A novel off-the-shelf bio-implant containing embryonic stem cells has the potential to revolutionize the treatment of cartilage injuries
More than a million Americans undergo knee and hip replacements each year. It’s a last resort treatment for pain and mobility issues associated with osteoarthritis, a progressive disease caused by degeneration of the protective layer of cartilage that stops our bones grinding together when we sit, stand, write, or move around.
But what if doctors could intervene and repair damaged cartilage before surgery is needed?
For the first time, researchers at the Keck School of Medicine of USC have used a stem cell-based bio-implant to repair cartilage and delay joint degeneration in a large animal model. The work will now advance into humans with support from a $6 million grant from the California Institute of Regenerative Medicine (CIRM).
The research, recently published in npj Regenerative Medicine, was led by two researchers at the Keck School of Medicine of USC: Denis Evseenko, MD, PhD, associate professor of orthopaedic surgery, and stem cell biology and regenerative medicine, director of the skeletal regeneration program, and vice chair for research of orthopaedic surgery; and Frank Petrigliano, MD, associate professor of clinical orthopaedic surgery and chief of the USC Epstein Family Center for Sports Medicine.
Osteoarthritis occurs when the protective cartilage that coats the ends of the bones breaks down over time, resulting in bone-on-bone friction. The disorder, which is often painful, can affect any joint, but most commonly affects those in our knees, hips, hands and spine.
To prevent the development of arthritis and alleviate the need for invasive joint replacement surgeries, the USC researchers are intervening earlier in the disease.
“In some patients joint degeneration starts with posttraumatic focal lesions, which are lesions in the articular (joint) cartilage ranging from 1 to 8 cm2 in diameter,” Evseenko said. “Since these can be detected by imaging techniques such as MRI, this opens up the possibility of early intervention therapies that limit the progression of these lesions so we can avoid the need for total joint replacement.”
That joint preservation technology developed at USC is a therapeutic bio-implant, called Plurocart, composed of a scaffold membrane seeded with stem cell-derived chondrocytes—the cells responsible for producing and maintaining healthy articular cartilage tissue. Building on previous research to develop and characterize the implant, the current study involved implantation of the Plurocart membrane into a pig model of osteoarthritis. The study resulted in the long-term repair of articular cartilage defects.
“This is the first time an orthopaedic implant composed of a living cell type was able to fully integrate in the damaged articular cartilage tissue and survive in vivo for up to six months,” Evseenko said. “Previous studies have not been able to show survival of an implant for such a long time.”
Evseenko said molecular characterization studies showed the bio-implant mimicked natural articular cartilage, with more than 95 percent of implanted cells being identified as articular chondrocytes. The cartilage tissue generated was also biomechanically functional—both strong enough to withstand compression and elastic enough to accommodate movement without breaking.
With support from the $6 million translational grant from CIRM, the researchers are using this technology to manufacture the first 64 Plurocart implants to be tested in humans.
“Many of the current options for cartilage injury are expensive, involve complex logistical planning, and often result in incomplete regeneration,” said Petrigliano. “Plurocart represents a practical, inexpensive, one-stage therapy that may be more effective in restoring damaged cartilage and improve the outcome of such procedures.”
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Stopping arthritis before it starts
Making stem cells from a patient’s adult cells – rather than human embryos – is one of the holy grails in modern medicine treatments. New research brings us two steps closer.
Biomedical engineers and medical researchers at UNSW Sydney have independently made discoveries about embryonic blood stem cell creation that could one day eliminate the need for stem cell blood donors.
The achievements are part of a move in regenerative medicine towards the use of ‘induced pluripotent stem cells’ to treat disease, where stem cells are reverse engineered from adult tissue cells rather than using live human or animal embryos.
But while we have known about induced pluripotent stem cells since 2006, scientists still have plenty to learn about how cell differentiation in the human body can be mimicked artificially and safely in the lab for the purposes of delivering targeted medical treatment.
Two studies have emerged from UNSW researchers in this area that shine new light on not only how the precursor blood stem cells occur in animals and humans, but how they may be induced artificially.
In a study published today in Cell Reports, researchers from UNSW School of Biomedical Engineering demonstrated how a simulation of an embryo’s beating heart using a microfluidic device in the lab led to the development of human blood stem cell ‘precursors’, which are stem cells on the verge of becoming blood stem cells.
