Posts Tagged stem cells

[FEATURE] The Role of PTs in Regenerative Medicine – PT in Motion

Physical therapists are playing a key role in the rehabilitation of patients who undergo regenerative procedures such as stem cell therapy and platelet-rich plasma injections.

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Kristin Bowne, PT, DPT, MS, clearly remembers the day in 2011 when she received the email that changed her career.

“It was an invitation to the First Annual Symposium on Regenerative Rehabilitation at the University of Pittsburgh,” she notes. The symposium, the message explained, would explore the emerging role of physical therapy in regenerative medicine, a field that focuses on treatment interventions including stem cell therapy and bio-scaffolding to repair, replace, or regenerate impaired or nonfunctional human tissue.

“I’d been in orthopedics and sports medicine for more than 20 years, and it just so happened that when I got that email I was thinking about what to do next—how my career might evolve,” Bowne says. “So, I flew out to Pennsylvania and went to the conference. It was so intriguing and exciting! I knew I’d found it. This was the future, and I wanted to be part of it.”

Fast-forward 5 years. Bowne’s growing outpatient private practice, Kristin Bowne Physical Therapy in Scotts Valley, California, bills itself as “the premier rehabilitation clinic for emerging regenerative therapies,” and as a center for clinical research into the field’s newest methods.

Her business “still is a general orthopedic, community-based practice,” Bowne notes, but each year she sees more and more patients and clients who come to her office immediately after having undergone regenerative procedures to address ailments such as joint pain, osteoarthritis (OA), and annular tears (rips in the tough exterior of an intervertebral disc). “Often, they’re opting for these procedures as an alternative to joint-replacement surgery,” she explains. “They’ll get the procedure done, then come in to start rehab the very next day.”

One recent patient, for example, arrived at Bowne’s clinic less than 24 hours after having received an injection to his knee consisting of autologous bone marrow aspirate concentrate (BMAC) combined with platelet-rich plasma (PRP). Another patient—a former professional tennis player—had just been given stem cell injections to treat advanced OA in his knees and hips.

For these patients and others like them, “you definitely have to take a different approach” from that taken with a typical patient, Bowne says. “First, we always try to see them before the procedure, if possible, to clear up their biomechanics and train them in exercises that will help them prepare. It’s also important to maintain an open line of communication with their regenerative physicians. You also need to understand molecular biology, the science behind these procedures, and how different treatments affect healing times and the healing process.”

In the years Bowne has worked with individuals who have undergone regenerative therapy, she has developed her own regenerative rehabilitation program. It combines appropriate rest, biomechanical loading, tissue mobilization, and a number of procedure-specific protocols designed to guide patients through the recovery process and ultimately help them regain function. Now, she says, she’s spending part of her time teaching these principles and therapeutic techniques to other physical therapists (PTs) around the country (including, notably, members of the physical therapy department at the Mayo Clinic in Rochester, Minnesota).

“Here’s the problem,” Bowne says. “The consensus is that rehab is vital to success” after regenerative interventions such as PRP and stem cell transplantation, “but many physicians—understandably, I think—still are very cautious regarding to whom they’ll send their patients after these procedures. While they recognize that rehab is important, they’re not yet convinced that PTs have the training, or are sufficiently well-versed in the specifics of what is needed by a regenerative patient, to make that referral for physical therapy.”

Her goal in teaching others what she knows, she says, is to facilitate collaborative relationships between regenerative physicians and PTs. It also is to ensure that individuals who undergo regenerative procedures can receive the rehab they need from a local PT. “I have some patients who travel a long way to get here, but that’s really not best for them,” she says. “What’s best is for them to connect with therapists in their area who know what they’re doing and are keeping up on the science as it evolves.”

“Exciting” Times

The evolving science has been a point of interest for Steve Wolf, PT, PhD, FAPTA, FAHA, since at least 2002. During a session at APTA’s annual conference that year, he cited regenerative medicine and rehabilitation as being among several emerging fields that one day would have a place within the physical therapy profession. Wolf, a professor in the physical therapy division in the Department of Rehabilitation Medicine at Emory University in Atlanta, later helped organize a group of APTA members and non-physical therapists to start a project named FiRST (Frontiers in Rehabilitative Science Technologies), which identified 4 areas, including regenerative rehab, as critical to the future of rehabilitation.

FiRST, Wolf explains, is about building the profession’s knowledge base—through research and education—in technology-focused fields. (The other 3 areas under the FiRST umbrella are bioengineering, genomics, and telehealth). And when it comes to regenerative rehabilitation, Wolf says, that base is growing “exponentially” every year. “Just to give you an idea” he says, “there were almost as many papers published in the last 18 months under the title ‘regenerative rehabilitation’ as a subcategory of ‘regenerative medicine’ as there had been in all the years prior. So the knowledge is increasing, and it’s all very promising. But,” he adds, “we’re still not there yet.”

The profession isn’t “there yet,” Wolf continues, because, while regenerative therapy is “beginning to enter the classroom, and we’re seeing the topic more at various symposia,” the evidence for the effectiveness of regenerative rehabilitation “has not yet been convincingly ascertained.” He’s not saying, he emphasizes, that PTs shouldn’t be trusted by physicians to help guide individuals within this patient population back to health. It’s just that the therapeutic strategies and principles around these medical procedures won’t gain widespread acceptance until they’re “completely understood by the PT community.”

Fabrisia Ambrosio, PT, MPT, PhD, agrees. Ambrosio, assistant professor in the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh and director of the Cellular Rehabilitation Laboratory there, says, “We have started to see regenerative rehabilitation gain momentum, especially in terms of recognizing that we need more research in the area.”

