23 Oct 2019

A multi-institutional group, including members of the Tau Consortium, unveiled a stem cell tool kit for scientists studying primary tauopathies. In the November 12 issue of Stem Cell Reports, researchers co-led by Celeste Karch ofWashington University, St. Louis, and Alison Goate and Sally Temple of Icahn School of Medicine in New York, describe a collection of fibroblasts, induced pluripotent stem cells, and neural precursor cells. The cells come from 140 skin samples, some given by donors with richly documented clinical histories who carry pathogenic MAPT mutations or risk variants. Others come from noncarrier family members, patients with a sporadic tauopathy, and cognitively normal controls. The set includes induced pluripotent stem cell lines from 31 donors and 21 CRISPR-engineered isogenic lines. The cells are available to other researchers for study.

These types of high-quality repositories are becoming increasingly important for the scientific community, Clive Svendsen of the Cedars-Sinai Medical Center in Los Angeles wrote to Alzforum.

This is the way the field is going, agreed Lawrence Golbe of CurePSP, New York. Golbes organization funds research into progressive nuclear palsy (PSP) and related disorders, and collaborates with the Tau Consortium on other projects. Enthusiastic about the resources potential, Golbe hopes CurePSP grantees will get an automatic pass to use the cells.

Choice Mutations. Cells in the new iPSC collection carry some of the most common MAPT mutations, covering a wide range of clinical and neuropathological phenotypes of frontotemporal lobe dementia (FTLD)-Tau. [Courtesy of Karch et al., 2019.]

Tauopathies have proven difficult to study in animal models, in part because unlike other neuropathologies, they seem to afflict only humans (Heuer et al., 2012). Moreover, while adult human brains express approximately equal amounts of the tau spliced isoforms 3R and 4R, rodents produce almost exclusively 4R (Trabzuni et al., 2012). This is problematic. For example, leading proposals to explain how tau mutations cause disease point to abnormalities in splicing and microtubule binding, which differ between isoforms. The models we had been focusing on were not capturing the complexity of MAPT in human cells, said first author Karch. As a result, human induced pluripotent stem cells (iPSCs) have been gaining popularity in the field. The NINDS Human Cell and Data Repository is helping meet the demand by offering iPSC lines derived from 10 patients harboring MAPT mutations.

However, Karch and her collaborators think the field could benefit from a larger and more diverse collection of human cells, including isogenic iPSC lines. To accomplish this, they collected skin samples from 140 people carrying MAPT pathogenic mutations or risk variants, non-mutation carriers, and patients with sporadic PSP or corticobasal syndrome (CBS), most with comprehensive clinical histories. Although a few cells came from the NINDS repository, most came from patients participating in longitudinal studies at the Memory and Aging Center at the University of California, San Francisco, and the Knight Alzheimer Disease Research Center at WashU. The clinical records of most of these patients include detailed neurological and neuropathological workups, as well as fluid biomarkers and neuroimaging data collected from MRI, A-PET, and tau-PET studies.

To capture a broad range of phenotypes associated with some of the most common MAPT mutations, the authors created 36 fibroblast lines and 29 iPSC lines from individuals carrying the P301L, S305I,IVS10+16, V337M, G389R, and R406W mutations, as well as from carriers of the A152T variant, which increases the risk for both PSP and CBS (image above). The latter could be particularly useful for dissecting the mechanisms that underlie the phenotypic differences between the two diseases. The researchers also obtained iPSC lines from two noncarrier family members, and two people who suffered from autopsy-confirmed sporadic PSP. In addition, they stored fibroblast lines from 12 patients with sporadic PSP, five with CBS, 10 with a mixed PSP/CBS presentation, and 69 cognitively normal controls.

Biopsies are available for 27 of the 31 patients whose cells were used to generate iPSCs, and autopsy data for seven, including the two cases of sporadic PSP.

Importantly, the researchers edited 21 iPSC lines using CRISPR/Cas 9. They corrected cells with these mutations: MAPT IVS10+16,P301L, S305I, R406W, and V337M. Conversely, they inserted into control iPSCs these mutations: R5H, P301L,G389R, S305I, or S305S.

The authors also created a stem cell line carrying MAPT P301S,a mutation commonly overexpressed in tauopathy mouse models but not present in the available donors, by editing the P301L line. Isogenic lines are so powerful, particularly in these diseases which are so variable in their onset and progression, even within the same family, said Karch. Gnter Hglinger and Tabea Strauss at the German Center for Neurodegenerative Disease (DZNE) in Munich agreed. Having a pool of cell lines with different disease-linked mutations and risk variants from several individuals and their isogenic control cells is an excellent resource for the research community to enlighten disease mechanisms, they wrote (full comment below).

Several of the reported lines have already starred in recent studies of tauopathy mechanisms and candidate therapies (e.g., Sep 2019 conference news; Nakamura et al., 2019; Hernandez et al., 2019; Silva et al., 2019).

Karch and colleagues have partially differentiated some of the iPSCs and stored them as neural progenitor cells (NPCs), so that researchers can relatively easily thaw, expand, and differentiate them into neurons. These NPCs have proved useful for large-scale functional-genomics studies, proteomics, and genetic modifier screens (e.g., Cheng et al., 2017; Boselli et al., 2017;Tian et al., 2019).

In addition, the authors inserted a neurogenin-2 transgene into two healthy controls and two MAPT mutant stem cells, P301L and R406W. Neurogenin-2 enables low-cost, large-scale differentiation of stem cells into homogenous excitatory neurons. These transgenic cells are particularly useful for high-throughput drug screens (Wang et al., 2017; Sohn et al., 2019).

Researchers can request all the reported cells online at http://neuralsci.org/tau. They must provide a summary of experimental plans, an institutional material transfer agreement, and a nominal fee to cover maintenance and distribution costs. Karch said the process resembles that of the Coriell Institute and the NINDS repository. Our goal is to share with as few hurdles as possible, she said.

While the authors are still reprogramming fibroblasts they have already collected, they also plan to add more causative mutations, generate more isogenic lines, and obtain more cells from members of the same families to help shed light on phenotypic variability. In addition, Karch said, she hopes repository users will resubmit lines with new modifications they generate.

Jeffrey Rothstein, Johns Hopkins University, Baltimore, welcomed the new resource. I think it is great they have assembled this collection, he said. Rothstein founded and co-directs the Answer ALS research project, which has amassed 600 iPSC lines from controls and patients with amyotrophic lateral sclerosis (ALS).

