Hearing loss is something that affect tens of millions of Americans. Usually people notice those changes as they get older but the damage can be done years before that through the use of some prescription drugs or exposure to loud noise (I knew I shouldn’t have sat in the 6th row of that Led Zeppelin concert!)
Now researchers at the University of Southern California (USC) have identified the mechanism that appears to stop cells that are crucial to hearing from regenerating.
In a news release Dr. Neil Segil says this could, in theory, help reverse some hearing loss. “Permanent hearing loss affects more than 60 percent of the population that reaches retirement age. Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”
The inner ear has two types of cells that are crucial for hearing; “hair cells” are sensory receptors and these help the brain detect sounds, and support cells that play, as the name implies, an important structural and supporting role for the hair cells.
In people, once the hair cells are damaged that’s it, you can’t repair or replace them and the resulting hearing loss is permanent. But mice, in the first few days of life, have ability to turn some of their support cells into hair cells, thus repairing any damage. So Segil and the team set out to identify how mice were able to do that and see if those lessons could be applied to people.
They identified specific proteins that played a key role in turning genes on and off, regulating if and when the support cells could turn into hair cells. They found that one molecule, H3K4mel, was particularly important in activating the correct genetic changes need to turn the support cells into hair cells. But in mice, levels of H3K4mel disappeared quickly after birth, so the team found a drug that helped preserve the molecule, meaning the support cells retained the ability to turn into hair cells.
Now, obviously because this was just done in mice there’s a lot more work that needs to be done to see if it can also work in people, but Segil says it’s certainly an encouraging and intriguing start.
“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing. Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”
There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.
Organ and tissue donation saves lives, increases knowledge of
diseases, and allow for the development of novel medications to treat them.
When individuals or their families authorize donation for transplant or medical
research, they allow their loved ones to build a long-lasting legacy of hope
that could not be accomplished in any other way.
Four of CIRM’s clinical trials involve organ donations –
three kidney transplant programs (you can read about those here,
and one targeting type 1
Dr. Nikole Neidlinger, the Chief
Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for
Northern California and Nevada – says it is important to recognize the critical
contribution made in a time of grief and crisis by the families of deceased
“For many families who donate, a
loved one has died, and they are in shock. Even so, they are willing to say yes
to giving others a second chance at life and to help others to advance science.
Without them, none of this would be possible. It’s the ultimate act of generosity
The latest CIRM-funded clinical trial involving donated
tissue is with Dr.
Peter Stock and his team at UCSF. They are working on a treatment for type
1 diabetes (T1D), where the body’s immune system destroys its own pancreatic
beta cells. These cells are necessary to produce insulin, which regulates blood
sugar levels in the body.
In the past people have tried transplanting beta cells,
from donated pancreatic islets, into patients with type 1 diabetes to try and
reverse the course of the disease. However, this requires islets from multiple
donors and the shortage of organ and tissue donors makes this difficult to do.
Dr. Stock’s clinical trial at UCSF aims to address these
limitations. He is going to transplant both pancreatic islets and
parathyroid glands, from the same donor, into T1 patients. It’s hoped this
combination approach will increase beta cell survival, potentially boosting long-term
insulin production and removing the need for multiple donors. And because
the transplant is placed in the patient’s forearm, it makes it easier to
monitor the effectiveness and accessibility of the islet transplants. Of equal
importance, the development of this site will facilitate the transplantation of
stem cell derived beta cells, which are very close to clinical application.
“As a transplant surgeon, it is an absolute privilege to
be able to witness the life-saving organ transplants made possible by the
selfless generosity of the donor families. It is hard to imagine how families
have the will to think about helping others at a time of their greatest grief.
It is this willingness to help others that restores my faith in humanity”
Donor Network West plays a
vital role in this process. In 2018 alone, the organization recovered 702 donor
samples for research. Thanks to the generosity of the donors/donor families, the donor
network has been able to provide parathyroid and pancreas tissue essential to
make this clinical trial a success”
“One organ donor can save the lives of up to eight people
and a tissue donor can heal more than 75 others,” says
Dr. Neidlinger. “For families, the knowledge that they are
transforming someone’s life, and possibly preventing another family from
experiencing this same loss, can serve as a silver lining during their time of
Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys. Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.
While we are here at ISSCR 2019 hearing various scientists talk about their work, we realize that there are various breakthroughs in stem cell research in a wide variety of different fields going on every day. It is wonderful to see how scientists are hard at work in developing the latest science and pushing innovation. Here are two remarkable stories you may have missed this week.