To that end, last September, the Alliance for Regenerative Rehabilitation Research and Training (AR3T)—a group Ambrosio founded with her colleagues at Pitt’s McGowan Institute for Regenerative Medicine and individuals at several other institutions—was awarded a $1.1 million grant by the National Institutes of Health’s National Center for Medical Rehabilitation Research.

AR3T, Ambrosio explains, was created to bring regenerative-medicine scientists together with rehabilitation researchers and clinicians. “Our goals are twofold,” she says. “First, to focus on education—on giving rehabilitation clinicians foundational knowledge in regenerative medicine and stem cell biology,” as well as the tools they need to collaborate effectively with regenerative-medicine physicians. The second goal is to promote that collaboration in the laboratory, “so clinicians and scientists are working side-by-side to develop and answer the research questions that will continue to move the field forward.”

Ambrosio, who back in 2011 was responsible for the email that Kristin Bowne and other PTs received—and who now is preparing for the fifth iteration of the same event, to be held this October at Emory—calls the current climate around regenerative medicine and physical therapy’s role in regenerative rehabilitation “exciting.” The basic-science community, she notes, citing as evidence a recent article in the cell and molecular biology-focused magazine The Scientist, “is now recognizing how vital rehab is to this area.”

That piece, published in December, stated that stem cell therapies and tissue engineering were “nearing medical prime time” and that a “growing number of scientists, clinicians, and physical therapists now are taking an interdisciplinary approach to rehabilitation, pairing exercise with technologies that regenerate bone, muscle, cartilage, ligaments, nerves, and other tissues.” In the article, Carmen Perez-Terzic, a cardiovascular disease researcher at the Mayo Clinic, described regenerative rehabilitation as “a new future” and predicted “It’s going to explode in the next 5 or 10 years.”

When she hears such statements, Ambrosio says, she knows regenerative rehab has turned the corner. “For a cell-biology publication to be making the case that, ‘Hey, you should be thinking about these rehabilitative protocols and how they’ll play a role in translating your technologies,’ I think that shows we’re making great progress.”

Working Outside the Boundaries

Further evidence of this progress can be found at MD Anderson Cancer Center in Houston, where Kimberly Presson, PT, DPT, CLT-LANA, is a senior PT in the Department of Rehabilitation Services. She works primarily with patients who are there to receive treatment for diseases and disorders that include leukemia, lymphoma, and myeloma. Almost all those patients have had stem cell transplants, she notes—including autologous transplants, in which the patient’s own stem cells are collected prior to chemotherapy and/or radiation, then transplanted back, and allogeneic transplants, in which patients are given healthy donor stem cells in place of their own.

The typical stem cell hematology patient remains at the hospital for about a month. (MD Anderson can accommodate up to 96 patients at any time.) “Our first goal,” Presson says, “is to see to them as early as we can,” before the transplant, if possible. She and her colleagues—including other PTs, physical therapist assistants (PTAs), and occupational therapists—lead patients through several low-intensity group-exercise classes each week. All patients who are able to attend are encouraged to do so. “We know that, given their chemotherapy, we’re probably not going to make them a lot stronger, but we do want them to maintain the strength they have,” Presson says.

Patients who are too weak to take the classes are seen 1-on-1, she adds. “Usually for them it’s about working on their mobility and core strength, and getting them out of bed, even if it’s just to a chair.”

Posttransplant, physical therapy interventions continue—provided the patient is able. “These patients have totally depleted bone marrow with very low hemoglobin and platelets, so we have to pay attention to their blood counts,” Presson says. “They also are fatigued. They’re so tired from the treatment, we do only as much as they can tolerate, even if it’s just a few exercises in the bed.”

Determining the approach to take with each patient requires close collaboration with other health care professionals, Presson adds. “We’re in constant communication with either the nurses or the clinical nurse leaders,” she says. “If somebody is on my list for the group class but hasn’t come in 2 or 3 days, and I haven’t seen that individual walking, the nurse probably has some valuable information for me.”

Every Thursday, all those involved in patient care spend an hour together in interdisciplinary rounds discussing each case. “The clinical nurse leaders, PTs, OTs, the dietician, the case manager, the social worker, the chaplain, ethicists, we all sit down together and make sure everyone knows exactly what’s going on.”

Presson first worked with stem cell patients during a clinical rotation at MD Anderson when she was still was in school. After graduation she spent 2 years in outpatient orthopedics before returning when a position opened up. “Most of what I’ve learned about regenerative rehabilitation has been through on-the-job training,” she says. “At a lot of the hematology courses a PT might attend, they’ll tell you that you can’t work with a patient with a hemoglobin under 8 or a platelet count of less than 10. Well, if my patients have a hemoglobin in the mid- to high-7s, that’s a good day,” Presson says. “So, we’re basically working outside the boundaries of what most clinicians would consider normal. But we have to. If we don’t, the patient’s condition probably will get worse.”

The physicians with whom she works, she says, “really appreciate the benefit of our services” and recognize that undergoing therapy immediately posttransplant may be the key to their patients’ success. “Just the other day, I heard a physician telling all of his patients, ‘Look, you really need to listen to this lady and do what she asks. She’s the one who’s going to get you out of here,'” Presson notes.

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Justin Reyes, PTA, works with patients at the MD Anderson Cancer Center under the supervision of Kimberly Presson, PT, DPT, CLT-LANA.

Justin Reyes, PTA, who works with many of Presson’s patients before and after they’ve had their stem cell transplants, has heard similar advice from MD Anderson’s physicians. He also has seen the determination of those patients. “The majority of them come in here just hoping for a second chance. They’re motivated; they want to return to their lives. Sometimes they’re tired. Or maybe they’re nauseated. But they’re usually still willing to do something, even if they can’t do a lot.”

