Stem cell stories that caught our eye: better ovarian cancer drugs, creating inner ear tissue, small fish big splash

Two drugs are better than one for ovarian cancer (Karen Ring). Earlier this week, scientists from UCLA reported that a combination drug therapy could be an effective treatment for 50% of aggressive ovarian cancers. The study was published in the journal Precision Oncology and was led by Dr. Sanaz Memarzadeh.

Women with high-grade ovarian tumors have an 85% chance of tumor recurrence after treatment with a common chemotherapy drug called carboplatin. The UCLA team found in a previous study that ovarian cancer stem cells are to blame because they are resistant to carboplatin. It’s because these stem cells have an abundance of proteins called cIAPs, which prevent cell death from chemotherapy.

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Ovarian cancer cells (blue) expressing cIAP protein (red) on the left are more sensitive to a combination therapy than cancer cells that don’t express the protein on the right. (UCLA Broad Stem Cell Research Center/Precision Oncology)

Memarzadeh discovered that an experimental drug called birinapant made some ovarian cancer tumors more sensitive to chemotherapy treatment by breaking down cIAPs. This gave her the idea that combining the two drugs, birinapant and carboplatin, might be a more effective strategy for treating aggressive ovarian tumors.

By treating with the two drugs simultaneously, the scientists improved the survival rate of mice with ovarian cancer. They also tested this combo drug treatment on 23 ovarian cancer cell lines derived from women with highly aggressive tumors. The treatment killed off half of the cell lines indicating that some forms of this cancer are resistant to the combination treatment.

When they measured the levels of cIAPs in the human ovarian cancer cell lines, they found that high levels of the proteins were associated with ovarian tumor cells that responded well to the combination treatment. This is exciting because it means that clinicians can analyze tumor biopsies for cIAP levels to determine whether certain ovarian tumors would respond well to combination therapy.

Memarzadeh shared her plans for future research in a UCLA news release,

“I believe that our research potentially points to a new treatment option. In the near future, I hope to initiate a phase 1/2 clinical trial for women with ovarian cancer tumors predicted to benefit from this combination therapy.”

In a first, researchers create inner ear tissue. From heart muscle to brain cells to insulin-producing cells, researchers have figured out how to make a long list of different human cell types using induced pluripotent stem cells (iPSCs) – cells taken from the body and reprogrammed into a stem cell-like state.

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Human inner ear organoid with sensory hair cells (cyan) and sensory neurons (yellow). An antibody for the protein CTBP2 reveals cell nuclei as well as synapses between hair cells and neurons (magenta). | Photo: Karl Koehler

This week, a research group at the Indiana University School of Medicine successfully added inner ear cells to that list. This feat, published in Nature Biotechnology, is especially important given the fact that the inner ear is one of the few parts of the body that cannot be biopsied for further examination. With these cells in hands, new insights into the causes of hearing loss and balance disorders may be on the horizon.

The inner ear contains 75,000 sensory hair cells that convert sound waves into electrical signals to the brain. Loud noises, drug toxicity, and genetic mutations can permanently damage the hair cells leading to hearing loss and dizziness. Over 15%  of the U.S. population have some form of hearing loss and that number swells to 67% for people over 75.

Due to the complex shape of the inner ear, the team grew the iPSCs into three dimensional balls of cells rather than growing them as a flat layer of cells on a petri dish. With educated guesses sprinkled in with some trial and error, the scientists, for the time, identified a recipe of proteins that stimulated the iPSCs to transform into inner ear tissue. And like any great recipe, it wasn’t so much the ingredient list but the timing that was key:

“If you apply these signals at the wrong time you can potentially generate a brain instead of an inner ear,” first author Dr. Karl Koehler said in an interview with Gizmodo. “The real breakthrough is that we figured out the exact timing to do each one of these [protein] treatments.”

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Senior author, Eri Hashino, Ph.D., and first author, Karl R. Koehler, Ph.D. Photo: Indiana University

Careful examination shows that the tissue, referred to as organoids, not only contained the sensory hair cells of the inner ear cell but also nerve cells, or neurons, that are responsible for relaying the sound waves to the brain. Koehler explained the importance of this result in a press release:

“We also found neurons, like those that transmit signals from the ear to the brain, forming connections with sensory cells. This is an exciting feature of these organoids because both cell types are critical for proper hearing and balance.”

Though it’s still early days, these iPSC-derived inner ear organoids are a key step toward the ultimate goal of repairing hearing loss. Senior author, Dr. Eri Hashino, talked about the team’s approach to reach that goal:

“Up until now, potential drugs or therapies have been tested on animal cells, which often behave differently from human cells. We hope to discover new drugs capable of helping regenerate the sound-sending hair cells in the inner ear of those who have severe hearing problems.”

This man’s research is no fish tale
And finally, we leave you this week with a cool article and video by STAT. It features Dr. Leonard Zon of Harvard University and his many, many tanks full of zebrafish. This little fish has made a huge splash in understanding human development and disease. But don’t take my word for it, watch the video!