Rothstein suggested the tauopathy collection may want to prioritize adding cells from donors with the most common form of disease, that is, sporadic. His group aims to generate 1,000 iPSC lines, with a large fraction representing sporadic diseasealso the most common form of ALSto identify the most prevalent disease subtypes. One strategy that has helped his group build their collection, he said, is using peripheral blood mononuclear cells instead of fibroblasts to create iPSCs. More donors are willing to donate blood than have a piece of skin punched out. In addition, iPSCs derived from blood cells are genetically more stable, he noted.

Rothstein emphasized the importance of assembling a large collection of healthy controls. Although isogenic controls are of great value, he cautioned they can be subject to artifacts. One problem is that the cell population can change due to selective pressures during CRISPR editing (Budde et al., 2017). To address this, Karch and colleagues are collecting not only modified iPSC clones, but also control clones that have gone through the editing pipeline but remain unmodified.

Stem-cell users studying tauopathies face another challenge: iPSC-derived neurons express primarily the fetal isoform of tau, 3R0N. However, citing a study that shows three-dimensional neuronal cultures switch to the adult profile relatively quickly (Miguel et al., 2019), Hglinger and Strauss wrote, [It] allows us to be optimistic that current challenges of this model system can be overcome in the future.Marina Chicurel

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Introducing: iPSC Collection from Tauopathy Patients - Alzforum

The Eastland Companion Animal Hospital in Bloomington is asking dog owners if they want to participate in research on using stem cells to treat dogs with arthritis.

Local dogs wouldjoin a double-blind, placebo-controlled studyto show the effectiveness of stem cells in treating large dogs(70 pounds or more) with arthritis in up to two joints of the knee, hip, elbow, or shoulder. The veterinary clinic has partnered with Animal Cell Therapies, who it's worked with before, to bring this study to Bloomington.

Dr. Kathy Petrucci, founder and CEO of Animal Cell Therapies, explained how dogs will receive the treatment.

The dogs that will receive the stem cells will be sedated, Petrucci said. Depending on what joints are affected, they will receive up to two injections in the joint and they will also receive an IV dose of stem cells.

The FDA oversees the cells that are received from donors for the study. Mothers donating these cells are screened for diseases, and cells are tested for any infections to ensure safety.

Stem cell therapy has been controversial, especially related to humans.

I think a lot of the controversy comes from the misunderstanding of the cell types, Petrucci said. The research in stem cells first started centered around embryonic or fetal tissue use. Its controversial to use embryos and fetal tissues for treatment for anything. The fact that we are using a disposable tissue as our cell sources makes it not controversial at all.

Why Umbilical-Derived Cells

Petrucci explained why umbilical-derived cells are more effective in treating arthritis versus other sources.

We looked at fat, bone marrow, embryonic cells, Petrucci said. The embryonic cells are a lot more unpredictable, and the bone marrow cells are more difficult to work with and less predictable. We didnt think the fat cells are as potent as umbilical-derived cells. Umbilical-derived cells are a lot younger and theyre a little bit more predictable. They are more easy to collect. We obtain cells from donors when the tissue would be normally thrown away. Theres no surgery required, no extra biopsies to obtain fat, no bone marrow from research animals. Its a good, ethical source of stem cells.

Umbilical-derived stem cells have proven successful in past studies on treatment for arthritis, according to Petrucci.

We did a study at the University of Florida on elbows only and we had success with that study, Petrucci said. We had good success with dogs under 70 pounds and (less) success with dogs over 70 pounds, so we changed our dose, which is why were testing dogs 70 pounds and over in this study.

Criteria for eligibility includes dogs weighing 70 pounds or more, being one year of age or older, in general good health, no neurologic issues, arthritis in up to two joints of the knee, hip, elbow, or shoulder, and have all four functioning limbs.

Owners must bring their dogs back to the clinic after 30 days to check for progress and complete a questionnaire. About 50 to 100 dogs are expected to participate in the study.

People like you value experienced, knowledgeable and award-winning journalism that covers meaningful stories in Bloomington-Normal. To support more stories and interviews like this one,please consider making a contribution.

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Bloomington Vet Joins Study For Stem Cell Therapy To Treat Dogs With Arthritis - WGLT News

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Up next,I have access to free beauty products, and I still choose these drugstore buys.

This article originally appeared on Who What Wear

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9 Iconic Anti-Aging Eye Creams, and Their More Affordable Dupes - Yahoo Lifestyle

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1 Report Overview1.1 Definition and Specification1.2 Report Overview1.2.1 Manufacturers Overview1.2.2 Regions Overview1.2.3 Type Overview1.2.4 Application Overview1.3 Industrial Chain1.3.1 Animal Stem Cell Therapy Overall Industrial Chain1.3.2 Upstream1.3.3 Downstream1.4 Industry Situation1.4.1 Industrial Policy1.4.2 Product Preference1.4.3 Economic/Political Environment1.5 SWOT Analysis

2 Product Type Market2.1 World Product Type Market Performance and Trend2.1.1 World Market Performance2.1.2 Different Type of Market Performance2.2 North America Product Type Market Performance and Trend2.2.1 North America Market Performance2.2.2 Different Type of Market Performance2.3 Europe Product Type Market Performance and Trend2.3.1 Europe Market Performance2.3.2 Different Type of Market Performance2.4 Asia-Pacific Product Type Market Performance and Trend2.4.1 Asia-Pacific Market Performance2.4.2 Different Type of Market Performance2.5 South America Product Type Market Performance and Trend2.5.1 South America Market Performance2.5.2 Different Type of Market Performance

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Animal Stem Cell Therapy Market by Manufacturers, Regions, Type and Application, Forecast to 2025 - Market Insights

Canine Stem Cell Therapy Market

The examination covers drivers and restrictions of the overall Canine Stem Cell Therapy Market. The impact of these drivers and restrictions on Canine Stem Cell Therapy market during the estimate time frame is additionally examined. The investigation likewise indicates worldwide and territorial conceivable outcomes in the Canine Stem Cell Therapy market. For this examination, we have sectioned the Canine Stem Cell Therapy market report into a kind, application/end-client and territorial fragment.