Reyes describes working with a recent patient who “we really thought wasn’t going to make it.” But then, Reyes says, “that individual was able to push and work and go to rehab, then on to outpatient care, and now the patient is back home in El Paso. That kind of thing makes this job rewarding.”

PRP: Simulating Injuries To Stimulate Healing

While advances such as tissue-engineered bladders and vascular grafts are the headline-grabbers of regenerative medicine, far more common is a simpler procedure involving injections of platelet-rich plasma (PRP). “The number of physicians performing PRP procedures has skyrocketed during the past 5 years,” says Stephen Clark, PT, DPT, MBA, OCS, president and founder of Athletic Physical Therapy in Los Angeles. He’s even had them himself, he notes—in both Achilles tendons and in a knee.

The procedure, Clark explains, involves a series of injections of a patient’s own blood after it has gone through a multistage centrifugation process that increases platelet concentration to 5-8 times its normal level. Once administered, the PRP simulates an injury at the site of the injection, which in turn triggers the body’s healing response.

“One of the issues with PRP is that there’s no single protocol all physicians follow,” Clark says. “Different physicians will use different platelet concentrations for the same injury. Some add activators [to stimulate healing], while others don’t. One might do 30 fenestrations [at the injection site] while another does 5.” Thus, he notes, while “everybody calls it PRP, it’s highly variable.”

Still, Clark says, the patients he sees—primarily athletes who are dealing with nagging pain in their elbows, knees, hips, and Achilles tendons—”seem to benefit” from the procedure. “But they do need rehab afterward,” he adds, “because it’s just as if they’ve been hurt again.” For that reason, he explains, he treats most of his PRP patients as though they’ve experienced an acute injury.

“We basically start at square one, and if I can get to them before their injection, that’s even better.” For those patients, he’ll typically try to stimulate blood flow to the injured area using instrument-assisted soft-tissue massage. The idea is to “provoke the injury a little” to kickstart the inflammatory response.

After the injection is administered, it’s usually recommended that the patient rest for a few days before starting physical therapy. “Once they come in, the main thing”—and the biggest difference between a PRP patient and most others—”is that, instead of trying to calm the inflammatory process down, we’re trying to help it continue for 7-10 days.” Clark varies therapy according to each patient’s tolerance, but he also works closely with physicians to ensure that everyone is on the same page. “They’re often pretty conservative,” he says. “They don’t want you to go too fast.”

In his own case, Clark says, his PRP injections have worked as advertised for almost 10 years. And he’s seen similar results with his patients—watching them, after they’ve finished their therapy, return to the sports and activities they love. “Insurance companies still consider PRP to be experimental,” he notes, explaining that all of his PRP patients pay cash. But Clark believes it won’t be long before the procedure is covered.

Stem Cells in Orthopedics

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Angie Garrett, PT, MS, OCS, BCB-PMD, and a patient.

Angie Garrett, PT, MS, OCS, BCB-PMD,works closely with a physician to provide a new option for patients with osteoarthritis of the shoulder.

Garrett, a PT at Mission Hospital in Mission Viejo, California, explains, “Studies have shown that when stem cells are injected into an area of damaged tissue, they begin to differentiate into the tissue of the designated area, resulting in the regrowth of new healthy tissue. These procedures typically are minimally invasive,” she notes, resulting in lower risks than with a conventional surgery. In the case of the shoulder, she adds, “the theory is that stem cells will differentiate into articular cartilage, returning the joint to a healthier functional state.”

She works with orthopedic surgeon Ralph Venuto, MD, of Newport Beach, California. He performs an arthroscopic debridement on the patient prior to surgery to optimize the stem cell uptake by the joint surface. The patient also undergoes a course of rehabilitative physical therapy. “The purpose of physical therapy,” Garrett explains, “is to regain as much mobility in the shoulder as possible, control pain and inflammation, and prevent the development of adhesive capsulitis, effectively preparing the shoulder for the stem cell procedure.”

Venuto uses both PRP and stem cells from adipose tissue, as well as hematopoietic stem cells from the bone marrow. Then comes a waiting period. “Immediate physical therapy will accomplish nothing,” Garrett explains, because the stem cells first must transform into new, regenerated cartilage. Physical therapy often begins about 2 weeks after the procedure and will continue for several months afterward.

“Although it is in its infancy, regenerative medicine is providing an additional option to these patients,” Garrett says. “Not surprisingly, these procedures are creating a nascent physical therapy niche, as well.”

Kristin Bowne sees a similar future for stem cell injections and other regenerative techniques, and the PT-led rehabilitation that often follows the procedures.

“This stuff works,” she says. “Biological injections combined with rehabilitation are generating positive results,” she says. It saves people time, it saves them from lost work, and it’s going to start replacing a lot of surgical procedures.” She recently saw a patient who had both PRP and stem cell injections to heal tears in her thoracic spine. As the patient’s PT, Bowne’s job now is to “restore the altered biomechanics she’s developed due to compensatory patterns, so that she doesn’t wear the discs down again.”

Regenerative medicine offers “a great opportunity for rehab science, and for PTs to get involved.” Bowne says. “It’s so exciting—like this big, wide-open door.”

Chris Hayhurst is a freelance writer.