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

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

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

Stem Cell Stories That Caught our Eye: Making blood and muscle from stem cells and helping students realize their “pluripotential”

Stem cells offer new drug for blood diseases. A new treatment for blood disorders might be in the works thanks to a stem cell-based study out of Harvard Medical School and Boston Children’s hospital. Their study was published in the journal Science Translational Medicine.

The teams made induced pluripotent stem cells (iPSCs) from the skin of patients with a rare blood disorder called Diamond-Blackfan anemia (DBA) – a bone marrow disease that prevents new blood cells from forming. iPSCs from DBA patients were then specialized into blood progenitor cells, the precursors to blood cells. However, these precursor cells were incapable of forming red blood cells in a dish like normal precursors do.

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

The blood progenitor cells from DBA patients were then used to screen a library of compounds to identify drugs that could get the DBA progenitor cells to develop into red blood cells. They found a compound called SMER28 that had this very effect on progenitor cells in a dish. When the compound was tested in zebrafish and mouse models of DBA, the researchers observed an increase in red blood cell production and a reduction of anemia symptoms.

Getting pluripotent stem cells like iPSCs to turn into blood progenitor cells and expand these cells into a population large enough for drug screening has not been an easy task for stem cell researchers.

Co-first author on the study, Sergei Doulatov, explained in a press release, “iPS cells have been hard to instruct when it comes to making blood. This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

In the future, the researchers will pursue the questions of why and how SMER28 boosts red blood cell generation. Further work will be done to determine whether this drug will be a useful treatment for DBA patients and other blood disorders.

 

Students realize their “pluripotential”. In last week’s stem cell stories, I gave a preview about an exciting stem cell “Day of Discovery” hosted by USC Stem Cell in southern California. The event happened this past Saturday. Over 500 local middle and high school students attended the event and participated in lab tours, poster sessions, and a career resource fair. Throughout the day, they were engaged by scientists and educators about stem cell science through interactive games, including the stem cell edition of Family Feud and a stem cell smartphone videogame developed by USC graduate students.

In a USC press release, Rohit Varma, dean of the Keck School of Medicine of USC, emphasized the importance of exposing young students to research and scientific careers.

“It was a true joy to welcome the middle and high school students from our neighboring communities in Boyle Heights, El Sereno, Lincoln Heights, the San Gabriel Valley and throughout Los Angeles. This bright young generation brings tremendous potential to their future pursuits in biotechnology and beyond.”

Maria Elena Kennedy, a consultant to the Bassett Unified School District, added, “The exposure to the Keck School of Medicine of USC is invaluable for the students. Our students come from a Title I School District, and they don’t often have the opportunity to come to a campus like the Keck School of Medicine.”

The day was a huge success with students posting photos of their experiences on social media and enthusiastically writing messages like “stem cells are our future” and “USC is my goal”. One high school student acknowledged the opportunity that this day offers to students, “California currently has biotechnology as the biggest growing sector. Right now, it’s really important that students are visiting labs and learning more about the industry, so they can potentially see where they’re going with their lives and careers.”

You can read more about USC’s Stem Cell Day of Discovery here. Below are a few pictures from the event courtesy of David Sprague and USC.

Students have fun with robots representing osteoblast and osteoclast cells at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Students have fun with robots representing osteoblast and osteoclast cells at the USC Stem Cell Day of Discovery. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the USC Stem Cell Day of Discovery. Photo by David Sprague

New stem cell recipes for making muscle: new inroads to study muscular dystrophy (Todd Dubnicoff)

Embryonic stem cells are amazing because scientists can change or specialize them into virtually any cell type. But it’s a lot easier said than done. Researchers essentially need to mimic the process of embryo development in a petri dish by adding the right combination of factors to the stem cells in just the right order at just the right time to obtain a desired type of cell.

Making human muscle tissue from embryonic stem cells has proven to be a challenge. The development of muscle, as well as cartilage and bone, are well characterized and known to form from an embryonic structure called a somite. Researches have even been successful working out the conditions for making somites from animal stem cells. But those recipes didn’t work well with human stem cells.

Now, a team of researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overcome this roadblock by carrying out a systematic approach using human tissue. As described in Cell Reports, the scientists isolated somites from early human embryos and studied their gene activity. By comparing somites that were just beginning to emerge with fully formed somites, the researchers pinpointed differences in gene activity patterns. With this data in hand, the team added factors to the cells that were known to affect the activity of those genes. Through some trial and error, they produced a recipe – different than those used in animal cells – that could convert 90 percent of the human stem cells into somites in only four days. Those somites could then readily transform into muscle or bone or cartilage.

This new method for making human muscle will be critical for the lab’s goal to develop therapies for Duchenne muscular dystrophy, an incurable muscle wasting disease that strikes young boys and is usually fatal by their 20’s.

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells.  Image: April Pyle Lab/UCLA

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells. Image: April Pyle Lab/UCLA

Stories that caught our eye: frail bones in diabetics, ethics of future IVF, Alzheimer’s

The connection between diabetes and frail bones uncovered
Fundamentally, diabetes is defined by abnormally high blood sugar levels. But that one defect over time carries an increased risk for a wide range of severe health problems. For instance, compared to healthy individuals, type 2 diabetics are more prone to poorly healing bone fractures – a condition that can dramatically lower one’s quality of life.