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Cell Therapy Sciences, Regeneus, Aratana Therapeutics, Medivet Biologics, Okyanos, Vetbiologics, VetMatrix, Magellan Stem Cells

Segmentation by Type: Allogeneic Stem Cells, Autologous Stem cells

Segmentation by Application: Veterinary Hospitals, Veterinary Clinics, Veterinary Research Institutes

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North America(United States, Canada and Mexico)Europe(Germany, France, UK, Russia and Italy)Asia-Pacific(China, Ja3D Depth Sensor, Korea, India and Southeast Asia)South America(Brazil, Argentina, Colombia etc.)Middle East and Africa(Saudi Arabia, UAE, Egypt, Nigeria and South Africa)

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The research report on the Canine Stem Cell Therapy includes a SWOT analysis and Porters five forces analysis, which help in providing the precise trajectory of the market. These market measurement tools help in identifying drivers, restraints, weaknesses, Canine Stem Cell Therapyopportunities, and threats. The research report offers global market figures as well as figures for regional markets and segments therein.

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Canine Stem Cell Therapy Market Developments, Competitive Analysis and Forecasts 2019-2025 - Markets Gazette

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Readers' Choice 2019: Pet Care - The Jewish News of Northern California

In March 2018, researchers reported evidence suggesting that adult humans do not generate new neurons in the hippocampusthe brains epicenter of learning and memory. The result contradicted two decades of work that said human adults actually do grow new neurons there, and revealed a need for new and better tools to study neurogenesis, Salk Institute President Fred Gage, who generated foundational evidence for adult human neurogenesis, told The Scientist at the time.

Since that study was published, several other teams have used similar techniquesbut have come to different conclusions, publishing evidence that adult humans do indeed grow new hippocampal neurons, even at the age of 99. Despite the equivocal results, Maura Boldrini, a neuroscientist at Columbia University, and a number of other neuroscientists tell The Scientist they think neurogenesis does occur in the adult human brain, bolstering learning and memory and possibly also our stress and emotional responses.

Neurogenesis is fundamentally important for the brain to react to all sorts of different insults and prevent neurological and psychiatric problems, Boldrini says. Because of its role in brain function, researchers want to learn how neurogenesis works to potentially use it to treat brain trauma, neurodegeneration, psychiatric disorders, such as depression, and possibly even the ill effects of aging.

The growth of new neurons is well studied in newborn and adult animals, especially rodents. Theres prolific neurogenesis as the brain develops, which then drops off and plateaus in adulthood, only occurring in particular areas of the brain. Examinations of human postmortem tissue suggest that the process is similar in people, based on antibody markers that label neural progenitors and young neurons. But those signals can be hard to detect in preserved cells, and the gap in time between the death of a donor and when her tissue is fixed and analyzed can affect the reliability of the markers, scientists say, which might explain the disparities in findings between different studies.

To get a reliable picture of the extent of neurogenesis in adults, scientists are pursuing a variety of new tools. Combining the direct detection techniques, such as RNA sequencing, with indirect ones, such as fMRI, Boldrini says, will indicate whats actually real when it comes to the human brains ability to make new neurons.

In a recent study, Boldrini and colleagues found that the dentate gyrus, a region of the hippocampus where neurogenesis occurs, is bigger in people who were more resilient to early life stresses, such as abuse or separation from their parents. They have more cells in the region, more neurons, and probably more neurogenesis, she says.

Of course, Boldrini notes, the study has limitations. She and colleagues were working with tissue from deceased patients brains, which brings with it the challenges of preservation and the limitations of studying dead cells. Studies in postmortem tissue have made it extremely difficult to assess whether treatments, especially in psychiatric disorders, are effective, Boldrini explains. Thats why colleagues in her department and in other labs around the world have been working to develop fMRI as a way to track neural changes that correlate with neurogenesis-related network activity in living patients.

Neurogenesis is fundamentally important for the brain to react to all sorts of different insults and prevent neurological and psychiatric problems.

Maura Boldrini, Columbia University

She and colleagues, for example, are tracking how different regions of the hippocampus in patients with depression connect with other brain regions before and after antidepressant treatment. The measurements, though, are indirect, so if the team sees increased connectivity, it cannot immediately conclude there is increased neurogenesis. You can say there is increased plasticity, Boldrini explains, which could be formed by dendrite sprouting or the making of new neurons. The same is true if the region grows in volume, which could be caused by an increase in blood capillaries or, again, the growth of new neurons. Whats generating the change cant be teased out of the results, she explains.

Studies in adult rodents have used MRI to visualize the migration of neural stem cells in the brain, but those need to be labeled with MRI contrast agents that are directly injected into neurogenic regions, a technique not suitable to use in humans.

Magnetic resonance spectroscopy, however, is non-invasive and measures biochemical changes in the body and brain. Scientists say they think it could give them a clue to how neurogenesis works in living humans, if they could identify a biomarker specific to neural stem cells or neural progenitor cells. In 2007, a team announced it had identified a metabolic biomarker that they could detect in living animals, and possibly in living humans, to track neurogenesis in vivo. That would certainly be very attractive to follow how the extent of neurogenesis is affected in an individual over time or for example in response to disease or medication, Jonas Frisn, a molecular biologist and stem cell scientist at the Karolinska Institute in Sweden, writes in an email to The Scientist. However, he says, that study has been difficult to reproduce, and that field has not taken off at all yet, unfortunately.

Another option in the works is PET imaging, a technique Yosky Kataokas team at the RIKEN Institute has been working on to identify new neuronal growth in living people. Three years ago, he and colleagues reported successfully tracking the proliferation of new cells in the neurogenic regions of rat brains using the PET tracer 3-deoxy-3-[18F]fluoro-l-thymidine and a drug called probenecid. The drug is a treatment for gout that appears to enhance the ability of the tracer to cross the blood-brain barrier. The tracer and drug together allowed the researchers to image the dentate gyrus and the subventricular zone, the two regions in adult rodents brains where neurogenesis takes place, and quantitatively visualize the neurogenic activity in the animals. The team says it is now testing the technique in adult non-human primates, with the intent to eventually use it in humans.

With PET, the challenge is to find a tracer small enough that it can be injected in the blood, pass the blood-brain barrier, and get to the brain to attach to some specific molecule that is stem-cell specific, Boldrini says. We are still trying to find markers that are stem-cell specific.

Identifying such specificity requires a more in-depth investigation of neural stem cells. The brain has tremendous heterogeneity, many, many different cell types. And if you dont look at every single cell type, you cant appreciate the complexity and heterogeneity of the brain, says Hongjun Song, a neuroscientist at the University of Pennsylvanias Perelman School of Medicine. Even the same cell type, he notes, can be in different states, so, for example, neural stem cells can be in an active state, proliferating rapidly and developing into new neurons, or a dormant state, rarely dividing and when they do, remaining as stem cells. Despite their distinct activities, cells in these different states may still express the same marker proteins, making them difficult to differentiate without single-cell analysis, such as single-cell RNA sequencing.