For More Information

American Physical Therapy Association

Regenerative Rehabilitation: www.apta.org/RegenerativeRehab/

Learning Center: Course LMS-426: Physical Therapy and the Future of Regenerative Medicine (http://learningcenter.apta.org/)

Alliance for Regenerative Rehabilitation Research and Training (AR3T)

www.ar3t.pitt.edu/index.html

International Society for Stem Cell Research

www.isscr.org/

Mayo Clinic Center for Regenerative Medicine

www.mayo.edu/research/centers-programs/center-regenerative-medicine

McGowan Institute for Regenerative Medicine

www.mirm.pitt.edu/

National Institutes of Health’s National Center for Medical Rehabilitation Research

www.nichd.nih.gov/about/org/ncmrr/Pages/overview.aspx

Comments

Hello, my name is Sheila and I am interested in getting information on the type of physical therapy that you are doing for a stem cell treatment. I received stem cell/ Platelet injections for my hip four months ago. I started physical therapy about a month after the procedure. I’m their first stem cell patient. Their style is not typical but again if I could get some information of what you are doing it would be very helpful. I’m just a bit discouraged. Trying to do everything I can before making the decision for a hip replacement. I live in northern Ca. at least 4 hours away from you. Is there someone close to Ukiah or Santa Rosa That you could recommend. Thank you for any advise, Sheila Fetzer
Posted by Sheila Fetzer on 5/25/2016 11:39:22 PM
It’s important to distinguish the putative effects of stem cell therapy from the possibility that stem cells develop into other cell types, eg, cartilage or connective tissue. In many other fields, injections of various kinds of stem cells have produced positive results, but the stem cells themselves were gone in less than a week. That raises the possibility that stem cells may elicit growth factors themselves or from other cells in the region, cause other cells to proliferate and differentiate, and a do a variety of other functions, but without the stem cells themselves differentiating and providing desired functions. This is not to say that stem cells may not do so in certain circumstances, but improved structure and function can not necessarily be attributed to stem cells differentiating and becoming part of the local cellular make up. To show that, one would need to be able to identify progeny of the stem cells, such as by using some sort of molecular tag.
Posted by Dan Keller on 7/13/2016 2:18:33 PM
This is for Sheila Fetzer on 5/25/2016 comment and question. Sheila I would like to know how your hips are progressing after your PRP shots as I’m thinking of using the same procedure.
Posted by Fred Sistilli on 2/14/2017 4:07:12 PM

 

via The Role of PTs in Regenerative Medicine

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[BLOG POST] Where does the controversial finding that adult human brains don’t grow new neurons leave ongoing research?

Scientists have known for about two decades that some neurons – the fundamental cells in the brain that transmit signals – are generated throughout life. But now a controversial new study from the University of California, San Francisco, casts doubt on whether many neurons are added to the human brain after birth.

As a translational neuroscientist, this work immediately piqued my interest. It has direct implications for the research my lab does: We transplant young neurons into damaged brain areas in mice in an attempt to treat epileptic seizures and the damage they’ve caused. Like many labs, part of our work is based on a foundational belief that the hippocampus is a brain region where new neurons are born throughout life.

If the new study is right, and human brains for the most part don’t add new neurons after infancy, researchers like me need to reconsider the validity of the animal models we use to understand various brain conditions – in my case temporal lobe epilepsy. And I suspect other labs that focus on conditions including drug addiction, depression and post-traumatic stress disorder are thinking about what the UCSF study means for their investigations, too.

In the brain of a baby who died soon after birth, there are many new neurons (green in this image) in the hippocampus. Sorrells et alCC BY-ND

When and where are new neurons born?

No doubt, the adult human brain is able to learn throughout life and to change and adapt – a capability brain scientists call neuroplasticity, the brain’s ability to reorganize itself by rewiring connections. Yet, a central dogma in the field of neuroscience for nearly 100 years had been that a child is born with all the neurons she will ever have because the adult brain cannot regenerate neurons.

Just over half a century ago, researchers devised a way to study proliferation of cells in the mature brain, based on techniques to incorporate a radioactive label into new cells as they divide. This approach led to the startling discovery in the 1960s that rodent brains actually could generate new neurons.

Neurogenesis – the production of new neurons – was previously thought to only occur during embryonic life, a time of extremely rapid brain growth and expansion, and the rodent findings were met with considerable skepticism. Then researchers discovered that new neurons are also born throughout life in the songbird brain, a species scientists use as a model for studying vocal learning. It started to look like neurogenesis plays a key role in learning and neuroplasticity – at least in some brain regions in a few animal species.

Even so, neuroscientists were skeptical that many nerve cells could be renewed in the adult brain; evidence was scant that dividing cells in mammalian brains produced new neurons, as opposed to other cell types. It wasn’t until researchers extracted neural stem cells from adult mouse brains and grew them in cell culture that scientists showed these precursor cells could divide and differentiate into new neurons. Now it is generally well accepted that neurogenesis takes place in two areas of the adult rodent brain: the olfactory bulbs, which process smell information, and the hippocampus, a region characterized by neuroplasticity that is required for forming new declarative memories.

Adult neural stem cells cluster together in what scientists call niches – hotbeds for cultivating the birth and growth of new neurons, recognizable by their distinctive architecture. Despite the mounting evidence for regional growth of new neurons, these studies underscored the point that the adult brain harbors only a few stem cell niches and their capacity to produce neurons is limited to just a few types of cells.

With this knowledge, and new tools for labeling proliferating cells and identifying maturing neurons, scientists began to look for postnatal neurogenesis in primate and human brains.

What’s happening in adult human brains?

Many neuroscientists believe that by understanding the process of adult neurogenesis we’ll gain insights into the causes of some human neurological disorders. Then the next logical step would be trying to develop new treatments harnessing neurogenesis for conditions such as Alzheimer’s disease or trauma-induced epilepsy. And stimulating resident stem cells in the brain to generate new neurons is an exciting prospect for treating neurodegenerative diseases.

Because neurogenesis and learning in rodents increases with voluntary exercise and decreases with age and early life stress, some workers in the field became convinced that older people might be able to enhance their memory as they age by maintaining a program of regular aerobic exercise.