And in an article published in Nature Cell Biology recently, researchers from UNSW Medicine & Health revealed the identity of cells in mice embryos responsible for blood stem cell creation.
Both studies are significant steps towards an understanding of how, when, where and which cells are involved in the creation of blood stem cells. In the future, this knowledge could be used to help cancer patients, among others, who have undergone high doses of radio- and chemotherapy, to replenish their depleted blood stem cells.
Emulating the heart
In the study detailed in Cell Reports, lead author Dr Jingjing Li and fellow researchers described how a 3cm x 3cm microfluidic system pumped blood stem cells produced from an embryonic stem cell line to mimic an embryo’s beating heart and conditions of blood circulation.
She said that in the last few decades, biomedical engineers have been trying to make blood stem cells in laboratory dishes to solve the problem of donor blood stem cell shortages. But no one has yet been able to achieve it.
“Part of the problem is that we still don’t fully understand all the processes going on in the microenvironment during embryonic development that leads to the creation of blood stem cells at about day 32,” Dr Li said.
“So we made a device mimicking the heart beating and the blood circulation and an orbital shaking system which causes shear stress – or friction – of the blood cells as they move through the device or around in a dish.”
These systems promoted the development of precursor blood stem cells which can differentiate into various blood components – white blood cells, red blood cells, platelets and others. They were excited to see this same process – known as haematopoiesis – replicated in the device.
Study co-author Associate Professor Robert Nordon said he was amazed that not only did the device create blood stem cell precursors that went on to produce differentiated blood cells, but it also created the tissue cells of the embryonic heart environment that is crucial to this process.
“The thing that just wows me about this is that blood stem cells, when they form in the embryo, form in the wall of the main vessel called the aorta. And they basically pop out of this aorta and go into the circulation, and then go to the liver and form what’s called definitive haematopoiesis, or definitive blood formation.
“Getting an aorta to form and then the cells actually emerging from that aorta into the circulation, that is the crucial step required for generating these cells.”
“What we’ve shown is that we can generate a cell that can form all the different types of blood cells. We’ve also shown that it is very closely related to the cells lining the aorta – so we know its origin is correct – and that it proliferates,” A/Prof. Nordon said.
The researchers are cautiously optimistic about their achievement in emulating embryonic heart conditions with a mechanical device. They hope it could be a step towards solving challenges limiting regenerative medical treatments today: donor blood stem cell shortages, rejection of donor tissue cells, and the ethical issues surrounding the use of IVF embryos.
“Blood stem cells used in transplantation require donors with the same tissue-type as the patient,” A/Prof. Nordon said.
“Manufacture of blood stem cells from pluripotent stem cell lines would solve this problem without the need for tissue-matched donors providing a plentiful supply to treat blood cancers or genetic disease.”
Dr Li added: “We are working on up-scaling manufacture of these cells using bioreactors.”
Meanwhile, and working independently of Dr Li and A/Prof. Nordon, UNSW Medicine & Health’s Professor John Pimanda and Dr Vashe Chandrakanthan were doing their own research into how blood stem cells are created in embryos.
In their study of mice, the researchers looked for the mechanism that is used naturally in mammals to make blood stem cells from the cells that line blood vessels, known as endothelial cells.
“It was already known that this process takes place in mammalian embryos where endothelial cells that line the aorta change into blood cells during haematopoiesis,” Prof. Pimanda said.
“But the identity of the cells that regulate this process had up until now been a mystery.”
Read more: Baby mice have a skill that humans want – and this microchip might help us learn it
In their paper, Prof. Pimanda and Dr Chandrakanthan described how they solved this puzzle by identifying the cells in the embryo that can convert both embryonic and adult endothelial cells into blood cells. The cells – known as ‘Mesp1-derived PDGFRA+ stromal cells’ -– reside underneath the aorta, and only surround the aorta in a very narrow window during embryonic development.
Dr Chandrakanthan said that knowing the identity of these cells provides medical researchers with clues on how mammalian adult endothelial cells could be triggered to create blood stem cells – something they are normally unable to do.
“Our research showed that when endothelial cells from the embryo or the adult are mixed with ‘Mesp1 derived PDGFRA+ stromal cells’ – they start making blood stem cells,” he said.
