Dr. Charles K.F. Chan (Left) and Dr. Michael Longaker (right), Stanford University
Cartilage is a flexible, connective tissue in our joints that is important for cushioning our bones against impacts. This cartilage deteriorates as we age due to normal wear and tear and in some instances excessive damage or a deteriorating disease. The deterioration of cartilage is also the primary cause of joint pain and arthritis, which affects more than 55 million Americans.
It was generally assumed that adult cartilage could not be regenerated after damage. Fortunately, a CIRM funded project by Dr. Charles K.F. Chan, Dr. Michael Longaker, and Dr. Matthew Murphy at Stanford University found a way to use chemical signals to steer skeletal stem cells, which are responsible for the production of bone and cartilage, to regrow cartilage in joints.
Damaged cartilage is currently treated with a technique known as microfracture. Tiny holes are drilled into the surface of a joint, which activates the body’s skeletal stem cells to create fibrocartilage in the joint. Unfortunately, this newly created tissue lacks the flexible properties and cushion of normal cartilage.
The team theorized that there might be a way to influence skeletal stem cells to produce normal cartilage after microfracture. In a mouse model, the researchers used a molecule called BMP2 to initiate bone formation after microfracture. Next, they stopped the bone formation process midway with another molecule called VEGF. The result of this process was the generation of cartilage that had the same important properties as natural cartilage.
In a Stanford press release, Dr. Chan elaborated on these findings.
“What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties, unlike the fibrocartilage that we usually get. It also restored mobility to osteoarthritic mice and significantly reduced their pain.”
To show that this process could work in humans, the team then transferred human tissue into special mice that wouldn’t reject the tissue. They showed that human skeletal stem cells could be steered toward bone development but stopped at the cartilage stage.
The next stage for this research is to conduct experiments in larger animals before eventually starting human clinical trials. The ultimate goal of this treatment would be to help prevent arthritis by rejuvenating cartilage in the joints before it is badly degraded.
In the same press release, Dr. Longaker discusses the advantages of using BMP2 and VEGF for this process.
“BMP2 has already been approved for helping bone heal, and VEGF inhibitors are already used as anti-cancer therapies. This would help speed the approval of any therapy we develop.”
The full results of this study were published in Nature.
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,
here
and here)
and one targeting type 1
diabetes.
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
donors.
“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
and compassion.”
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
sorrow. .”
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.
Illustration of mice adapting to their custom-designed space habitat on board the International Space Station. Image courtesy of the Center for the Advancement of Science in Space
Astronauts on the International Space Station (ISS) received some furry guests this weekend with the launch of SpaceX’s Dragon supply capsule. On Saturday June 3rd, 40 mice were sent to the ISS along with other research experiments and medical equipment. Scientists will be treating the mice with a bone-building drug in search of a new therapy to combat osteoporosis, a disease that weakens bones and affects over 200 million people globally.
The bone-building therapy comes out of CIRM-funded research by UCLA scientists Dr. Chia Soo, Dr. Kang Ting and Dr. Ben Wu. Back in 2015, the UCLA team published that a protein called NELL-1 stimulates bone-forming stem cells, known as mesenchymal stem cells, to generate new bone tissue more efficiently in mice. They also found that NELL-1 blocked the function of osteoclasts – cellular recycling machines that break down and absorb bone – thus increasing bone density in mice.
Encouraged by their pre-clinical studies, the team decided to take their experiments into space. In collaboration with NASA and a grant from the Center for the Advancement of Science in Space (CASIS), they made plans to test NELL-1’s effects on bone density in an environment where bone loss is rapidly accelerated due to microgravity conditions.
Bone loss is a major concern for astronauts living in space for extended periods of time. The earth’s gravity puts pressure on our bones, stimulating bone-forming cells called osteoblasts to create new bone. Without gravity, osteoblasts stop functioning while the rate of bone resorption increases by approximately 1.5% per month. This translates to almost a 10% loss in bone density for every 6 months in space.