However, obtaining rigorous proof for adult neurogenesis in the human and primate brain has been technically challenging – both due to the limited experimental approaches and the larger sizes of the brains, compared to reptiles, songbirds and rodents.

Researchers injected a compound found in DNA, nicknamed BrdU to identify brand new neurons in human adult hippocampus – but the labeled cells were extremely rare. Other groups demonstrated that adult human brain tissue obtained during neurosurgery contained stem cell niches that housed progenitor cells that could generate new neurons in the lab, showing that these cells had an inborn neurogenic capacity, even in adults.

But even when scientists saw evidence for new neurons in the brain, they tended to be scarce. Some neurogenesis experts were skeptical that evidence based on incorporating BrdU into DNA was a reliable method for proving that new cells were actually being born through cell division, rather than just serving as a marker for other normal cell functions.

Further questions about how long human brains retain the capacity for neurogenesis arose in 2011, with a study that compared numbers of newborn neurons migrating in the olfactory bulbs of infants versus older individuals up to 84 years of age. Strikingly, in the first six months of life, the baby brains contained lots of chains of young neurons migrating into the frontal lobes, regions that guide executive function, long-range planning and social interactions. These areas of the human cortex are hugely increased in size and complexity compared to rodents and other species. But between 6 to 18 months of age, the migrating chains dwindled to a thin stream. Then, a very different pattern emerged: Where the migrating chains of neurons had been in the infant brain, a cell-free gap appeared, suggesting that neural stem cells become depleted during the first six months of life.

Questions still lingered about the human hippocampus and adult neurogenesis as a source for its neuroplasticity. One group came up with a clever approach based on radiocarbon dating. They measured how much atmospheric ¹⁴C – a radioactive isotope derived from nuclear bomb tests – was incorporated into people’s DNA. This method suggested that as many as 700 new cells are added to the adult human hippocampus every day. But these findings were contradicted by a 2016 study that found that the neurogenic cells in the adult hippocampus could only produce non-neuronal brain cells called microglia.

Rethinking neurogenesis research

Now the largest and most comprehensive study conducted to date presents even stronger evidence that robust neurogenesis doesn’t continue throughout adulthood in the human hippocampus – or if it does persist, it is extremely rare. This work is controversial and not universally accepted. Critics have been quick to cast doubt on the results, but the finding isn’t totally out of the blue.

So where does this leave the field of neuroscience? If the UCSF scientists are correct, what does that mean for ongoing research in labs around the world?

Because lots of studies of neurological diseases are done in mice and rats, many scientists are invested in the possibility that adult neurogenesis persists in the human brain, just as it does in rodents. If it doesn’t, how valid is it to think that the mechanisms of learning and neuroplasticity in our model animals are comparable to those in the human brain? How relevant are our models of neurological disorders for understanding how changes in the hippocampus contribute to disorders such as the type of epilepsy I study?

In my lab, we transplant embryonic mouse or human neurons into the adult hippocampus in mice, after damage caused by epileptic seizures. We aim to repair this damage and suppress seizures by seeding the mouse hippocampus with neural stem cells that will mature and form new connections. In temporal lobe epilepsy, studies in adult rodents suggest that naturally occurring hippocampal neurogenesis is problematic. It seems that the newborn hippocampal neurons become highly excitable and contribute to seizures. We’re trying to inhibit these newborn hyperexcitable neurons with the transplants. But if humans don’t generate new hippocampal neurons, then maybe we’re developing a treatment in mice for a problem that has a different mechanism in people.

Perhaps our species has evolved separate mechanisms for neuroplasticity, distinct from those used by species such as rats and mice. One possibility is that there are other sites in the human brain where neurogenesis occurs – its a big structure and more exploration will be necessary. If it turns out to be true that the human brain has a diminished capacity for neurogenesis after birth, the finding will have important implications for how neuroscientists like me think about tackling brain disorders.

Perhaps most importantly, this work underscores how crucial it is to learn how to increase the longevity of the neurons we do have, born early in life, and how we might replace or repair neurons that become damaged.

via Where does the controversial finding that adult human brains don’t grow new neurons leave ongoing research?

 

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[VIDEO] Why Can’t WE Reverse Nerve Damage ? – Reversing Nerve Damage: Central Nervous System Inhibits Cell Regeneration, But Stem Cell Treatment May Help

 

Our nervous system is involved in everything our body does, from maintaining our breath to controlling our muscles. Our nerves are vital to all we do; therefore, nerve pain and damage can heavily influence our quality of life. In Discovery News’ latest video, “Why Can’t We Reverse Nerve Damage?” host Lissette Padilla explains the central nervous system (CNS) has certain proteins that inhibit cell regeneration, because each cell in the nervous system has a unique function on the pathway, like a circuit, and can’t be replaced.

The nervous system can be divided into two sections, with the brain and spinal cord making up the CNS. Nerves are made up of sensory fibers and motor neurons, which comprise the peripheral nervous system. Nerve cells are made up of many parts, but they send signals through threads covered in a protective sheet of myelin. These threads are called axons.

Axons are the long part of the cell that reaches out to neighboring cells to send information down the line. Schwann cells, found only in the peripheral nervous system, are glial cells that produce protective myelin. Schwann cells could potentially clean up damaged nerves, which could make way for healing process to take place and new nerves to be formed.

The problem is these Schwann cells are missing from the CNS. The CNS is comprised of myelin-producing cells called oligodendrocytes. And these cells don’t clean up damaged nerve cells at all, hence the damage problem.

However, research is currently underway to examine the potential success of system cell treatment, where stem cells are injected directly at the injury site. It will still take a few years to see the results of such trials, but since the peripheral nervous system doesn’t have the same blocking proteins that the CNS has, the idea is Schwann cells could help heal the damage.