A three-dimensional reconstruction of nine cubic millimeters of mouse hippocampus, a part of the brain involved in memory, profiled with Slide-seq. Different cell types are shown in red, green, and blue.

Chen and Macosko labs, courtesy of Broad Institute of MIT and Harvard

The question I think were all interested in in the human brain is, do we really have cells with stem cell properties or immature neurons? I think theres probably less of a debate about whether we have those cells or not, Song says. The question is . . . are they the same as in rodents or are they very different than in rodents? Single-cell sequencing will allow us to get that kind of unbiased view.

Isolating neuronal precursor cells in the human brain isnt easy. Its much different than doing it in rodents, Song explains. In animals brains, researchers can label neuronal stem cells when the rodent is alive, and later extract and study those cells with RNA sequencing, which he and colleagues did in 2015, revealing the transcriptomes of neural stems and the cells they mature into in the adult mouse hippocampus. In humans, however, researchers again have to work with postmortem brain tissue and cant label the cells while a patient is alive. Instead, scientists have to go cell-by-cell looking for neural progenitors. The human brain, Song adds, is much larger than the mouse brain, so the cells are sparser and farther apart. You have to go through many, many cells to find them in humans, Song says.

His team and others, including Boldrinis and Frisns, have been working on RNA sequencing in postmortem human brains for several years now, and Boldrini says a new technique developed by Harvard University and MIT scientists in March might help with sorting human hippocampal nerve cells. Called Slide-seq, the technique uses genetic sequencing to draw 3-D tissue maps that identify a cells type, function, and location in tissue samples. So far, its only been tested on mouse tissue, but may hold promise for studying neural stem cells and newly made neurons, Boldrini says.

Ashley Yeager is an associate editor atThe Scientist. Email her at ayeager@the-scientist.com.

Continued here:
New Tools in the Works to Probe Adult Human Neurogenesis - The Scientist

By Dr. Mercola

Kristin Comella,1 named No. 1 on the Academy of Regenerative Practices list of Top 10 stem cell innovators, has been a stem cell researcher for nearly two decades. She has extensive knowledge on the enormous regenerative potential of stem cell therapy.

Comella, who holds degrees in chemical and biomedical engineering, began working with stem cells in graduate school, using a technique called magnetic cell sorting, which involves tagging nanoparticle magnets onto cells and then separating the cells based on the proteins they express.

"What we've learned over the years is that stem cells express different proteins than other kinds of cells in your body," she explains. "That began my career in the field of stem cells."

Over the years, she's worked for several different companies. At a start-up in Maryland, she used stem cells from bone marrow (culture-expanded mesenchymal stem cells) for meniscus regeneration. By placing these cells directly into the knee joint, you can repair or even grow back a damaged meniscus.

For a time, she also headed up the Good Manufacturing Practices (GMP) facility at Tulane University, which is a U.S. Food and Drug Administration (FDA) facility located at the Tulane Center for Gene Therapy. There, her work revolved around using bone marrow mesenchymal stem cells for spinal cord regeneration.

For the past 13 years, she's worked for U.S. Stem Cell, a company founded in 1999. The company began bringing stem cells for cardiac care to the public. Muscle-derived stem cells can be used to repair heart damage associated with heart attacks. "Our company treated our first patient in 2001. Since that time, we've treated over 7,000 patients. We began looking at other indications about a decade ago. We also began looking at stem cells from a variety of different sources," she says.

The primary purpose of stem cells is to maintain, heal and regenerate tissues wherever they reside in your body. This is a continuous process that occurs inside your body throughout your life. If you didn't have stem cells, your lifespan would be about an hour, because there would be nothing to replace exhausted cells or damaged tissue. In addition, any time your body is exposed to any sort of toxin, the inflammatory process causes stem cells to swarm the area to repair the damage.

"As an example, you might have gone to the gym this morning [and] done some squats. As a result of that, you would get tiny tears inside the muscle. The stem cells that reside beneath the muscle would come out and repair all those tears.

The reason that, if you continuously go to the gym, you would start to build new muscle, is because those stem cells, hard at work underneath your muscle, are helping to repair and build that new muscle. This would apply to all of the tissues inside your body," Comella explains.

While it's easy to think of stem cell therapy as a magic bullet, it would be wise to implement strategies that nourish and thereby help optimize the stem cells you already have in your body. As noted by Comella:

"You have to create an appropriate environment for these cells to function in. If you are putting garbage into your body and you're constantly burdening your body with toxins, your stem cells are getting too distracted trying to fight off those toxins. By creating an appropriate environment, optimizing your diet and reducing exposure to toxins, that will allow the stem cells that we're putting in to really home in and focus on the true issue that we're trying to treat.

The other thing we've discovered over the years is that [stem cell therapy] is not the type of thing where you take one dose and you're cured forever. Your tissues are constantly getting damaged You're going to have to repeat-dose and use those stem cells to your advantage.

When you think about a lizard that loses its tail, it takes two years to grow back the tail. Why would we put unrealistic expectations on the stem cells that we're trying to apply to repair or replace damaged tissue? This is a very slow process. This is something that will occur over months and may require repeat dosing."

Historically, stem cells were isolated from bone marrow, and have been used for bone marrow transplants for cancer patients since the 1930s. However, you can get stem cells from just about any tissue in your body, as every tissue contains stem cells.

Your bone marrow actually has very low amounts of mesenchymal stem cells, which are now believed to be the most important, from a therapeutic perspective. Mesenchymal stem cells help trigger an immunomodulatory response or a paracrine effect, which means they send signals out to the rest of your body, calling cells to the area to help promote healing.

"What we've discovered in more recent years is that a more plentiful source of stem cells is actually your fat tissue. [Body] fat can contain up to 500 times more cells than your bone marrow, as far as these mesenchymal type stem cells go.

One thing that's also critically important when you're talking about isolating the cells is the number of other cells that are going to be part of that population. When you're isolating a bone marrow sample, this actually is very high in white blood cells, which are pro-inflammatory."

White blood cells are part of your immune response. When an injury occurs, or a foreign body enters your system, white blood cells will attack. Unfortunately, white blood cells do not discriminate, and can create quite a bit of damage as they clean the area out.