In a UCLA news release, Dr. Wu explained how they modified the NELL-1 treatment to stand up to the tests of space:
“To prepare for the space project and eventual clinical use, we chemically modified NELL-1 to stay active longer. We also engineered the NELL-1 protein with a special molecule that binds to bone, so the molecule directs NELL-1 to its correct target, similar to how a homing device directs a missile.”
The 40 mice will receive NELL-1 injections for four weeks on the ISS, at which point, half of the mice will be sent back to earth to receive another four weeks of NELL-1 treatment. The other half will stay in space and receive the same treatment so the scientists can compare the effects of NELL-1 in space and on land.
The Rodent Research Hardware System includes three modules: Habitat, Transporter, and Animal Access Unit. Credits: NASA/Dominic Hart
“We are hoping this study will give us some insights on how NELL-1 can work under these extreme conditions and if it can work for treating microgravity-related bone loss, which is a very accelerated, severe form of bone loss, then perhaps it can (be used) for patients one day on Earth who have bone loss due to trauma or due to aging or disease.”
If you want to learn more about this study, watch this short video below provided by UCLA.
Scientists from Cedars-Sinai Medical Center have developed a new stem cell-based technology in animals that mends broken bones that can’t regenerate on their own. Their research was published today in the journal Science Translational Medicine and was funded in part by a CIRM Early Translational Award.
Over two million bone grafts are conducted every year to treat bone fractures caused by accidents, trauma, cancer and disease. In cases where the fractures are small, bone can repair itself and heal the injury. In other cases, the fractures are too wide and grafts are required to replace the missing bone.
It sounds simple, but the bone grafting procedure is far from it and can cause serious problems including graft failure and infection. People that opt to use their own bone (usually from their pelvis) to repair a bone injury can experience intense pain, prolonged recovery time and are at risk for nerve injury and bone instability.
The Cedars-Sinai team is attempting to “bridge the gap” for people with severe bone injuries with an alternative technology that could replace the need for bone grafts. Their strategy combines “an engineering approach with a biological approach to advance regenerative engineering” explained co-senior author Dr. Dan Gazit in a news release.
Gazit’s team developed a biological scaffold composed of a protein called collagen, which is a major component of bone. They implanted these scaffolds into pigs with fractured leg bones by inserting the collagen into the gap created by the bone fracture. Over a two-week period, mesenchymal stem cells from the animal were recruited into the collagen scaffolds.
To ensure that these stem cells generated new bone, the team used a combination of ultrasound and gene therapy to stimulate the stem cells in the collagen scaffolds to repair the bone fractures. Ultrasound pulses, or high frequency sound waves undetectable by the human ear, temporarily created small holes in the cell membranes allowing the delivery of the gene therapy-containing microbubbles into the stem cells.
Image courtesy of Gazit Group/Cedars-Sinai.
Animals that received the collagen transplant and ultrasound gene therapy repaired their fractured leg bones within two months. The strength of the newly regenerated bone was comparable to successfully transplanted bone grafts.
Dr. Gadi Pelled, the other senior author on this study, explained the significance of their research findings for treating bone injuries in humans,
“This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal’s own stem cells can effectively be used to treat non-healing bone fractures. It addresses a major orthopedic unmet need and offers new possibilities for clinical translation.”
You can learn more about this study by watching this research video provided by the Gazit Group at Cedars-Sinai.
Bone marrow transplants are currently the only approved stem cell-based therapy in the United States. They involve replacing the hematopoietic, or blood-forming stem cells, found in the bone marrow with healthy stem cells to treat patients with cancers, immune diseases and blood disorders.
For bone marrow transplants to succeed, patients must undergo radiation therapy to wipe out their diseased bone marrow, which creates space for the donor stem cells to repopulate the blood system. Radiation can lead to complications including hair loss, nausea, fatigue and infertility.
Scientists at UC San Diego have a potential solution that could make current bone marrow transplants safer for patients. Their research, which was funded in part by a CIRM grant, was published yesterday in the journal PNAS.
