were tested in 12 day-old and 28 day-old iPSC-CMs. The results show that only the 12 day-old cells subjected to the increasing amounts of stimulation gave rise to fully mature heart muscle cells. On top of that, it only took four weeks to make those cells. Seila Selimovic, Ph.D., an expert at the National Institutes of Health who was not involved in the study, explained the importance of these findings in a press release:

“The resulting engineered tissue is truly unprecedented in its similarity to functioning human tissue. The ability to develop mature cardiac tissue in such a short time is an important step in moving us closer to having reliable human tissue models for drug testing.”

Read more at: https://phys.org/news/2018-04-early-bioengineered-human-heart-cells.html#jCp


Yes we do, no we don’t. More confusion over growing new brain cells as we grow older (Kevin McCormack)

First we didn’t, then we did, then we didn’t again, now we do again. Or maybe we do again.

The debate over whether we are able to continue making new neurons as we get older took another twist this week. Scientists at Columbia University said their research shows we do make new neurons in our brain, even as we age.

This image shows what scientists say is a new neuron in the brain of an older human. A new study suggests that humans continue to make new neurons throughout their lives. (Columbia University Irving Medical Center)

In the study, published in the journal Cell Stem Cell, the researchers examined the brains of 28 deceased donors aged 14 to 79. They found similar numbers of precursor and immature neurons in all the brains, suggesting we continue to develop new brain cells as we age.

This contrasts with a UCSF study published just last month which came to the opposite conclusion, that there was no evidence we make new brain cells as we age.

In an interview in the LA Times, Dr. Maura Boldrini, the lead author on the new study, says they looked at a whole section of the brain rather than the thin tissues slices the UCSF team used:

“In science, the absence of evidence is not evidence of absence. If you can’t find something it doesn’t mean that it is not there 100%.”

Well, that resolves that debate. At least until the next study.