So it is possible to regrow nerves, albeit slowly. For instance, if you cut a nerve into your shoulder, it could take a year to regrow. By that time, the muscles in your arms could become atrophied. Researchers are working on helping the body heal faster.

Source: Reversing Nerve Damage: Central Nervous System Inhibits Cell Regeneration, But Stem Cell Treatment May Help

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[Thesis] The road to optimized nerve reconstruction by Caroline A. Hundepool, 2016 – Full Text PDF

1. Introduction

Peripheral nerve injuries are devastating injuries, which can lead to severe disability. Nerve injuries are relatively common. It occurs with up to 3% of all patients admitted to Level I trauma centers. Most of the injuries to peripheral nerves occur in the upper extremities. Nerve injury will lead to significant impairment in motor function and causes sensory loss. Depending on the level of nerve injury the consequences can be devastating and have great impact on a patient’s life and ability to perform daily activities such as work and hobbies. Nerve injury not only causes physical disability. There is evidence it also has great consequences psychologically. Cognitive, emotional and behavioral aspects influence recovery. It is important these factors are recognized so that the quality of patient care can be improved[1]. The last decades both experimental and clinical research has been focused on optimizing the reconstruction of nerve injuries. The studies in this thesis are focused on the optimization of nerve reconstruction.

Full Text PDF

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[WEB SITE] Scientists discover neuron-producing stem cells in the membranes covering the brain

Credit: Heidi Cartwright, Wellcome Images

 

Discovery brings with it possible implications for brain regeneration –

In a cross-domain study directed by professor Peter Carmeliet (VIB – KU Leuven), researchers discovered unexpected cells in the protective membranes that enclose the brain, the so called meninges. These ‘neural progenitors’ (stem cells that differentiate into different kinds of neurons) are produced during embryonic development.

See Also: Stem cells in the brain: Limited self-renewal

These findings show that the neural progenitors found in the meninges produce new neurons after birth, highlighting the importance of meningeal tissue as well as these cells’ potential in the development of new therapies for brain damage or neurodegeneration. A paper highlighting the results is published in the journal Cell Stem Cell.

Scientists’ understanding of brain plasticity, or the ability of the brain to grow, develop, recover from injuries and adapt to changing conditions throughout our lives, has been greatly broadened in recent years. Before the discoveries of the last few decades, neurologists once thought that the brain became ‘static’ after childhood. This dogma has changed, with researchers finding more and more evidence that the brain is capable of healing and regenerating in adulthood, thanks to the presence of stem cells. However, neuronal stem cells were generally believed to only reside within the brain tissue, not in the membranes surrounding it.

The meninges: unappreciated no more

Believed in the past to serve a mainly protective function to dampen mechanical shocks, the meninges have been historically underappreciated by science as having neurological importance in its own right. The data gathered by the team challenges the current idea that neural precursors—or stem cells that give rise to neurons—can only be found inside actual brain tissue.

Learn More: Scientists sniff out unexpected role for stem cells in the brain

Prof. Peter Carmeliet notes: “The neuronal stems cells that we discovered inside the meninges differentiate to full neurons, electrically-active and functionally integrated into the neuronal circuit. To show that the stem cells reside in the meninges, we used the extremely powerful single-cell RNA sequencing technique, a very novel top-notch technique, capable of identifying the [complex gene expression signature] nature of individual cells in a previously unsurpassed manner, a première at VIB.”

Following up on future research avenues

When it comes to future leads for this discovery, the scientists also see possibilities for translation into clinical application, though future work is required.

“An intriguing question is whether these neuronal stem cells in the meninges could lead to better therapies for brain damage or neurodegeneration. However, answering this question would require a better understanding of the molecular mechanisms that regulate the differentiation of these stem cells,” says Carmeliet. “How are these meningeal stem cells activated to become different kinds of neurons? Can we therapeutically ‘hijack’ their regeneration potential to restore dying neurons in, for example, Alzheimer’ Disease, Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders? Also, can we isolate these neurogenic progenitors from the meninges at birth and use them for later transplantation? These findings open up very exciting research opportunities for the future.”

Moving into unchartered territory is high risk, and can offer high gain, but securing funding for such type of research is challenging. However, Carmeliet’s discoveries were made possible to a large extent by funding through “Opening the Future: pioneering without boundaries”, a recently created Mecenas Funding Campaign for funding of high risk brain research but with potential for breakthrough discoveries, started up by the KU Leuven in 2013 and unique in Flanders.

Read Next: A better way to grow motor neurons from stem cells

“Being able to use such non-conventional funding channels is of utmost importance to break new boundaries in research,” says Carmeliet. “This unique Mecenas funding initiative by the KU Leuven is innovative and boundary-breaking by itself. Our entire team is enormously grateful for the opportunities it has created for our investigations”.

Note: Material may have been edited for length and content. For further information, please contact the cited source.

VIB – Flanders Institute for Biotechnology   press release

Publication

Bifari F et al. Neurogenic Radial Glia-like Cells in Meninges Migrate and Differentiate into Functionally Integrated Neurons in the Neonatal Cortex.   Cell Stem Cell, Published Online November 23 2016. doi: 10.1016/j.stem.2016.10.020

Source: Scientists discover neuron-producing stem cells in the membranes covering the brain

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[VIDEO] What are stem cells, and why are they important – YouTube

 

What are stem cells, and why are they important?

Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions.