Stem cells, in particular your mesenchymal cells, quiet down the white blood cells and then start the regeneration phase, which leads to new tissue. Bone marrow tends to be very high in white blood cells and low in the mesenchymal cells. Isolating stem cells from fat tissue is preferred not only because it's easier on the patient, but fat also contains a higher population of mesenchymal cells and fewer white blood cells.

"The benefit also of isolating [stem cells from] fat is that it's a relatively simple procedure. There's typically no shortage of fat tissue, especially in Americans," Comella says. "[Also], as you age, your bone marrow declines with regards to the number of cells in it, whereas the fat tissue maintains a pretty high number of stem cells, even in older individuals.

We can successfully harvest fat off of just about anyone, regardless of their age or how thin they are. The procedure is done under local [anesthesia], meaning that the patient stays awake. They don't have to go under general anesthesia. We can harvest as few as 15 cubic centimeters of fat, which is a very small amount of fat, and still get a very high number of stem cells."

A stem cell procedure can cost anywhere from $5,000 to $15,000, depending on what you're having done, and rarely if ever will insurance cover it. Still, when you compare it to the cost of long-term medications or the out-of-pocket cost of getting a knee replacement, stem cell therapy may still be a less expensive alternative. Also, a single extraction will typically yield enough stem cells for 20 to 25 future treatments, should you decide to store your stem cells for future need.

"I think it's accessible for patients," Comella says. "It's an out-patient procedure. You plan to be in clinic for about two hours; no real limitations afterwards, just no submerging in water, no alcohol, no smoking for a week. But other than that, patients can resume their normal activities and go about their regular daily lives."

Interestingly, Comella notes that patients who eat a very healthy diet, focusing on organic and grass fed foods, have body fat that is very hearty and almost sticky, yielding high amounts of very healthy stem cells.

"We can grow much better and faster stem cells from that fat than [the fat from] somebody who eats a grain-based diet or is exposed to a lot of toxins in their diet," she says. "Their fat tends to be very fluffy, buttery yellow. The cells that come out of that are not necessarily as good a quality. It's just been very interesting. And of note, patients that are cigarette smokers, their fat is actually gray-tinged in color. The stem cells do not grow well at all."

What's been described above is what's called an autologous donation, meaning you're getting the stem cells from yourself. A number of companies provide non-autologous donations using cells harvested from other people, typically women, like amniotic or embryonic mesenchymal cells. This is an important distinction.

"There are now just a couple of studies that have been published comparing an autologous source, meaning cells from you own body, to an allogeneic source, meaning cells from someone else.

So far, what has been discovered is that the autologous cells, meaning your own cells, will outperform somebody else's cells inside your body. Now, this is not fully understood at this point. It may be that the environment that your cells function in, they're used to that environment. They recognize it. It's the same DNA and they can function well.

However, once you culture expand and get a pure population of these mesenchymal cells not necessarily the sample that's coming right off of the liposuction, but a sample that has been taken to the lab and grown those cells will not elicit an immune response if you use them in someone else. You could scientifically and medically use those in an unmatched person. However, there are some regulatory aspects of that with regards to the FDA."

In the U.S., there are a variety of new stem cell products available, referred to as amniotic, cord blood products or placenta products, which are prepared at a tissue bank. Such facilities must be registered with the FDA, and the products must undergo additional processing.

For example, they must be morselized, or snap frozen or blended in some way. Such processing typically breaks the membrane, releasing growth factors, and the resulting products are called acellular, meaning there are no living cells remaining in the sample.

The amniotic products available in the U.S. are not so much stem cell products as they are growth factor products. According to Comella, they can be useful in creating an immunomodulatory response, which can help to promote healing, but that still differs from the living stem cell procedures that can be done by either isolating cells from your fat or bone marrow. As a general rule, you don't achieve the clinical benefits when using an amniotic product, primarily because they don't contain living stem cells.

"I want to contrast that to what are called embryonic stem cells," Comella adds. "The products obtained from cord blood, from women who are having babies, are not embryonic stem cells. Embryonic stem cells are when you are first bringing the egg and sperm together. Three days after that, you can isolate what is called an inner cell mass. This inner cell mass can be used to then grow cells in culture, or that inner cell mass could eventually lead to the formation of a baby.

Those are embryonic stem cells, and those are pluripotential, meaning that they have the ability to form an entire being, versus adult stem cells or stem cells that are present in amniotic tissue, [which] are multipotential, which only have the ability to form subsets of tissue.

When you're dealing with different diseases or damaged tissue or inflammation, mostly you want to repair tissue. If somebody has damage in their knee, they don't necessarily need embryonic cells because they don't need a baby in their knee. They need new cartilage in their knee."

A common question is whether stem cells can cause overgrowth, leading to cancer or tumor formation. As noted by Comella, this is a problem associated with embryonic stem cells, which tend to grow very rapidly and can form a teratoma because of the rapid cell growth. Adult stem cells the cells obtained from your own body have growth inhibitions and will not form teratomas.

"The theoretical concern that has been addressed in animal models or in petri dishes is that if you take cancer cells that are growing in a dish and apply stem cells, it may make those cancer cells grow more rapidly. But this does not translate in-vivo to humans.

If there was truly an issue with applying stem cells to a patient who has cancer, we would know about it by now, because we've been dosing cancer patients with stem cells since the '30s. The safety profile is strong and there are tens of thousands of patients documented with these treatments," Comella says.

Another useful therapy is platelet-rich plasma (PRP). Your peripheral blood contains platelets, which act as first responders when there's an injury. They come in and start the clotting mechanism, thereby preventing you from bleeding to death. They also give marching orders to other cells. For example, platelets can command stem cells to multiply and grow, or to differentiate and form new tissue.

These platelets also have many different growth factors associated with them, which can help to promote healing and stop inflammation. PRP involves taking a blood sample and then spinning the blood in a centrifuge to isolate the platelets. The platelet-rich plasma is then injected back into the area that is inflamed.

"One of the most common uses of platelet-rich plasma or PRP is in a joint. Now, platelets are going to be most successful in something that is rich in stem cells [such as] an acute or a very recent injury.

If you just hurt your knee, the first thing you should do is get PRP, because it's going to help promote healing, and those platelets will attach to the surface receptors of the stem cells that are already going to the area to promote healing. It would be like putting fertilizer on your seed, which are the stem cells.

If you have something more chronic, this tends to be a stem cell-poor environment. In other words, you have osteoarthritis or you've got knee pain that's 5 years old and it's been there for a long time; just putting PRP in it would be like putting fertilizer on dirt without planting a seed first."