While more research is needed before this can be translated into clinical practice – including confirming the results in human cells – the discovery could provide a potential new tool to generate engraftable haematopoietic cells.
“Using your own cells to generate blood stem cells could eliminate the need for donor blood transfusions or stem cell transplantation. Unlocking mechanisms used by nature brings us a step closer to achieving this goal,” Prof. Pimanda said.
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More and more athletes are turning to stem cell treatments, because the pressure to get back on the field is high and access to these experimental therapies is continuing to increase. Athletes commonly suffer serious injuries that could potentially end their careers and cause them serious long-term health complications. Most of them turn to surgery to resolve those injuries.
However, some of them are pursuing stem cell treatments and regenerative therapies, because these procedures are less invasive than surgery and have the potential to speed and augment repair. While the effectiveness of these surgeries is largely unknown, what is clear is that a growing number of athletes are turning to this approach.
Athletes Who Have Undergone Stem Cell Treatments
This article outlines 40 pro athletes who have undergone stem cell treatments for their knees, hips, ankles, shoulders, and more. It also includes athletes who have pursued regenerative therapies, such as platelet-rich plasma (PRP) therapy.
In my case as a professional athlete, I received both of these therapies within a short time frame with each other, because there is evidence to indicate that PRP injections can positively impact stem cell treatment outcomes.
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40 Pro Athletes Who Have Had Stem Cell Treatments
It’s been about half a century since the first transplant of bone marrow from a donor to a recipient was completed. Since then, bone marrow transplantation has become an integral part of care for many patients with persistent leukemia, lymphoma, multiple myeloma and other blood cancers, as well as noncancerous blood disorders such as sickle cell disease. Specifically, we are transplanting stem cells — nascent cells with the capacity to mature into functioning blood and immune system cells — from a matched or partially matched donor into the body of a patient whose own blood-forming system has been destroyed with toxic medication to make way for a healthy new system to grow and develop.
In recent years, however, our field has expanded to include other treatments that work in similar ways as bone marrow transplantation. They are collectively known as “cellular therapies” because they do one of three things: provide healthy new cells to replace diseased cells, release an influx of specially modified immune cells to teach the body’s immune cells how to fight disease, or provide cells that connect immune cells with cancer cells they are designed to kill. Study after study has demonstrated how these approaches are extending patients’ lives. This progression of therapies is reflected in bone marrow transplant services around the country, many of which — including our own at Hackensack University Medical Center — now include the words “cellular therapy” in their names.
It is an exciting time for those of us in the stem cell transplantation and cellular therapy field. For years, we have concentrated on improving the outcomes of stem cell transplants. We have significantly improved techniques to reduce the risk of graft-versus-host disease, a potentially serious complication of transplantation that occurs when immune cells from the donor identify the tissues of the recipient as foreign and attack them, causing a host of inflammatory symptoms. We have learned which medications to give to prevent post-transplant infections such as cytomegalovirus, a common virus that can be damaging in people with compromised immune systems. We are using stem cells from umbilical cord blood to perform more transplants in adult patients. And we have matched more patients with donors by learning how to perform “haploidentical” transplants, where the patient receives a transplant from someone who is partially matched immunologically. These advances are making stem cell transplantation a safer and more effective treatment option for more patients who need them.
But where we are really seeing a revolution in care is the field of cellular therapy — particularly CAR T-cell immunotherapy. Cancer cells have found ways to escape being detected and destroyed by immune cells. Immunotherapies work by helping the immune system find and kill cancer cells.
With CAR T-cell therapy, immune cells called T cells are removed from the patient, genetically modified in a lab to recognize and attach to certain targets on cancer cells, grown to larger quantities (hundreds of millions), and returned to the patient. There, the modified T cells can find, bind to and kill cancer cells. The treatment is given intravenously. Long after the patient goes home, however, his or her newly educated immune cells continue to detect and destroy cancer cells, which is why this treatment is often referred to as a “living therapy.”
CAR T-cell therapies are typically administered in bone marrow transplantation units, and for good reason: Patients receive chemotherapy beforehand, which reduces the immune response. The treatment itself can cause immunologic side effects which, albeit temporary, can be severe — including high fever, body aches and chills. The administration of CAR T-cell therapies requires round-the-clock care from a specially trained and credentialed team. As bone marrow transplant specialists, our experience and knowledge of immunology enable us to recognize and manage the inflammatory complications that may result.