Scientists developing way to help premature babies breathe easier
Researchers at Cincinnati Children’s Hospital Medical Center are looking at ways to stimulate lung development in premature infants who suffer from a rare condition called Bronchopulmonary Dysplasia (BPD), which can cause lifelong breathing problems and even death. Using a mouse model of BPD, extensive analysis, and testing, the scientists were able to create a proposal to develop a stem cell therapy based on what are called c-KIT endothelial progenitor cells.
Premature babies, unable to breathe on their own, rely on machines to help them breathe. Unfortunately, these machines can interfere with lung development as well. The cells proposed in the stem cell therapy are common in the lungs of infants still in the womb and help in the formation of capillaries and air sacs in the lungs called alveoli.
In a press release, Dr. Vlad Kalinichenko, lead investigator for this work, was quoted as saying,
“The cells are highly sensitive to injury by high oxygen concentrations, so lung development in premature babies on mechanical oxygen assistance is impeded. Our findings suggest using c-KIT-positive endothelial cells from donors, or generating them with pluripotent stem cells, might be a way to treat BPD or other pediatric lung disorders associated with loss of alveoli and pulmonary microvasculature.”
The full results were published in American Journal of Respiratory and Critical Care Medicine.
Mice with a human immune system help research into cancer and infections
Speaking of a mouse model, researchers from Aarhus University and Aarhus University Hospital have succeeded in using mice with a transplanted human immune system to study functions in the immune system which are otherwise particularly difficult to study. This work could open the possibilities towards looking further into disease areas such as cancer, HIV, and autoimmune diseases.
Before potential treatments can be tested in humans, there needs to be extensive animal testing and data generated. However, when the disease relate’s to the human immune system, it can be particularly challenging to evaluate this in mice. The research team succeeded in transplanting human stem cells into mice whose own immune system is disabled, and then triggered a type of reaction in the immune system which normally reacts to meeting a range of viruses and bacteria.
In a press release, Dr. Anna Halling Folkmar, one of the researchers behind the study, says that,
“The humanised mice are an important tool in understanding how human immune cells behave during diseases and how they react to different medical treatments.”
CIRM has funded a number of educational and research training programs over the past ten years to give younger students and graduate/postdoc scholars the opportunity to explore stem cell science.
Two of the main programs we support are the Bridges and the CIRM Scholars Training Program. These programs fund future scientists from an undergraduate to postdoctoral level with a goal of creating “training programs that will significantly enhance the technical skills, knowledge, and experience of a diverse cohort of… trainees in the development of stem cell based therapies.”
The Stem Cellar team was interested to hear from Bridges and CIRM scholars themselves about their experience with these programs, how their careers have benefited from CIRM funding, and what research accomplishments they have under their belt. We were able to track some of these scholars down, and will be publishing a series of interview-style blogs featuring them over the next few months.
We start off with a Matt Donne, a PhD student at the University of California, San Francisco (UCSF) in the Developmental and Stem Cell Biology graduate program. Matt is a talented scientist and has a pretty cool story about his research training path. I sat down with Matt to ask him a few questions.
Q: Tell us how you got into a Stem Cell graduate program at UCSF.
MD: I was fortunate to have Dr. Carmen Domingo from San Francisco State support my application into the CIRM Bridges Program. I’d been working for Dr. Susan Fisher at UCSF for a couple of years and realized that I wanted to get a PhD and go to UCSF. I thought the best way to do that was improve my GPA and get a masters degree in stem cell biology. I applied to the CIRM program at SF State, and was accepted.
The Bridges Program has been a great feeder platform to get students more science experience exposure than they would have otherwise received, and prepares them well to move on to competitive graduate schools.
After receiving my Masters degree, I was admitted into the first year of the Developmental and Stem Cell Biology program at UCSF. When the opportunity to apply for a training grant from CIRM came about between my first and second year of at UCSF, I knew I had to give it a chance and apply. With the help of my mentor, Dr. Jason Rock, I wrote a solid proposal and was awarded the fellowship.
While at SF State, Carmen was extremely supportive and always available for her students. Since then, many of us still keep in touch and more have joined the UCSF graduate school community.
Q: Can you describe your graduate research?