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Bones of the healthy animals (top) form larger calluses during healing which lead to stronger repaired bones. Bones of the diabetic mice (bottom) have smaller calluses and the healed bones are more brittle. Image: Stanford University

To help these people, researchers are trying to tease out how diabetes impacts bone health. But it’s been a complicated challenge since there are many factors at play. Is it from potential side effects of diabetes drugs? Or is the increased body weight associated with type 2 diabetes leading to decreased bone density? This week a CIRM-funded team at Stanford pinpointed skeletal stem cells, a type of adult stem cell that goes on to make all the building blocks of the bone, as important pieces to this scientific puzzle.

Reporting in Science Translational Medicine, the team, led by Michael Longaker – co-director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine – found that, compared to healthy animals, type 2 diabetic mice have a reduced number of skeletal stem cells after bone fracture. A study of the local cellular “neighborhood” of these stem cells showed that the diabetic mice also had a reduction in the levels of a protein called hedgehog. Blocking hedgehog activity in healthy mice led to the slow bone healing seen in the diabetic mice. More importantly, boosting hedgehog levels near the site of the fracture in diabetic mice lead to bone healing that was just as good as in the healthy mice.

To see if this result might hold up in humans, the team analyzed hedgehog levels in bone samples retrieved from diabetics and non-diabetics undergoing joint replacement surgeries. Sure enough, hedgehog was depleted in the diabetic bone exactly reflecting the mouse results.

Though more studies will be needed to develop a hedgehog-based treatment in humans, Longaker talked about the exciting big picture implications of this result in a press release:

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Michael Longaker

“We’ve uncovered the reason why some patients with diabetes don’t heal well from fractures, and we’ve come up with a solution that can be locally applied during surgery to repair the break. Diabetes is rampant worldwide, and any improvement in the ability of affected people to heal from fractures could have an enormously positive effect on their quality of life.”

 

Getting the ethics ahead of the next generation of fertility treatments
The Business Insider ran an article this week with a provocative title, “Now is the time to talk about creating humans from stem cells.” I initially read too much into that title because I thought the article was advocating the need to start the push for the cloning of people. Instead, author Rafi Letzter was driving at the importance for concrete, ethical discussion right now about stem cell technologies for fertility treatments that may not be too far off.

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These mice were born from artificial eggs that were made from stem cells in a dish.
It’s great news for infertility specialist but carries many ethical dilemmas. 
(Image: K. Hayashi, Kyushu University)

In particular, he alludes to a paper from October (read our blog about it) that reported the creation of female mouse eggs from stem cells. These eggs were fertilized, implanted into the mother and successfully developed into living mice. What’s more, one set of stem cells were derived from mouse skin samples via the induced pluripotent stem cell method. This breakthrough could one day make it possible for an infertile woman to simply go through a small skin biopsy or mouth swab to generate an unlimited number of eggs for in vitro fertilization (IVF). Just imagine how much more efficient, less invasive and less costly this procedure could be compared to current IVF methods that require multiple hormone injections and retrieval of eggs from a woman’s ovaries.

But along with that hope for couples who have trouble conceiving a child comes a whole host of ethical issues. Here, Letzter refers to a perspective letter published on Wednesday in Science Translation Medicine by scientists and ethicists about this looming challenge for researchers and policymakers.

It’s an important read that lays out the current science, the clinical possibilities and regulatory and ethical questions that must be addressed sooner than later. In an interview with Letzter, co-author Eli Adashi, from the Alpert Medical School at Brown University, warned against waiting too long to heed this call to action:

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Eli Adashi

“Let’s start the [ethical] conversation now. Like all conversations it will be time consuming. And depending how well we do it, and we’ve got to do it well, it will be demanding. It will not be wise to have that conversation when you’re seeing a paper in Science or Nature reporting the complete process in a human. That would not be wise on our collective part. We should be as much as possible ready for that.”

 

 

Tackling Frontotemporal dementia and Alzheimer’s by hitting the same target.
To develop new disease therapies, you usually need to understand what is going wrong at a cellular level. In some cases, that approach leads to the identification of a specific protein that is either missing or in short supply. But this initial step is just half the battle because it may not be practical to make a drug out of the protein itself. So researchers instead search for other proteins or small molecules that lead to an increase in the level of the protein.

A CIRM-funded project at the Gladstone Institutes has done just that for the protein called progranulin. People lacking one copy of the progranulin gene carry an increased risk for  frontotemporal dementia (FTD), a degenerative disease of the brain that is the most common cause of dementia in people under 60 years of age. FTD symptoms are often mistaken for Alzheimer’s. In fact, mutations in progranulin are also associated with Alzheimer’s.

Previous studies have shown that increasing levels of progranulin in animals with diseases that mimic FTP and Alzheimer’s symptoms can reverse symptoms. But little was known how progranulin protein levels were regulated in the cells. Amanda Mason, the lead author on the Journal of Biological Chemistry report, explained in a press release how they tackled this challenge:

“We wanted to know what might regulate the levels of progranulin. Many processes in biology are controlled by adding or removing a small chemical group called phosphate, so we started there.”