The beauty of stem cell therapy is that it mimics a process that is ongoing in your body all the time. Your stem cells are continuously promoting healing, and they do not have to be manipulated in any way. The stem cells naturally know how to home in on areas of inflammation and how to repair damaged tissue.

"All we're doing is harnessing the cells from one location where they're sitting dormant and relocating them to exactly where we want them and we need them to work," Comella says. "Basically, anything inside your body that is inflamed, that is damaged in some way, that is lacking blood supply, the [stem] cells can successfully treat.

That means orthopedics, knee injections, shoulder injections, osteoarthritis, acute injuries, anterior cruciate ligament tears in your back back pain associated with degenerative disc disease or damaged tendons or ligaments, herniated and bulging discs. You can also use it in systemic issues, everything from diabetes, to cardiac, to lungs any tissue organ inside your body that's been damaged.

Autoimmune diseases [can also be treated]. The stem cells are naturally immunosuppressant, meaning they can help quiet down an over reactive immune system and help the immune system function in a more normal way. Neurological diseases, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's. All of these have to do with tissue that's not functioning properly. The cells can be used to address that."

It's quite impressive, the list of different diseases that could benefit from this intervention. That said, I want to reemphasize that this is not a magic bullet. However, you can dramatically improve the benefits of this intervention by combining it with other healthy lifestyle factors that optimize mitochondrial function, such as eating a healthy whole food diet, exercising, sleeping well, avoiding toxins and detoxifying from toxic influences.

Stem cells can also be used as part of an antiaging program. Comella has used stem cells on herself for several years, and report feeling better now than she did a decade ago.

"The ability to reduce inflammation inside your body is basically making yourself live longer. Inflammation is what kills us all. It's what makes our telomeres shrink. It's what causes us pain and discomfort. It's what makes the tissues start to die. The ability to dose yourself with stem cells and bring down your inflammation, which is most likely caused by any sort of toxin that you've been exposed to breathing air is exposure to toxins this is going to lengthen your lifespan.

I typically will do a dose every six to 12 months, regardless of what's going on. If I have anything that's bothering me, if I tweak my knee at the gym, then I absolutely will come in and do an injection in my knee. I want to keep my tissue healthy for as long as possible.

I want to stay strong. I don't want to wait until something is wrong with me. I think that this is the future of medicine. This is what we're going to start to see. People will begin to get their regular doses of [their own] stem cells and it'll just be common practice."

Keep in mind there's a gradual and progressive decline in the quality and the number of stem cells as you age, so if you're considering this approach, it would be to your advantage to extract and bank your stem cells as early on as possible. U.S. Stem Cell provides a stem cell bank service, so you can store them until a later date when you might need them.

"Your stem cells are never as young as they are right now. Every minute that you live, your telomeres are shrinking. The ability to lock in the youth of your cells today can be very beneficial for you going forward, and for your health going forward. God forbid something happens. What if you have a heart attack? You're not going to get clearance to get a mini-lipo aspirate procedure.

If you have your cells waiting in the bank, ready for you, it becomes very easy to pull a dose and do an IV delivery of cells. It's almost criminal that we're not doing this for every single one of our cardiac patients. This should be standard practice. We should be having every single patient bank their stem cells at a young age and have them waiting, ready and available. The technology is there. We have it. I'm not sure why this technology is not being made available to everyone," she says.

"I think stem cell therapy is very different than traditional medicine. Stem cell therapy may actually make it so that you don't have to be dependent on pharmaceutical medications. You can actually repair the tissue and that's it. This is a very different way of viewing medicine."

If you're interested in having this procedure done, contact the U.S. Stem Cell Clinic on USStemCellClinic.com. You could either have the procedure done at their facility, or if there's a physician in your area providing the service, you can go there. U.S. Stem Cell can help you locate a qualified doctor.

Oftentimes, practitioners will specialize in specific procedures, such as spinal procedures, or knee procedures. There's also a veterinary division, called Vet Biologics, which offers treatment to small pets like cats and dogs, as well as horses.

"One of the things that we've been treating recently is traumatic brain injuries," Comella says. "We had a woman who fell two stories and hit her head. She spent months in a coma and was not able to talk or walk or do any activities. By the time she came to us, it was two years after her injury. The best hospitals in the world told her this was her life 'You're never going to be able to talk or walk or take care of your young children again.' That was just not good enough.

She came to us and we began applying stem cells in a way to allow the cells to cross the blood-brain barrier and to get to her brain. After her first treatment, when she walked into the clinic on her own and began telling me, in full sentences, about the day she had the head injury, tears came down my face. This is the kind of thing that traditional medicine would say is impossible.

We've had patients who were wheelchair-bound, whether it's from multiple sclerosis or Parkinson's, up and out of their chair, literally jogging around cones. This is life-changing Patients who were told they weren't going to return to sports for years are back on the field and playing. There's just many ways that you can heal your tissue to change the course of an injury or a disease."

Read this article:
How Stem Cell Therapy Can Help Repair and ... - Mercola.com

by David M. Panchision*

Diseases of the nervous system, including congenital disorders, cancers, and degenerative diseases, affect millions of people of all ages. Congenital disorders occur when the brain or spinal cord does not form correctly during development. Cancers of the nervous system result from the uncontrolled spread of aberrant cells. Degenerative diseases occur when the nervous system loses functioning of nerve cells. Most of the advances in stem cell research have been directed at treating degenerative diseases. While many treatments aim to limit the damage of these diseases, in some cases scientists believe that damage can be reversed by replacing lost cells with new ones derived from cells that can mature into nerve cells, called neural stem cells. Research that uses stem cells to treat nervous system disorders remains an area of great promise and challenge to demonstrate that cell-replacement therapy can restore lost function.

The nervous system is a complex organ made up of nerve cells (also called neurons) and glial cells, which surround and support neurons (see Figure 3.1). Neurons send signals that affect numerous functions including thought processes and movement. One type of glial cell, the oligodendrocyte, acts to speed up the signals of neurons that extend over long distances, such as in the spinal cord. The loss of any of these cell types may have catastrophic results on brain function.