MD: The field of regenerative medicine is searching for ways to allow us to repair injuries similar to how the Marvel Comic Wolverine can repair his wounds in the movies. One interesting fact which has been known for several decades, but has not been able to be investigated more deeply until now, is the innate ability for the adult lung to regrow lost lung tissue without any sort of intervention. My thesis focuses on defining the molecular mechanisms and stem cell niches that allow for this normal, healthy adult lung tissue growth. The working hypothesis is if we can understand what makes a cell undergo healthy tissue proliferation and differentiation, we could stimulate this response to cure individuals who suffer from diseases such as chronic obstructive pulmonary disease (COPD). Similarly, if we understand how a cell decides to respond in a diseased way, we could stop or revert the disease process from occurring.
One of the models we use in our lab is a “pneumosphere” culture. We essentially grow alveoli, which are the site of gas exchange in the lung, in a dish to attempt to understand how specific alveolar stem cells signal and interact with one another. This information will teach us how these cells behave so we can in turn either promote a healthy response to injury or, potentially, stop the progression of unhealthy cell responses. The technique of growing alveoli in a dish allows us to cut down on the “noise” and focus on major cellular pathways, which we can then more selectively apply to our mouse model systems.
Pneumospheres or “lung cells in a dish”. (Photo by Matt Donne)
Lung pneumospheres under a microscope. (Photo by Matt Donne)
We are now in the process of submitting a paper demonstrating some of the molecular players that are involved in this regenerative lung response. Hopefully the reviewers will think our paper is as awesome we as believe it to be.
Q: How has being a CIRM scholar benefited your graduate research career?
MD: Starting in my second year at UCSF, I was awarded the CIRM fellowship. I think it helped the lab to have the majority of my stipend covered through the CIRM fellowship, and personally I was very excited about the $5,000 discretionary budget. These monies allowed me to go to conferences every year for the past three years, and also have helped to support the costs of my experiments.
The first conference I attended was a Gordon Conference in Italy on Developmental Biology. There I was able to learn more about the field and also make friends with many professors, students, and postdocs from around the world. Last year, I went to my first lung-specific conference, and attended again this year. That has been one of the highlights of my PhD career. While there, one is able to speak and interact with professors whose names are seen in many textbooks and published papers. I never thought I would be able to so casually interact with them and develop relationships. Since then, I have been able to work on small collaborations with professors from across the US.
It was great that I could go to these conferences and establish important relationships with professors without being a major financial burden to my Professor. Plus, it has been hugely beneficial for my career as I now have professors whom I can reach out to as I look towards my future as a scientist.
Q: What other benefits did the CIRM scholars program provide you?
MD: Dr. Susan Fisher has been in charge of the CIRM program at UCSF. She organized lunch-time research talks that involved both academic as well as non-academic leaders in the field. I enjoyed the extra exposure to new fields of stem cell biology as well as the ability to learn more about the start-up and non-academic world. There are not many programs that offer this type of experience, and I felt fortunate to be a part of it. Also, the free lunches on occasion were a nice perk for a grad student living in San Francisco!
I attended the CIRM organized conferences whenever they happened. It’s always great presenting at or attending poster sessions at these events, seeing familiar faces and meeting new people. I took full advantage of the learning and networking that CIRM allowed me to do. The CIRM elevator pitch competition was really cool too. I didn’t win, came in third, but I enjoyed the challenge of trying to break down my thesis project into a digestible one-minute pitch.
Q: Where do you see the field of lung biology and regenerative medicine heading?
MD: My take away from the research conferences I have attended with the help of CIRM-funding is that we are in a very exciting time for lung stem cell research. The field overall is still young, but there are many labs across the world now working on a “lung mapping project” to better define stem cell populations in the lung. I see this research in the future translating in to regenerative therapies by which diseased cells/tissue will be targeted to actually stop the disease progression, and in turn possibly repair and regenerate healthy new tissue. This research has wide reaching implications as it has the potential to help everyone from a premature baby more quickly develop mature healthy lungs, to adults suffering from COPD brought on by environmental factors, such as air pollution. As many scientists are often quoted, “This is a very exciting time for our field.”
Q: What are your future plans?
MD: I expect to graduate in about a year’s time. In the future, I want to pursue a career focusing on the social impact of science. I aspire to be someone like UCSF’s former chancellor Dr. Susan Desmond-Hellmand. It’s really cool to go from someone who was the president of product development at Genentech, to chancellor at UCSF, to now president of the Bill and Melinda Gates Foundation. Bringing science to impact society in that way is what I hope to do with my future.