These phosphate groups hold a lot of energy in their chemical bonds and can be harnessed to activate or turn off the function of proteins and DNA. The team systematically observed the effects of enzymes that add and remove phosphate groups and zeroed in on one called Ripk1 that leads to increases in progranulin levels. Now the team has set their sights on Ripk1 as another potential target for developing a therapeutic that could be effective against both FTP and Alzheimer’s. Steve Finkbeiner, the team lead, gave a big picture perspective on these promising results:

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Steve Finkbeiner

“This is an exciting finding. Alzheimer’s disease was discovered over 100 years ago, and we have essentially no drugs to treat it. To find a possible new way to treat one disease is wonderful. To find a way that might treat two diseases is amazing.”

 

Stem cell stories that caught our eye: glowing stem cells and new insights into Zika and SCID

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Glowing stem cells help scientists understand how cells work. (Karen Ring)
It’s easy to notice when something is going wrong. It’s a lot harder to notice when something is going right. The same thing can be said for biology. Scientists dedicate their careers to studying unhealthy cells, trying to understand why people get certain diseases and what’s going wrong at the cellular level to cause these problems. But there is a lot to be said for doing scientific research on healthy cells so that we can better understand what’s happening when cells start to malfunction.

A group from the Allen Institute for Cell Science is doing just this. They used a popular gene-editing technology called CRISPR/Cas9 to genetically modify human stem cell lines so that certain parts inside the cell will glow different colors when observed under a fluorescent microscope. Specifically, the scientists inserted the genetic code to produce fluorescent proteins in both the nucleus and the mitochondria of the stem cells. The final result is a tool that allows scientists to study how stem cells specialize into mature cells in various tissues and organs.

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

The director of stem cells and gene editing at the Allen Institute, Ruwanthi Gunawardane, explained how their technology improves upon previous methods for getting cells to glow in an interview with Forbes:

 “We’re trying to understand how the cell behaves, how it functions, but flooding it with some external protein can really mess it up. The CRISPR system allows us to go into the DNA—the blueprint—and insert a gene that allows the cell to express the protein in its normal environment. Then, through live imaging, we can watch the cell and understand how it works.”

The team has made five of these glowing stem cell lines available for use by the scientific community through the Coriell Institute for Medical Research (which also works closely with the CIRM iPSC Initiative). Each cell line is unique and has a different cellular structure that glows. You can learn more about these cell lines on the Coriell Allen Institute webpage and by watching this video:

 

Zika can take multiple routes to infect a child’s brain. (Kevin McCormack)
One of the biggest health stories of 2016 has been the rapid, indeed alarming, spread of the Zika virus. It went from an obscure virus to a global epidemic found in more than 70 countries.

The major concern about the virus is its ability to cause brain defects in the developing brain. Now researchers at Harvard have found that it can do this in more ways than previously believed.

Up till now, it was believed that Zika does its damage by grabbing onto a protein called AXL on the surface of brain cells called neural progenitor cells (NPCs). However, the study, published in the journal Cell Stem Cell, showed that even when AXL was blocked, Zika still managed to infiltrate the brain.

Using induced pluripotent stem cell technology, the researchers were able to create NPCs and then modify them so they had no AXL expression. That should, in theory, have been able to block the Zika virus. But when they exposed those cells to the virus they found they were infected just as much as ordinary brain cells exposed to the virus were.

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

In a story in the Harvard Gazette, Kevin Eggan, one of the lead researchers, said this shows scientists need to re-think their approach to countering the virus:

“Our finding really recalibrates this field of research because it tells us we still have to go and find out how Zika is getting into these cells.”

 

Treatment for a severe form of bubble baby disease appears on the horizon. (Todd Dubnicoff)
Without treatment, kids born with bubble baby disease typically die before reaching 12 months of age. Formally called severe combined immunodeficiency (SCID), this genetic blood disorder leaves infants without an effective immune system and unable to fight off even minor infections. A bone marrow stem cell transplant from a matched sibling can treat the disease but this is only available in less than 20 percent of cases and other types of donors carry severe risks.

In what is shaping up to be a life-changing medical breakthrough, a UCLA team has developed a stem cell/gene therapy treatment that corrects the SCID mutation. Over 40 patients have participated to date with a 100% survival rate and CIRM has just awarded the team $20 million to continue clinical trials.

There’s a catch though: other forms of SCID exist. The therapy described above treats SCID patients with a mutation in a gene responsible for producing a protein called ADA. But an inherited mutation in another gene called Artemis, leads to a more severe form of SCID. These Artemis-SCID infants have even less success with a standard bone marrow transplant compared to those with ADA-SCID. Artemis plays a role in DNA damage repair something that occurs during the chemo and radiation therapy sessions that are often necessary for blood marrow transplants. So Artemis-SCID patients are hyper-sensitive to the side of effects of standard treatments.

A recent study by UCSF scientists in Human Gene Therapy, funded in part by CIRM, brings a lot of hope to these Artemis-SCID patient. Using a similar stem cell/gene therapy method, this team collected blood stem cells from the bone marrow of mice with a form of Artemis-SCID. Then they added a good copy of the human Artemis gene to these cells. Transplanting the blood stem cells back to mice, restored their immune systems which paves the way for delivering this approach to clinic to also help the Artemis-SCID patients in desperate need of a treatment.