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic “somatic” or “adult” stem cells. The functions and characteristics of these cells will be explained in this document. Scientists discovered ways to derive embryonic stem cells from early mouse embryos more than 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be “reprogrammed” genetically to assume a stem cell-like state. This new type of stem cell, called induced pluripotent stem cells (iPSCs), will be discussed in a later section of this document.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lungs, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells’ essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

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[BLOG POST] Exciting research suggests the brain can repair itself – with help

BY: SOPHIA VOUMVAKIS

In June of last year I wrote a post entitled Can the Brain Repair Itself? The answer to this question according to research conducted by Dr. Siddharthan Chandran, director of the Centre for Clinical Brain Sciences, is “Yes, just not well enough.”

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photo credit: SumaLateral Whole Brain Image via photopin (license)

In 2013, Dr. Chandran and his associates were able to extract stem cells from the bone marrow of patients with Multiple Sclerosis, use these stem cells to grow myelin cells – damage of myelin cells is associated with diseases such as Multiple Sclerosis (MS) – and then inject these cultured myelin cells back into the patient’s veins. To measure whether the intervention was successful, the scientists examined the optic nerve. The size of the optic nerve was measured before the injection of the lab grown myelin cells, three and six months post injection (patients with MS usually have vision problems). Results showed the optic nerve had stopped shrinking, which Dr. Chandran believes is the result of the injected myelin cells. These cells promoted the brain’s own stem cells to do their job of laying down more myelin.

In December 2015, neurosurgeon Dr. Jocelyne Bloch gave a TED talk entitled The Brain May Be Able To Repair Itself With Help. In this research, Dr. Bloch, along with Dr. Jean-Francois Brunet were able to culture cells from pieces of swollen brain tissue that had been removed from patients with brain trauma in order to reduce intracranial pressure.

What they discovered, after many failed attempts to grow cells from these pieces of brain tissue, is that under the microscope, these cells looked very much like stem cells. Stem cells are immature cells that we can grow into any other type of cell. Remember, Dr. Chandran and his colleagues were able to grow myelin cells from a patient’s own stem cells.

The culture that Drs. Bloch and Brunet had grown was however somewhat different from other stem cells – they looked like stem cells, but behaved differently. This new cell population was not as active as other stem cells, that is, they divided less rapidly, and unlike other stem cells, they died. The stem cells came from doublecortin-positive cells, which make up four per cent of our cortical brain cells and during our fetal development doublecortin-positive cells facilitate our brain folding itself.

Drs. Bloch and Brunet postulated that doublecortin-positive cells may promote brain repair because they found a higher concentration of these cells in areas of brain lesions. This observation is a correlation, not a cause and effect. So, the scientists designed an experiment to demonstrate that these stem cells derived from doublecortin-positive cells do indeed promote brain repair. The experimental design that Drs. Bloch and Brunet created involved the biopsy of cortical cells, culturing these cells, labelling the cultured cells and re-injecting the cultured cells into the same individual.

Working with professor Eric Rouller, from the University of Fribourg, Switzerland, Drs. Bloch and Brunet re-implanted the cultured stem cells into the a healthy monkey’s brain. What they observed several weeks later, was that the re-implanted stem cells had completely disappeared. Dr. Bloch postulates that the cells were not needed, as there was no damage, and simply went somewhere else. However, when these cultured stem cells were re-implanted into the brain of a monkey with a lesioned brain, the cultured stem cells remained and became mature neurons!

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photo credit: Marmoset embryonic stem cells forming neurons via photopin(license)

The next question posed by Drs. Bloch and Brunet was – “can these cells help a monkey after a lesion?” The scientists trained monkeys to perform a manual dexterity task – picking pellets of food off a tray. Once the monkeys had reached a plateau of performance, the scientists lesioned a section of the motor cortex that corresponds to the hand motion that the monkeys had been trained to perform. The monkeys were rendered pelagic, they could not move their hands anymore.

As with humans, the monkeys did, in time, spontaneously recover to a certain extent, due to the neuroplasticity of the brain. When the scientists were confidant that the monkeys had reached their plateau of spontaneous recovery, they re-implanted its’ own cultured cortical cells.

The monkey that had spontaneously recovered, and had not had its’ cultured cortical cells reimplanted, performed the task at about 40 -50% of his previous performance – not particularly accurate, and not too quick. The monkey with the re-implanted stem cells? Two months later, same performance as before the lesion!

Since then scientists have learned a lot more about these cells – they have been able to cryopreserve them for future use, and they have used them to treat other neuropathologies, such as Parkinson’s Disease. The next step is to go to human trials – a long, complicated and arduous process. I am optimistic that these brilliant scientists will one day get there and there will come a day when we will see the use of our own brain cells in the treatment of neuropathology’s in humans.

Since her TBI in 2011, Sophia has educated herself about TBI. She is interested in making research into TBI accessible to other survivors.

Source: Exciting research suggests the brain can repair itself – with help

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[WEB SITE] Clinical study to evaluate safety of investigational cell therapy to treat chronic motor deficits after stroke.

University Hospitals Case Medical Center is the first surgical site for a Phase 2b clinical trial study to further evaluate the safety and efficacy of an investigational cell therapy for the treatment of chronic motor deficit following an ischemic stroke.

“With strokes, focus has been on prevention or treatment within the first few hours,” said Jonathan Miller, MD, Director of the Center for Functional and Restorative Neurosurgery at UH Case Medical Center and Assistant Professor of Neurosurgery at Case Western Reserve University School of Medicine, who performs the stem cell surgery as part of the study. “Stroke is the leading cause of adult disability in the U.S., and there really hasn’t been much for this patient population.”

Ischemic strokes account for approximately 87 percent of all strokes in the US and occur when there is an obstruction in a blood vessel supplying oxygen to the brain. With approximately 800,000 strokes occurring in the United States every year, stroke is the leading cause of acquired disability in the United States. Traditional stroke treatments generally show little or no improvement in patients after the first six months following a stroke.