Engineered bone with functional bone marrow in the center. (Varghese Lab)
Led by bioengineering professor Dr. Shyni Varghese, the team engineered artificial bone tissue that contains healthy donor blood stem cells. They implanted the engineered bone under the skin of normal mice and watched as the “accessory bone marrow” functioned like the real thing by creating new blood cells.
The implant lasted more than six months. During that time, the scientists observed that the cells within the engineered bone structure matured into bone tissue that housed the donor bone marrow stem cells and resembled how bones are structured in the human body. The artificial bones also formed connections with the mouse circulatory system, which allowed the host blood cells to populate the implanted bone tissue and the donor blood cells to expand into the host’s bloodstream.
Normal bone structure (left) and engineered bone (middle) are very similar. Bone tissue shown on top right and bone marrow cells on bottom right. (Varghese lab)
The team also implanted these artificial bones into mice that received radiation to mimic the procedures that patients typically undergo before bone marrow transplants. The engineered bone successfully repopulated the blood systems of the irradiated mice, similar to how blood stem cell functions in normal bone.
“We’ve made an accessory bone that can separately accommodate donor cells. This way, we can keep the host cells and bypass irradiation. We’re working on making this a platform to generate more bone marrow stem cells. That would have useful applications for cell transplantations in the clinic.”
The authors concluded that engineered bone tissue would specifically benefit patients who needed bone marrow transplants for non-cancerous bone marrow-related diseases such as sickle cell anemia or thalassemia where there isn’t a need to destroy cancer-causing cells.
Inspiring cancer patients with designer socks. (Karen Ring) Here’s a motivating story we found in the news this week about a cancer survivor who’s bringing inspiration to other cancer patients with designer socks. Yes, you read that correctly, socks.
Jake Teitelbaum is a student at Wake Forest University and suffers from a rare form of blood cancer called Refractory Hodgkin’s lymphoma. Since his diagnosis, Jake has been admitted to hospitals multiple times. Each time he received a welcome package of a gown and a pair of beige, “lifeless” socks. After his fifth welcome package, this time to receive a life-saving stem cell treatment, Jake had had enough of the socks.
“[Those socks] represented chemotherapy and being in isolation. They were the embodiment of that experience.”
Jake ditched the hospital socks and started bringing his own to prove that his cancer didn’t define him. Even though his cancer kept coming back, Jake wanted to prove he was just as resilient.
Jake Teitelbaum
Feeling liberated and in control, Jake decided to share his socks with other patients by starting the Resilience Project. Patients can go to the Resilience website and design their own socks that represent their experiences with cancer. The Resilience project also raises money for cancer patients and their families.
“We provide tangible benefits and create fun socks, but what we’re doing comes back to the essence of resilience,” said Jake. “These terrible circumstances where we’re at our most vulnerable also give us the unique opportunity to grow.”
Jake was declared cancer free in October of 2016. You can learn more about the Resilience project on their website and by watching Jake’s video below.
Feeding disease knowledge with stem cell-derived stomach cells. Using educated guess work and plenty of trial and error in the lab, researchers around the world have successfully generated many human tissues from stem cells, including heart muscle cells, insulin-producing cells and nerve cells to name just a few. Reporting this week in Nature, stem cell scientists at Cincinnati’s Children Hospital have a new cell type under their belt. Or maybe I should say above their belt, because they have devised a method for coaxing stem cells to become stomach mini organs that can be studied in a petri dish.
Confocal microscopic image shows tissue-engineered human stomach tissues from the corpus/fundus region, which produce acid and digestive enzymes. Image: Cincinnati Children’s Hospital Medical Center
With this method in hand, the team is poised to make new discoveries about how the stomach forms during human development and to better understand stomach diseases. In a press release, team lead Jim Wells pointed out the need to find new therapies for stomach disease:
“Diseases of the stomach impact millions of people in the United States and gastric [stomach] cancer is the third leading cause of cancer-related deaths worldwide.”
The cells they generated are those found in the corpus/fundus area of the stomach which releases enzymes and hydrochloric acid to help us break down and digest the food we eat. The team is particularly interested to use the mini organs to study the impact of H. pylori infection, a type of bacteria that causes ulcers and has been linked to stomach cancers.