Throwback Thursday: Progress to a Cure for Type 1 Diabetes

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of valuable stem cell stories on our blog. Some of these stories represent crucial advances towards stem cell-based cures for serious diseases and deserve a second look.

novemberawarenessmonthThis week in honor of Diabetes Awareness Month, we are featuring type 1 diabetes (T1D), a chronic disease that destroys the insulin-producing beta cells in your pancreas. Without these important cells, patients cannot maintain the proper levels of glucose, a fancy name for sugar, in their blood and are at risk for many complications including heart disease, blindness, and even death.

Cell replacement therapy is evolving into an attractive option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots (or insulin pumps) that many T1D patients currently take.

So let’s take a look at the past year’s advances in stem cell research for diabetes.

Making Insulin-Producing Cells from Stem Cells and Skin

This year, there were a lot of exciting studies that improved upon previous methods for generating pancreatic beta cells in a dish. Here’s a brief recap of a few of the studies we covered on our blog:

  • Make pancreatic cells from stem cells. Scientists from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute developed a method that makes beta cells from T1D patient-derived induced pluripotent stem cells (iPSCs) that behave very similarly to true beta cells both in a dish and when transplanted into diabetic mice. Their discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future and the authors of the study predicted that their technology could be ready to test in humans in the next three to five years.
  • Making functional pancreatic cells from skin. Scientists from the Gladstone Institutes used a technique called direct reprogramming to turn human skin cells directly into pancreatic beta cells without having to go all the way back to a pluripotent stem cell state. The pancreatic cells looked and acted like the real thing in a dish (they were able to secrete insulin when exposed to glucose), and they functioned normally when transplanted into diabetic mice. This study is exciting because it offers a new and more efficient method to make functioning human beta cells in mass quantities.

    Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

    Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

  • Challenges of stem cell-derived diabetes treatments. At this year’s Ogawa-Yamanaka Stem Cell Award ceremony Douglas Melton, a well-renowned diabetes researcher from Harvard, spoke about the main challenges for developing stem cell-derived diabetes treatments. The first is the need for better control over the methods that make beta cells from stem cells. The second was finding ways to make large quantities of beta cells for human transplantation. The last was finding ways to prevent a patient’s immune system from rejecting transplanted beta cells. Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.

Progress to a Cure: Clinical Trials for Type 1 Diabetes

Speaking of encapsulation devices, CIRM is funding a Phase I clinical trial sponsored by a San Diego-based company called ViaCyte that’s hoping to develop a stem cell-based cure for patients with T1D. The treatment involves placing a small encapsulated device containing stem cell-derived pancreatic precursor cells under the skin of T1D patients. Once implanted, these precursor cells should develop into pancreatic beta cells that can secrete insulin into the patient’s blood stream. The goal of this trial is first to make sure the treatment is safe for patients and second to see if it’s effective in improving a patient’s ability to regulate their blood sugar levels.

To learn more about this exciting clinical trial, watch this fun video made by Youreka Science.

ViaCyte is still waiting on results for their Phase 1 clinical trial, but in the meantime, they are developing a modified version of their original device for T1D called PEC-Direct. This device also contains pancreatic precursor cells but it’s been designed in a way that allows the patient’s blood vessels to make direct connections to the cells inside the device. This vascularization process hopefully will improve the survival and function of the insulin producing beta cells inside the device. This study, which is in the last stage of research before clinical trials, is also being funded by CIRM, and we are excited to hear news about its progress next year.

ViaCyte's PEC-Direct device allows a patient's blood vessels to integrate and make contact with the transplanted beta cells.

ViaCyte’s PEC-Direct device allows a patient’s blood vessels to integrate and make contact with the transplanted beta cells.


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From Pig Parts to Stem Cells: Scientist Douglas Melton Wins Ogawa-Yamanaka Prize for Work on Diabetes

Since the 1920s, insulin injections have remained the best solution for managing type 1 diabetes. Patients with this disease do not make enough insulin – a hormone that regulates the sugar levels in your blood – because the insulin-producing cells, or beta cells, in their pancreas are destroyed.

Back then, it took two tons of pig parts to make eight ounces of insulin, which was enough to treat 10,000 diabetic patients for six months. Biotech and pharmaceutical companies have since developed different types of human insulin treatments that include fast and long acting versions of the hormone. It’s estimated that $22 billion will be spent on developing insulin products for patients this year and that costs will rise to $32 billion in the year 2019.

These costs are necessary to keep insulin-dependent diabetes patients alive and healthy, but what if there was a different, potentially simpler solution to manage diabetes? One that looks to insulin-producing beta cells as the solution rather than daily hormone shots?

Douglas Melton Receives Stem Cell Prize for Work on Diabetes

Harvard scientist Douglas Melton envisions a world where one day, insulin-dependent diabetic patients are given stem cell transplants rather than shots to manage their diabetes. In the 90s, Melton’s son was diagnosed with type 1 diabetes. Motivated by his son’s diagnosis, Melton dedicated the focus of his research on understanding how beta cells develop from stem cells in the body and also in a cell culture dish.