The ACTIsSIMA “Allogeneic Cell Therapy for Ischemic Stroke to Improve Motor Abilities” trial will examine the effects of genetically modified adult bone-marrow-derived stem cells in patients who have experienced an ischemic stroke in the previous six months to five years and still suffer from motor impairments.

Dr. Miller said, “For the hundreds of thousands of people living with the debilitating effects of ischemic stroke, the ACTIsSIMA trial will help determine whether this investigational cell therapy is a safe and effective treatment option.”

The Phase 2b clinical trial follows a previous open label Phase 1/2a clinical trial in a similar patient population. The Phase 2b study will further evaluate the safety and efficacy of the treatment in a blinded and controlled setting.

The study will enroll 156 patients with chronic motor deficits after stroke. They are being recruited through 50 assessment sites throughout the United States. Patients will range in age from 18 to 75 years of age. Once enrolled through an assessment site, patients will come to one of 18 surgical sites such as UH Case Medical Center, for the injection of cells. The patient will then be monitored for the duration of the study at the assessment sites. The closest assessment sites to UH are in Toledo and Detroit.

The ACTIsSIMA trial will further evaluate the safety and efficacy of intracranial administration of modified adult bone-marrow-derived stem cells when administered to patients with chronic motor deficit secondary to ischemic stroke.

“UH Case Medical Center has been in the forefront of adult stem cell research,” said Dr. Miller. “We are excited to be part of this study to evaluate the potential of this treatment for stroke. Although it will take time, this study and others involving stem cells, may lead to new methods of helping patients.”

Source: University Hospitals Case Medical Center

Source: Clinical study to evaluate safety of investigational cell therapy to treat chronic motor deficits after stroke

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[TED Talk] Jocelyne Bloch: The brain may be able to repair itself – with help

Through treating everything from strokes to car accident traumas, neurosurgeon Jocelyne Bloch knows the brain’s inability to repair itself all too well. But now, she suggests, she and her colleagues may have found the key to neural repair: Doublecortin-positive cells. Similar to stem cells, they are extremely adaptable and, when extracted from a brain, cultured and then re-injected in a lesioned area of the same brain, they can help repair and rebuild it. “With a little help,” Bloch says, “the brain may be able to help itself.”

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[Blog Post] Can the brain repair itself?

JUNE 29, 2015 ~ BRAIN INJURY BLOG TORONTO

BY: SOPHIA VOUMAKIS

When I suffered my traumatic brain injury (TBI) in 2011, I believed that the cells in my brain which had been damaged were irreparable. But recent research suggests that the brain can repair itself, and that what was once damaged may be able to heal.

Before we explore the scientific evidence, we need to have a rudimentary understanding of how the brain works. Very simply, the brain is made up of two main groups of cells, neurons and glial. When these cells work together, the electrical activity they create enables us to move, think, emote, feel, remember – essentially, to live.

"Human neural stem cells (shown in red), originally reprogrammed from adult skin cells, differentiate efficiently into brain cells (shown in green), after being cultured with star-shaped cells called astrocytes." Photo credit:  Chen Lab, Penn State University via Pen State NewsHuman neural stem cells (red), originally reprogrammed from adult skin cells, functioning efficiently with  brain cells (green). Photo credit: Chen Lab, Penn State University via Pen State News

However when one of these cells gets damaged or dies, the result is damaged wiring and connections. If the damaged nerve is a motor neuron, then motor functioning is impaired. If the myelin cell is damaged, diseases such as Multiple Sclerosis (MS) develop.

Speaking at a TED Conference in July 2013, Dr. Siddharthan Chandran, director of the Centre for Clinical Brain Sciences, describes a case of a patient with MS whose brain scan showed myelin damage. Subsequent scans showed some repair in the area of the brain which had originally displayed damage. This repair had occurred with no medical intervention, which led Dr. Chandran to conclude that “the brain can repair itself, just not well enough.”

Dr. Chandran believes this discovery will lead to a new direction in finding therapies to treat brain disorders. Human stem cells, which can can self-renew to create new bone or liver cells, show great promise in this endeavour. Scientists hope that one day stem cells can be used to create new motor nerve or myelin cells.

In 2006, Japanese scientist Dr. Shinya Yamanaka discovered that just four ingredients can convert any adult cell into a master stem cell. This means that scientists can create a stem cell from any of us, and then make that cell relevant to our disease or injury, such as a motor neuron or a myelin cell. Yamanaka won a Nobel Prize for his work in 2012.

A recent clinical trial by Dr. Chandran, in collaboration with other scientists,  illustrates this point. Researchers took stem cells from the bone marrow of patients with MS, grew myelin cells in the lab, and then injected them back into the patients’ veins. To measure whether the intervention was successful, the scientists examined the optic nerve. The size of the optic nerve was measured before the injection of the lab grown myelin cells, three and six months post injection (patients with MS usually have vision problems). Results showed the optic nerve had stopped shrinking, which Dr. Chandran believes is the result of the injected myelin cells, which promoted the brain’s own stem cells to do their job of laying down more myelin.

In addition, scientists can now use human cells to find ways to promote and activate the stem cells, which are already in our brain, to repair damage. Dr. Chandran believes this technique could replace animal testing in the future.

Although Dr. Chandran discussed these new advances in the treatment of brain disorders such as MS and Parkinson’s, these scientific advances may have applicability to the brain injury as well. To quote Dr. Chandran, “the day we can repair the damaged brain is sooner than we think.”

Since her TBI in 2011, Sophia has educated herself about TBI. She is interested in making research into TBI accessible to other survivors.

via Can the brain repair itself? | Brain Injury Blog TORONTO.

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