In an earlier study, Wells’ group devised stem cell recipes for making cells from an area of the stomach, called the antrum, that produces hormones that affect digestion and appetite. Wells thinks having both tissue types recreated in a petri dish may help provide a complete picture of stomach function:
James Wells
“Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it’s possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments.”
A silver bullet for antibiotic-resistant bone infections? Alexander Fleming’s discover of penicillin in the 1920’s marked the dawn of antibiotics – drugs which kill off bacteria and help stop infections. Rough estimates suggest that over 200 million lives have been saved by these wonder drugs. But over time there’s been a frightening rise in bacteria that are resistant to almost all available antibiotics.
These super resistant “bugs” are particularly scary for people with chronic bone infections because the intense, long term antibiotic medication required to keep the infection in check isn’t effective. But based on research published this week in Tissue Engineering, the use of stem cells and silver may provide a new treatment option.
Scanning Electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown spheres) surrounded by cellular debris. MRSA, the bacteria examined in this study, is resistant by many antibiotics. (Wikimedia)
It’s been known for many years that silver in liquid form can kill bacteria and scientists have examined ways to deliver a controlled release of silver nanoparticles at the site of the bone infection. But there has been a lot of concern, including by the Food and Drug Administration (FDA), about the toxicity of silver nanoparticles to human cells.
In this study, a team led by Elizabeth Loboa from the University of Missouri instead looked at the use of silver ions which are safer than the nanoparticles. The team developed a three-dimensional cell culture system that resembles bone by growing human bone-forming stem cells on a tissue engineered scaffold, which also slowly releases silver ions.
The researchers stimulated the stem cells within the scaffold to specialize into bone cells and included a strain of bacteria that’s resistant to multiple antibiotics. They found that the silver ions effectively killed the bacteria and at the same time did not block the bone-forming stem cells. If this work holds up, doctors may one day use this silver ion-releasing, biodegradable scaffold to directly treat the area of bone infection. And to help prevent infection after joint replacement procedures, surgeons may rely on implants that are coated with these scaffolds.
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.
Functioning liver tissue. Scientists are looking to stem cells as a potential alternative treatment to liver transplantation for patients with end-stage liver disease. Efforts are still in their early stages but a study published this week in Stem Cells Translational Medicine, shows how a CIRM-funded team at the Children’s Hospital Los Angeles (CHLA) successfully generated partially functional liver tissue from mouse and human stem cells.
Biodegradable scaffold (left) and human tissue-engineered liver (right) (Photo courtesy of The Saban Research Institute at Children’s Hospital Los Angeles)
The lab had previously developed a protocol to make intestinal organoids from mouse and human stem cells. They were able to tweak the protocol to generate what they called liver organoid units and transplanted the tissue-engineered livers into mice. The transplants developed cells and structures found in normal healthy livers, but their organization was different – something that the authors said they would address in future experiments.
Impressively, when the tissue-engineered liver was transplanted into mice with liver failure, the transplants had some liver function and the liver cells in these transplants were able to grow and regenerate like in normal livers.
In a USC press release, Dr. Kasper Wang from CHLA and the Keck school of medicine at USC commented:
“A cellular therapy for liver disease would be a game-changer for many patients, particularly children with metabolic disorders. By demonstrating the ability to generate hepatocytes comparable to those in native liver, and to show that these cells are functional and proliferative, we’ve moved one step closer to that goal.”
Making new bone. Next up is a story about making new bone from stem cells. A group at UC San Diego published a study this week in the journal Science Advances detailing a new way to make bone forming cells called osteoblasts from human pluripotent stem cells.
One way that scientists can turn pluripotent stem cells into mature cells like bone is to culture the stem cells in a growth medium supplemented with small molecules that can influence the fate of the stem cells. The group discovered that by adding a single molecule called adenosine to the growth medium, the stem cells turned into osteoblasts that developed vascularized bone tissue.
When they transplanted the stem cell-derived osteoblasts into mice with bone defects, the transplanted cells developed new bone tissue and importantly didn’t develop tumors.