Almost 30 years later, Melton has made huge strides towards understanding the biology of beta cell development and has generated methods to “reprogram” or coax pluripotent stem cells into human beta cells.

Melton was honored for his important contributions to stem cell and diabetes research at the second annual Ogawa-Yamanaka Stem Cell Prize ceremony last week at the Gladstone Institutes. This award recognizes outstanding scientists that are translating stem cell research from the lab to clinical trials in patients.

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Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, explained why Melton was selected as this year’s prize winner:

Deepak Srivastava, Gladstone Institutes

Deepak Srivastava, Gladstone Institutes

“Doug’s research on genetic markers expressed during pancreas development have led to a reliable way to reprogram stem cells into human beta cells. His work provides the foundation for the ultimate goal of transplantable, patient-specific beta cells.”

 

Making Beta Cells for Patients

During the awards ceremony, Melton discussed his latest work on generating beta cells from human stem cells and how this technology could transform the way insulin-dependent patients are treated.

Douglas Melton, Harvard University.

Douglas Melton, Harvard University.

“I don’t mean to say that this [insulin treatment] isn’t a good idea. That’s keeping these people alive and in good health,” said Melton during his lecture. “What I want to talk about is a different approach. Rather than making more and better insulins and providing them by different medical devices, why not go back to nature’s solution which is the beta cells that makes the insulin?”

Melton first described his initial research on making pancreatic beta cells from embryonic and induced pluripotent stem cells in a culture dish. He described the power of this system for not only modeling diabetes, but also screening for potential drugs, and testing new therapies in animal models.

He also mentioned how he and his colleagues are developing methods to manufacture large amounts of human beta cells derived from pluripotent stem cells for use in patients. They are able to culture stem cells in large spinning flasks that accelerate the growth and development of pluripotent stem cells into billions of human beta cells.

Challenges and Future of Stem-Cell Derived Diabetes Treatments

Melton expressed a positive outlook for the future of stem cell-derived treatments for insulin-dependent diabetes, but he also mentioned two major challenges. The first is the need for better control over the methods that make beta cells from stem cells. These methods could be more efficient and generate higher numbers of beta cells (beta cells make up 16% of stem cell-derived cells using their current culturing methods). The second is preventing an autoimmune attack after transplanting the stem-cell derived beta cells into patients.

Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.

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He mentioned a CIRM-funded clinical trial by ViaCyte, which is testing an encapsulation device that is placed under the skin. The device contains embryonic stem cell-derived pancreatic progenitor cells that develop into beta cells that secrete insulin into the blood stream. The device also prevents the immune system from attacking and killing the beta cells.

Melton also discussed a biological approach to protecting transplanted beta cells. In collaboration with Dan Anderson at MIT, they coated stem cell-derived beta cells in a biomaterial called alginate, which comes from seaweed. They injected alginate microcapsule-containing beta cells into diabetic mice and were able control their blood sugar levels.

At the end of his talk, Melton concluded that he believes that beta cell transplantation in an immunoprotective device containing stem cell-derived cells will have the most benefit for diabetes patients.

Gladstone Youtube video of Douglas Melton’s lecture at the Ogawa-Yamanaka Prize lecture.


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Circular RNAs: the Mind-Boggling Dark Matter of the Human Genome

We were just a few hours into the 2016 annual meeting of the International Society for Stem Cell Research (ISSCR) yesterday afternoon and my mind was already blown away. Pier Paolo Pandolfi of the Beth Israel Deaconess Medical Center at Harvard, spoke during the first plenary session about circular RNAs, which he dubbed, “the mind-boggling dark matter of the human genome” because their existence wasn’t confirmed until just four years ago.

To introduce the topic, Pandolfi compared human DNA to that of bacteria. Both species contain stretches of DNA sequence called genes that contain the instructions for making proteins which collectively form our bodies. Each gene is first transcribed into messenger RNA (mRNA) which in turn is translated into a protein.

Iceberg

Our DNA contains 20,000 genes. But that genetic material is just the tip of the iceberg.

But with the ability to sequence all the mRNA transcripts of an organism, or its transcriptome, came a startling fact about how differently our genetic structure is organized compared to bacteria. It turns out that 88% of DNA sequence in bacteria make up genes that code for proteins but only 2% of human DNA sequence directly codes for proteins. So what’s going with the other 98%? Scientist typically call this 98% chunk of the genome “regulatory DNA” because it contains sequences that act as control switches for turning genes on or off. But Pandolfi explained that more recent studies suggest that a whopping 70% of our genome (maybe even 95%) is transcribed into RNA but those RNA molecules just don’t get translated into protein.

 

One type of this “non-coding” RNA which we’ve blogged about plenty of times is called microRNA (miRNA). So far, about 5,000 human miRNAs have been identified compared to the 20,000 messenger RNAs that code for proteins. But by far the most abundant non-coding RNA in our transcriptome is the mysterious circular RNA (circRNA) with at least 100,000 different transcripts. circRNA was first observed as cellular structures in the 1980’s via electronic microscope images. Then in the 1990’s a scientist published DNA sequencing data suggesting the existence of circRNA. But the science community at that time panned the results, discrediting it as merely background noise of the experiments.