Although reports dating back as early as the 1960s pointed towards the possibility that new nerve cells are formed in adult mammalian brains, this knowledge was not applied in the context of curing devastating brain diseases until the 1990s. While earlier medical research focused on limiting damage once it had occurred, in recent years researchers have been working hard to find out if the cells that can give rise to new neurons can be coaxed to restore brain function. New neurons in the adult brain arise from slowly-dividing cells that appear to be the remnants of stem cells that existed during fetal brain development. Since some of these adult cells still retain the ability to generate both neurons and glia, they are referred to as adult neural stem cells.

These findings are exciting because they suggest that the brain may contain a built-in mechanism to repair itself. Unfortunately, these new neurons are only generated in a few sites in the brain and turn into only a few specialized types of nerve cells. Although there are many different neuronal cell types in the brain, we now know that these new neurons can quot;plug inquot; correctly to assist brain function.1 The discovery of these cells has spurred further research into the characteristics of neural stem cells from the fetus and the adult, mostly using rodents and primates as model species. The hope is that these cells may be able to replenish those that are functionally lost in human degenerative diseases such as Parkinson's Disease, Huntington's Disease, and amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), as well as from brain and spinal cord injuries that result from stroke or trauma.

Scientists are applying these new stem cell discoveries in two ways in their experiments. First, they are using current knowledge of normal brain development to modulate stem cells that are harvested and grown in culture. Researchers can then transplant these cultured cells into the brain of an animal model and allow the brain's own signals to differentiate the stem cells into neurons or glia. Alternatively, the stem cells can be induced to differentiate into neurons and glia while in the culture dish, before being transplanted into the brain. Much progress has been made the last several years with human embryonic stem (ES) cells that can differentiate into all cell types in the body. While ES cells can be maintained in culture for relatively long periods of time without differentiating, they usually must be coaxed through many more steps of differentiation to produce the desired cell types. Recent studies, however, suggest that ES cells may differentiate into neurons in a more straightforward manner than may other cell types.

Figure 3.1. The NeuronWhen sufficient neurotransmitters cross synapses and bind receptors on the neuronal cell body and dendrites, the neuron sends an electrical signal down its axon to synaptic terminals, which in turn release neurotransmitters into the synapse that affects the following neuron. The brain neurons that die in Parkinson's Disease release the transmitter dopamine. Oligodendrocytes supply the axon with an insulating myelin sheath.

2001 Terese Winslow

Second, scientists are identifying growth (trophic) factors that are normally produced and used by the developing and adult brain. They are using these factors to minimize damage to the brain and to activate the patient's own stem cells to repair damage that has occurred. Each of these strategies is being aggressively pursued to identify the most effective treatments for degenerative diseases. Most of these studies have been carried out initially with animal stem cells and recipients to determine their likelihood of success. Still, much more research is necessary to develop stem cell therapies that will be useful for treating brain and spinal cord disease in the same way that hematopoietic stem cell therapies are routinely used for immune system replacement (see Chapter 2).

The majority of stem cell studies of neurological disease have used rats and mice, since these models are convenient to use and are well-characterized biologically. If preliminary studies with rodent stem cells are successful, scientists will attempt to transplant human stem cells into rodents. Studies may then be carried out in primates (e.g., monkeys) to offer insight into how humans might respond to neurological treatment. Human studies are rarely undertaken until these other experiments have shown promising results. While human transplant studies have been carried out for decades in the case of Parkinson's disease, animal research continues to provide improved strategies to generate an abundant supply of transplantable cells.

The intensive research aiming at curing Parkinson's disease with stem cells is a good example for the various strategies, successful results, and remaining challenges of stem cell-based brain repair. Parkinson's disease is a progressive disorder of motor control that affects roughly 2% of persons 65 years and older. Triggered by the death of neurons in a brain region called the substantia nigra, Parkinson's disease begins with minor tremors that progress to limb and bodily rigidity and difficulty initiating movement. These neurons connect via long axons to another region called the striatum, composed of subregions called the caudate nucleus and the putamen. These neurons that reach from the substantia nigra to the striatum release the chemical transmitter dopamine onto their target neurons in the striatum. One of dopamine's major roles is to regulate the nerves that control body movement. As these cells die, less dopamine is produced, leading to the movement difficulties characteristic of Parkinson's disease. Currently, the causes of death of these neurons are not well understood.

For many years, doctors have treated Parkinson's disease patients with the drug levodopa (L-dopa), which the brain converts into dopamine. Although the drug works well initially, levodopa eventually loses its effectiveness, and side-effects increase. Ultimately, many doctors and patients find themselves fighting a losing battle. For this reason, a huge effort is underway to develop new treatments, including growth factors that help the remaining dopamine neurons survive and transplantation procedures to replace those that have died.

The strategy to use new cells to replace lost ones is not new. Surgeons first attempted to transplant dopamine-releasing cells from a patient's own adrenal glands in the 1980s.2,3 Although one of these studies reported a dramatic improvement in the patients' conditions, U.S. surgeons were only able to achieve modest and temporary improvement, insufficient to outweigh the risks of such a procedure. As a result, these human studies were not pursued further.

Another strategy was attempted in the 1970s, in which cells derived from fetal tissue from the mouse substantia nigra was transplanted into the adult rat eye and found to develop into mature dopamine neurons.4 In the 1980s, several groups showed that transplantation of this type of tissue could reverse Parkinson's-like symptoms in rats and monkeys when placed in the damaged areas.The success of the animal studies led to several human trials beginning in the mid-1980s.5,6 In some cases, patients showed a lessening of their symptoms. Also, researchers could measure an increase in dopamine neuron function in the striatum of these patients by using a brain-imaging method called positron emission tomography (PET) (see Figure 3.2).7

The NIH has funded two large and well-controlled clinical trials in the past 15 years in which researchers transplanted tissue from aborted fetuses into the striatum of patients with Parkinson's disease.7,8 These studies, performed in Colorado and New York, included controls where patients received quot;shamquot; surgery (no tissue was implanted), and neither the patients nor the scientists who evaluated their progress knew which patients received the implants. The patients' progress was followed for up to eight years. Unfortunately, both studies showed that the transplants offered little benefit to the patients as a group. While some patients showed improvement, others began to suffer from dyskinesias, jerky involuntary movements that are often side effects of long-term L-dopa treatment. This effect occurred in 15% of the patients in the Colorado study.7 and more than half of the patients in the New York study.8 Additionally, the New York study showed evidence that some patients' immune systems were attacking the grafts.

However, promising findings emerged from these studies as well. Younger and milder Parkinson's patients responded relatively well to the grafts, and PET scans of patients showed that some of the transplanted dopamine neurons survived and matured. Additionally, autopsies on three patients who died of unrelated causes, years after the surgeries, indicated the presence of dopamine neurons from the graft. These cells appeared to have matured in the same way as normal dopamine neurons, which suggested that they were acting normally in the brain.