In a UC newsroom release, senior author on the study and UC San Diego Bioengineering Professor Shyni Varghese concluded:
“It’s amazing that a single molecule can direct stem cell fate. We don’t need to use a cocktail of small molecules, growth factors or other supplements to create a population of bone cells from human pluripotent stem cells like induced pluripotent stem cells.”
Stem cells and mental health. Brad Fikes from the San Diego Union Tribune wrote a great article on a new academic-industry partnership whose goal is to use human stem cells to find new drugs for mental disorders. The project is funded by a $15.4 million grant from the National Institute of Mental Health.
Academic scientists, including Rusty Gage from the Salk Institute and Hongjun Song from Johns Hopkins University, are collaborating with pharmaceutical company Janssen and Cellular Dynamics International to develop induced pluripotent stem cells (iPSCs) from patients with mental disorders like bipolar disorder and schizophrenia. The scientists will generate brain cells from the iPSCs and then work with the companies to test for potential drugs that could be used to treat these disorders.
In the article, Fred Gage explained that the goal of this project will be used to help patients rather than generate data points:
Rusty Gage, Salk Institute.
“Gage said the stem cell project is focused on getting results that make a difference to patients, not simply piling up research information. Being able to replicate results is critical; Gage said. Recent studies have found that many research findings of potential therapies don’t hold up in clinical testing. This is not only frustrating to patients, but failed clinical trials are expensive, and must be paid for with successful drugs.”
“The future of this will require more patients, replication between labs, and standardization of the procedures used.”
If you grew up during the 90’s, you most certainly will remember the famous “Got Milk?” advertising campaign to boost milk consumption. The plug was that milk was an invaluable source of calcium, a mineral that’s essential for growing strong bones. Drinking three glasses of the white stuff a day, supposedly would help deter osteoporosis, or the weakening and loss of bone with old age.
Research has proven that calcium is essential for growing and maintaining healthy bones. But milk isn’t the only source of calcium in the human diet, and a diet rich in calcium alone won’t prevent everyone from experiencing some amount of bone loss as they grow older. It also won’t help patients who suffer from bone skeletal defects grow new bone.
So whatever are we to do about bone loss and bone abnormalities? Here, we tell the “Tale of two stem cell treatments” where scientists tackle these problems using stem cell-derived therapies.
Our first story comes from a CIRM-funded team of UCLA scientists. This team is interested in developing a better therapy to treat bone defects and osteoporosis. The current treatment for bone loss is an FDA-approved bone regenerating therapy involving the protein BMP-2 (bone morphogenetic protein-2). The problem with BMP-2 is that it can cause serious side effects when given in high doses. Two of the major ones are abnormal bone growth and also making stem cells turn into fat cells as well as bone cells.
The UCLA group attempted to improve the BMP-2 treatment by adding a second protein called NELL-1 (which they knew was good at stimulating bone growth from previous studies). The combination of BMP-2 and NELL-1 resulted in bone growth and also prevented stem cells from making fat cells.
Upon further exploration, they found that NELL-1 acts as a signaling switch that controls whether a stem cell becomes a bone cell or a fat cell. Thus, with NELL-1 present, BMP-2 can only turn stem cells into bone cells.
Kang Ting, a lead author on the study, explained the significance of their new strategy to improve bone regeneration in a UCLA press release:
Kang Ting, UCLA
“Before this study, large bone defects in patients were difficult to treat with BMP2 or other existing products available to surgeons. The combination of NELL-1 and BMP2 resulted in improved safety and efficacy of bone regeneration in animal models — and may, one day, offer patients significantly better bone healing.”
Chia Soo, another lead author on the study, emphasized the importance of using NELL-1 in combination with BMP-2:
“In contrast to BMP2, the novel ability of NELL-1 to stimulate bone growth and repress the formation of fat may highlight new treatment approaches for osteoporosis and other therapies for bone loss.”
Stem cells that could fix deformed skulls
Our second story comes from a group at the University of Rochester. Their goal is to repair bones in the face and skull of patients suffering from congenital deformities, or damage due to injury or cancer surgery.