Pandolfi_2

Pier Paolo Pandolfi
Image: Beth Israel Deaconess Medical Center

But four years ago, the circRNAs were directly sequenced and their existence confirmed. The circRNAs are formed when messenger RNA goes through a well-described trimming process of its sequence. Some of the excised pieces of RNA form into the circular RNAs. It would seem that these circRNAs are just throw away debris but Pandolfi’s lab has found evidence that they directly play a role in cellular functions and even cancer.

His team studies a gene called Pokemon which, when genetically “knocked out” or removed from a mouse’s genome, leads to cancer. Now, it turns out this knockout not only removes the Pokemon protein but also a Pokemon circRNA (circPok). When the lab added back just the Pokemon gene, as you might expect, it acted to suppress cancer in the mice. But when just the circPok was added back, stunningly, it increased the formation of cancer in the mice. Given that genetic knockouts are one of the most pervasive techniques in biomedical science, a closer look at circRNAs that may have been overlooked in all of those results is clearly warranted.

Though this finding is somewhat scary in the fact that it’s a whole aspect of our genome that we’ve been unaware of, one fortunate aspect of circRNA is that they all carry a particular sequence which could be used as a target for a new class of drugs.

This data may extend to stem cells as well. We know that microRNAs have critical roles in regulating the maturation of stem cells into specialized cell types. Since circRNAs are thought to act by competing microRNA, it may not be long before we learn about circRNA’s role in stem cell function.

The other speakers at the first plenary session of the ISSCR annual meeting all gave high caliber talks. Luckily, Paul Knoepfler live blogged on two of those presentations. Here are the links:

 

Scientists Make Insulin-Secreting Cells from Stem Cells of Type 1 Diabetes Patients

Stem cell research for diabetes is in a Golden Age. In the past few years, scientists have developed methods to generate insulin-secreting pancreatic beta cell-like cells from embryonic stem cells, induced pluripotent stem cells (iPS cells), and even directly from human skin. We’ve covered a number of recent studies in this area on our blog, and you can read more about them here.

Patients with type 1 diabetes (T1D) suffer from an autoimmune response that attacks and kills the beta cells in their pancreas. Without these important cells, patients can no longer secrete insulin in response to increased glucose or sugar levels in the blood. Cell replacement is evolving into an attractive therapeutic option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots that many T1D patients currently take.

Cell replacement therapy for type 1 diabetes

Stem cells are the latest strategy that scientists are pursuing for T1D cell replacement therapy. The strategy involves generating beta cells from pluripotent stem cells, either embryonic or iPS cells, that function similarly to beta cells found in a healthy human pancreas. Making beta cells from a patient’s own iPS cells is the ideal way to go because this autologous form (self to self) of transplantation would reduce the chances  of transplant rejection because a patient’s own cells would be put back into their body.

Scientists have generated beta cell-like cells from iPS cells derived from T1D patients previously, but the biological nature and function of these cells wasn’t up to snuff in a side by side comparison with beta cells from non-diabetic patients. They didn’t express the appropriate beta cell markers and failed to secrete the appropriate levels of insulin when challenged in a dish and when transplanted into animal models.

However, a new study published yesterday in Nature Communications has overcome this hurdle. Teams from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute have developed a method that makes beta cells from T1D patient iPS cells that behave very similarly to true beta cells. This discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future.

These beta cells could be the real deal

Their current work is based off of an earlier 2014 study – from the lab of Douglas Melton at Harvard – that generated functional human beta cells from both embryonic and iPS cells of non-diabetic patients. In the current study, the authors were interested in learning whether it was possible to generate functional beta cells from T1D patients and whether these cells would be useful for transplantation given that they could potentially be less functional than non-diabetic beta cells.

The study’s first author, Professor Jeffrey Millman from the Washington University School of Medicine, explained:

Jeffrey Millman

Jeffrey Millman

“There had been questions about whether we could make these cells from people with type 1 diabetes. Some scientists thought that because the tissue would be coming from diabetes patients, there might be defects to prevent us from helping the stem cells differentiate into beta cells. It turns out that’s not the case.”

After generating beta cells from T1D iPS cells, Millman and colleagues conducted a series of experiments to test the beta cells both in a dish and in mice. They found that the T1D-derived beta cells expressed the appropriate beta cell markers, secreted insulin in the presence of glucose, and responded well to anti-diabetic drugs that stimulated the beta cells to secrete even more insulin.

When T1D beta cells were transplanted into mice that lacked an immune system, they survived and functioned similarly to transplanted non-diabetic beta cells. When the mice were treated with a drug that killed off their mouse beta cells, the surviving human T1D beta cells were successful in regulating the blood glucose levels in the mice and kept them alive.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients.