Current CAR T-cell therapies are FDA-approved for the treatment of recurrent or persistent diffuse B-cell lymphoma, follicular lymphoma, multiple myeloma and mantle cell lymphoma (which is a very aggressive and challenging cancer) in adults, as well as acute lymphoblastic leukemia in children and young adults up to age 25. We are intrigued by other innovative cellular therapies under study in clinical trials, such as natural killer (NK) cells and tumor-infiltrating lymphocytes (TILs). These treatments are made from a patient’s own tumor tissue, so it has already been exposed to the patient’s own immune system. Immune cells within a tumor, which on their own were unable to kill the cancer, are isolated from tumor tissue removed during surgery, modified and multiplied in a lab, and returned to the patient with other medications to boost the immune response against cancer.
Not only is the technology getting better, but the types of tumors we are treating is broadening. New CAR T-cell therapies, NK and TIL treatments, and another approach that combines CAR T-cell and NK therapies may broaden the application of these “living therapies” to patients with solid tumors, including melanoma, breast cancer and pancreatic cancer. We’re also looking at combining cellular immunotherapies with stem cell transplantation to augment the anticancer immune response even further.
Cellular therapies are truly game-changers in cancer care. It has been inspirational for us as bone marrow transplant professionals to be part of their development. What we’re witnessing now is just the tip of the iceberg. We’re only getting better at identifying the best immune cells and engineering them in the best fashion to harness the immune system in the most effective way. Discovery is exponential and the field of immunotherapy is growing at warp speed. It’s not impossible to think that we’re going to be curing cancer.
Michele Donato, MD, is chief of the Adult Stem Cell Transplantation and Cellular Therapy Program at John Theurer Cancer Center, Hackensack University Medical Center.
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Neurodegenerative diseases damage and destroy neurons, ravaging both mental and physical health. Parkinson’s disease, which affects over 10 million people worldwide, is no exception. The most obvious symptoms of Parkinson’s disease arise after the illness damages a specific class of neuron located in the midbrain. The effect is to rob the brain of dopamine — a key neurotransmitter produced by the affected neurons.
In new research, Jeffrey Kordower and his colleagues describe a process for converting non-neuronal cells into functioning neurons able to take up residence in the brain, send out their fibrous branches across neural tissue, form synapses, dispense dopamine and restore capacities undermined by Parkinson’s destruction of dopaminergic cells.
The current proof-of-concept study reveals that one group of experimentally engineered cells performs optimally in terms of survival, growth, neural connectivity, and dopamine production, when implanted in the brains of rats. The study demonstrates that the result of such neural grafts is to effectively reverse motor symptoms due to Parkinson’s disease.
Stem cell replacement therapy represents a radical new strategy for the treatment of Parkinson’s and other neurodegenerative diseases. The futuristic approach will soon be put to the test in the first of its kind clinical trial, in a specific population of Parkinson’s disease sufferers, bearing a mutation in the gene parkin. The trial will be conducted at various locations, including the Barrow Neurological Institute in Phoenix, with Kordower as principal investigator.
The work is supported through a grant from the Michael J. Fox Foundation.
“We cannot be more excited by the opportunity to help individuals who suffer from this genetic form of Parkinson’s disease, but the lessons learned from this trial will also directly impact patients who suffer from sporadic, or non-genetic forms of this disease,” Kordower says.
Kordower directs the ASU-Banner Neurodegenerative Disease Research Center at Arizona State University and is the Charlene and J. Orin Edson Distinguished Director at the Biodesign Institute. The new study describes in detail the experimental preparation of stem cells suitable for implantation to reverse the effects of Parkinson’s disease.
The research appears in the current issue of the npj journal Nature Regenerative Medicine.
New perspectives on Parkinson’s disease
You don’t have to be a neuroscientist to identify a neuron. Such cells, with their branching arbor of axons and dendrites are instantly recognizable and look like no other cell type in the body. Through their electrical impulses, they exert meticulous control over everything from heart rate to speech. Neurons are also the repository of our hopes and anxieties, the source of our individual identity.
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