In a report published in Nature Communications, the scientists identified a population of skeletal stem cells that orchestrate the formation of the skull and can promote craniofacial bone repair in mice.
They identified this special population of skeletal stem cells by their expression of a protein called Axin2. Genetic mutations in the Axin2 gene can cause a birth defect called craniosynostosis. This condition causes the bone plates of a baby’s skull to fuse too early, causing skull deformities and impaired brain development.
Axin2 stem cells shown in red and blue generated new bones cells after transplantation.
According to a news release from the University of Rochester, the group’s “latest evidence shows that stem cells central to skull formation are contained within Axin2 cell populations, comprising about 1 percent—and that the lab tests used to uncover the skeletal stem cells might also be useful to find bone diseases caused by stem cell abnormalities.”
Additionally, senior author on the study, Wei Hsu, “believes his findings contributee to an emerging field involving tissue engineering that uses stem cells and other materials to invent superior ways to replace damaged craniofacial bones in humans due to congenital disease, trauma, or cancer surgery.”
Two different studies, one common goal
Both studies have a common goal: to repair or regenerate bone to treat bone loss, damage, or deformities. I can’t help but wonder whether these different strategies could be combined in a way to that would bring more benefit to the patient than using either strategy alone.
Could we use BMP-2 and NELL-1 treatment along with Axin2 skeletal stem cells to treat craniosynostosis or repair damaged skulls? Or could we identify new stem cell populations in bone that would help patients suffering from osteoporosis?
I’m sure scientists will answer these questions sooner rather than later, and when they do, you’ll be sure to read about it on the Stem Cellar!
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.
Image of the hydrogel containing mesenchymal stem cells. Credit Harvard SEAS/Wyss Institute
A better way to grow bone. The term hydrogel gets tossed around a lot in tissue engineering discussions. The porous, generally pliable materials used to hold stem cells in place when creating new tissue are far from uniform. They have highly variable properties. Making a version that mimics the natural environment where bone grows allowed a Harvard team to grow better quality bone and more of it than prior methods.
It turns out stem cells prefer to turn into bone when grown in an environment that readily relaxes in response to stress. Think of Silly Putty instead of hard rubber. When the Harvard team grew stem cells on a fast relaxing hydrogel, they saw an increased number of stem cells turn into bone and those cells continued to create more bone for weeks.
“This work both provides new insight into the biology of regeneration, and is allowing us to design materials that actively promote tissue regeneration,” said David Mooney, who led the team.
Replacement diaphragms. Paolo Macchiarini, the Italian scientist based at Sweden’s Karolinska Institute who created much news and a bit of controversy with surgeries to give patients lab-made windpipes, burst back into the news this week. This time with replacement diaphragms, that muscle in the abdomen critical for breathing. The tireless muscle is much more complex than the static windpipe, or trachea, and Macchiarini readily noted that his current work in rats is not nearly ready for patients.
When it is, it could be a life changer and maybe life saver for the one in 2,500 babies born with defects in their diaphragm. Using a technique similar to his work with the trachea, his team took stem cells from bone marrow and grew them on an artificial polymer scaffold. When they transplanted sections of the synthetic diaphragm into a damaged diaphragm in the animals the sections of muscle beat in synchrony with the rest of the rat’s existing diaphragm. But Macchiarini notes they have no idea why this happened and until they do, the procedure will not be ready for the clinic.
“If you ask me why it happens, to be very honest I don’t know,” he told Alice Park writing for Time. “I can just say that we saw many proteins, extracellular matrix components that belong to the nervous system. So probably via this, the muscle was able to contract again.”
The team wants to refine the process by determining which of the stem cells are destined to become muscle. The university put a bit more detail in a press release.
Video on synthetic windpipe. Since Macchiarini’s early reports of giving patients new windpipes, or tracheas, several teams around the world have tried to refine the procedure. The East Coast TV station WFMZ did an easy-to-understand segment on one team’s efforts at Mount Sinai in New York City. So far, their work remains confined to lab animals, but hey hope to treat patients within 18 months.