Beta cells derived from type 1 diabetes patient stem cells (top) express the same beta cell markers as beta cells derived from non-diabetic (ND) patients. (Nature Communications)

Big Picture

The authors concluded that the beta cells they generated from T1D iPS cells were indistinguishable from healthy beta cells derived from non-diabetic patients. In a news release, Millman commented on the big picture of their study:

“In theory, if we could replace the damaged cells in these individuals with new pancreatic beta cells — whose primary function is to store and release insulin to control blood glucose — patients with type 1 diabetes wouldn’t need insulin shots anymore. The cells we’ve manufactured sense the presence of glucose and secrete insulin in response. And beta cells do a much better job controlling blood sugar than diabetic patients can.”

He further commented that the T1D- derived beta cells “could be ready for human research in three to five years. At that time, Millman expects the cells would be implanted under the skin of diabetes patients in a minimally invasive surgical procedure that would allow the beta cells access to a patient’s blood supply.”

“What we’re envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin,” he said.

In fact, such devices already exist. CIRM is funding a type 1 diabetes clinical trial sponsored by the San Diego based company ViaCyte. They are currently testing a combination drug delivery system that implants a medical device capsule containing pancreatic progenitor cells derived from human embryonic stem cells. Once implanted, the progenitor cells are expected to specialize into mature pancreatic cells including beta cells that secrete insulin.


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Taking Steps Toward Personalized Heart Transplants

Over five million Americans have heart failure (HF), a condition in which the heart muscles become too weak to pump an adequate amount of blood, oxygen and nutrients to the body’s other organs. People with heart failure suffer from shortness of breath, chronic weakness and a fifty percent chance of dying within the first five years of diagnosis.

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Heart failure weakens the heart’s ability to pump blood to the body.
Image credit: Fran Milner, http://www.franimation.com

Heart transplants: swapping one disease for another
The only true cure for heart failure is an organ transplant but donor organs are in limited supply. And those lucky enough to receive a transplant need to take life long immunosuppressive drugs to fight off organ rejection, which often leads to other serious health problems like risk of infection, high blood pressure, diabetes and kidney failure.

It’s not a pretty picture for patients and with a cost to the nation of $32 billion annually, heart failure affects us all.

In a recent Circulation Research journal article, a team at the Massachusetts General Hospital (MGH) Center for Regenerative Medicine (CRM) reported on an incremental yet important step toward an alternative approach to heart transplants: growing bioengineered hearts with a patient’s own stem cells.

Bioengineered hearts: been there, done that
Bioengineered hearts may sound far fetched but eight years have already passed since researchers showed it’s possible with animal models. In that 2008 study, scientists at the University of Minnesota soaked rat hearts in detergents that cleaned away all of the heart cells, leaving behind a scaffold of connective tissue that is secreted by the cells. They then “re-seeded” the scaffold with rat progenitor heart muscle cells. Incredibly, after 4 days in a bioreactor, the tissue began contracting. After 8 days, using electrical stimulation, the hearts could pump with measurable strength.

heartscaffold

Custom built bioreactor with a partially recellularized human whole-heart cardiac scaffold. Image credit: Bernhard Jank, MD, Ott Lab, CRM MGH

Harald Ott, the first author of that proof of concept study, now leads the MGH team in the current study. With an eye toward bringing this method to the clinic, Ott aimed to reproduce the rat studies using human cells and hearts. Specific consent was obtained to recover seventy-three human hearts donated after brain death or cardiac death and were determined to be unusable for clinical transplant.

Just as in the previous study, heart scaffolds were created by clearing away the cells from these organs. Half a billion human heart muscle cells, or cardiomyocytes, that had been grown from human induced pluripotent stem cells (iPS) were then injected into the scaffolds. At this early stage of research, the team did not attempt to reseed the entire heart but specifically focused on areas around the left ventricle – the heart chamber responsible for pumping oxygenated blood out to the rest of the body.

In order to recellularize the scaffold under conditions that resemble the contractions that actually occur in a human heart inside the body, pressure was rhythmically applied using a balloon inside the ventricle – watch it in action by downloading this video.

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Decellularized heart scaffold is injected with iPS heart muscle cells and incubated in a bioreactor to grow new heart muscle (Circ Res. 2016;118:56-72).

After incubating the heart for 14 days in a bioreactor, the team confirmed the cardiomyocytes had formed into functioning heart muscle, or myocardial, tissue that contracted upon electrical stimulation (watch the beating heart by downloading this video).

Looking ahead to a “grow yourself a new heart” future
These results set a course for a future in which scientists could grow a new, personalized heart for people with heart failure. Since the bioengineered heart would be built using iPS cells derived from the patient’s own skin or blood sample, this technique would likely get around the problems of organ rejection and the need for immunosuppressive drugs. Additional analysis in the current study also confirmed that the donor heart scaffold itself, which is void of cells, probably will not pose tissue rejection problems either.

The other key problem, a limited supply of donor hearts, was also addressed. Heart scaffolds donated after cardiac death performed just as well as those donated after brain death which would make this technique available to more patients waiting anxiously for a transplant.

The MGH team would be the first to tell you this “grow yourself a new heart” scenario is still off on the horizon. But as first author, Jacques Guyette, stated in a news release, there are milestones to reach along the way:

“Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial [heart muscle tissue] patch that could replace cardiac tissue damaged due a heart attack or heart failure.”

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