Lab grown trachea. Credit University College London.
Neural music synthesizer. On first read, this one sounds a little far fetched. The headline says “world’s first neural synthesizer.” And even crazier, the artist did it with iPSC-type stem cells reprogrammed from his own skin.
“Music is fed into the neurons as electrical stimulations and the neurons respond by controlling the synthesizer, creating an improvised post-human sound piece.”
Image from Guy Ben-Ary website.
It provides a bit more description and notes that the project by artist Guy Ben-Ary is supported by a creative Australia Fellowship award to develop a biologic self-portrait. The article does provide a link to Ben-Ary’s web site, which goes into great detail on every aspect of the project called “cellF.” He describes everything from the procedure for making the stem cells in Barcelona to how they are grown into nerve cells in special plates that can both send and receive signals to respond to the natural electro physiology of nerves. He explains the special lab plates in this way:
“The dishes that host my ‘external brain’ (neural networks) consist of a grid of electrodes that can record the electric signals that the neurons produce and at the same time send stimulation to the neurons – essentially a read-and-write interface.”
The first concert using the synthesizer occurred October 4. A guest musician, a drummer from Tokyo, provided the sound that was converted to electrical stimulus for the nerves. The nerves responded by controlling the music synthesizer. The video documenting the performance is due to be posted later this month.
Prostate cancer, which currently affects 3 million men in the United States, is no longer a death sentence if caught early. The five-year survival rate is very high (~98%) because of effective treatments like hormone therapy, chemotherapy, surgery, and radiation—and for many men with slow progressing tumors, the wait-and-watch approach offers an alternative to treatment.
However, for those patients who have more aggressive forms of prostate cancer, where the tumors spread to other organs and tissues, the five-year survival rate is much lower (~28%) and standard therapies only work temporarily until the tumors become resistant to them. Thus there is a need for finding new therapeutic targets that would lead to more effective and longer-lasting treatments.
Kinases are ABL to cause cancer
We recently wrote a blog about prostate cancer featuring the work of a pioneer in cancer research, Dr. Owen Witte from the UCLA Broad Stem Cell Research Center. Dr. Witte is well known for his work on understanding the biology of blood cancers (leukemias) and the role of cancer stem cells. One of his key discoveries was that the cancer-causing BCR-ABL gene produces an overactive protein kinase that causes chronic myelogenous leukemia (CML).
Protein kinases are enzymes that turn on important cell processes like growth, signaling, and metabolism, but they also can be involved in causing several different forms of cancer. This has made some kinases a prime target for developing cancer drugs that block their cancer-causing activity.
New targets for late-stage prostate cancer
Recently, Dr. Witte’s interests have turned to understanding and finding new treatments for aggressive prostate cancers. He has been on the hunt for new targets, and this week, Witte and his group published a CIRM-funded study in the journal PNAS showing that a specific set of kinases are involved in causing advanced stage prostate cancer that spreads to bones.
They selected a group of 125 kinases that are known to be active in aggressive forms of human cancers. From this pool, they found that 20 of these kinases caused metastasis, or the spreading of cancer cells from the starting tumor to different areas of the body, when activated in mouse prostate cancer cells that were injected into the tail veins of mice.
To narrow down the pool further, they activated each of the 20 kinases in human prostate cancer cells and injected these cells into the tails of mice. They found that five of the kinases caused the cancer cells to leave the tail and metastasize into the bones. When they compared the activity of these five kinases in the late-stage and early-stage prostate cancer cells as well as normal prostate cells, they only saw activity of these kinases in the late-stage cancer cells.
Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.
New treatment option?
Witte and his colleagues concluded that these five kinases can cause prostate tumor cells to spread and metastasize into bones, and that targeting kinase activity could be a new therapeutic strategy for late-stage prostate cancer patients that have exhausted normal treatment options.
In a UCLA press release, Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab commented:
Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis. Now we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.
Dr. Witte followed up by mentioning the promise of targeting kinase activity for late-stage prostate cancer:
Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people. I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.
The Stem Cellar 