Figure 3.2. Positron Emission Tomography (PET) images from a Parkinson's patient before and after fetal tissue transplantation. The image taken before surgery (left) shows uptake of a radioactive form of dopamine (red) only in the caudate nucleus, indicating that dopamine neurons have degenerated. Twelve months after surgery, an image from the same patient (right) reveals increased dopamine function, especially in the putamen. (Reprinted with permission from N Eng J Med 2001;344(10) p. 710.)

Researchers in Sweden followed the severity of dyskinesia in patients for eleven years after neural transplantation and found that the severity was typically mild or moderate. These results suggested that dyskinesias were due to effects that were distinct from the beneficial effects of the grafts.9 Dyskinesias may therefore be related to the ways that transplantation disturbs other cells in the brain and so may be minimized by future improvements in therapy. Another study that involved the grafting of cells both into the striatum (the target of dopamine neurons) and the substantia nigra (where dopamine neurons normally reside) of three patients showed no adverse effects and some modest improvement in patient movement.10 To determine the full extent of therapeutic benefits from such a procedure and confirm the reliability of these results, this study will need to be repeated with a larger patient population that includes the appropriate controls.

The limited success of these studies may reflect variations in the fetal tissue used for transplantation, which is of limited quantity and can not be standardized or well-characterized. The full complement of cells in these fetal tissue samples is not known at present. As a result, the tissue remains the greatest source of uncertainty in patient outcome following transplantation.

The major goal for Parkinson's investigators is to generate a source of cells that can be grown in large supply, maintained indefinitely in the laboratory, and differentiated efficiently into dopamine neurons that work when transplanted into the brain of a Parkinson's patient. Scientists have investigated the behavior of stem cells in culture and the mechanisms that govern dopamine neuron production during development in their attempts to identify optimal culture conditions that allow stem cells to turn into dopamine-producing neurons.

Preliminary studies have been carried out using immature stem cell-like precursors from the rodent ventral midbrain, the region that normally gives rise to these dopamine neurons. In one study these precursors were turned into functional dopamine neurons, which were then grafted into rats previously treated with 6-hydroxy-dopamine (6-OHDA) to kill the dopamine neurons in their substantia nigra and induce Parkinson's-like symptoms. Even though the percentage of surviving dopamine neurons was low following transplantation, it was sufficient to relieve the Parkinson's-like symptoms.11 Unfortunately, these fetal cells cannot be maintained in culture for very long before they lose the ability to differentiate into dopamine neurons.

Cells with features of neural stem cells have been derived from ES-cells, fetal brain tissue, brain tissue from neurosurgery, and brain tissue that was obtained after a person's death. There is controversy about whether other organ stem cell populations, such as hematopoietic stem cells, either contain or give rise to neural stem cells

Many researchers believe that the more primitive ES cells may be an excellent source of dopamine neurons because ES-cells can be grown indefinitely in a laboratory dish and can differentiate into any cell type, even after long periods in culture. Mouse ES cells injected directly into 6-OHDA-treated rat brains led to relief of Parkinson-like symptoms. Further investigation showed that these ES cells had differentiated into both dopamine and serotonin neurons.12 This latter type of neuron is generated in an adjacent region of the brain and may complicate the response to transplantation. Since ES cells can generate all cell types in the body, unwanted cell types such as muscle or bone could theoretically also be introduced into the brain. As a result, a great deal of effort is being currently put into finding the right quot;recipequot; for turning ES cells into dopamine neuronsand only this cell typeto treat Parkinson's disease. Researchers strive to learn more about normal brain development to help emulate the natural progression of ES cells toward dopamine neurons in the culture dish.

The recent availability of human ES cells has led to further studies to examine their potential for differentiation into dopamine neurons. Recently, dopamine neurons from human embryonic stem cells have been generated.13 One research group used a special type of companion cell, along with specific growth factors, to promote the differentiation of the ES cells through several stages into dopamine neurons. These neurons showed many of the characteristic properties of normal dopamine neurons.13 Furthermore, recent evidence of more direct neuronal differentiation methods from mouse ES cells fuels hope that scientists can refine and streamline the production of transplantable human dopamine neurons.

One method with great therapeutic potential is nuclear transfer. This method fuses the genetic material from one individual donor with a recipient egg cell that has had its nucleus removed. The early embryo that develops from this fusion is a genetic match for the donor. This process is sometimes called quot;therapeutic cloningquot; and is regarded by some to be ethically questionable. However, mouse ES cells have been differentiated successfully in this way into dopamine neurons that corrected Parkinsonian symptoms when transplanted into 6-OHDA-treated rats.14 Similar results have been obtained using parthenogenetic primate stem cells, which are cells that are genetic matches from a female donor with no contribution from a male donor.15 These approaches may offer the possibility of treating patients with genetically-matched cells, thereby eliminating the possibility of graft rejection.

Scientists are also studying the possibility that the brain may be able to repair itself with therapeutic support. This avenue of study is in its early stages but may involve administering drugs that stimulate the birth of new neurons from the brain's own stem cells. The concept is based on research showing that new nerve cells are born in the adult brains of humans. The phenomenon occurs in a brain region called the dentate gyrus of the hippocampus. While it is not yet clear how these new neurons contribute to normal brain function, their presence suggests that stem cells in the adult brain may have the potential to re-wire dysfunctional neuronal circuitry.

The adult brain's capacity for self-repair has been studied by investigating how the adult rat brain responds to transforming growth factor alpha (TGF), a protein important for early brain development that is expressed in limited quantities in adults.16 Injection of TGF into a healthy rat brain causes stem cells to divide for several days before ceasing division. In 6-OHDAtreated (Parkinsonian) rats, however, the cells proliferated and migrated to the damaged areas. Surprisingly, the TGF-treated rats showed few of the behavioral problems associated with untreated Parkinsonian rats.16 Additionally, in 2002 and 2003, two research groups isolated small numbers of dividing cells in the substantia nigra of adult rodents.17,18

These findings suggest that the brain can repair itself, as long as the repair process is triggered sufficiently. It is not clear, though, whether stem cells are responsible for this repair or if the TGF activates a different repair mechanism.

Many other diseases that affect the nervous system hold the potential for being treated with stem cells. Experimental therapies for chronic diseases of the nervous system, such as Alzheimer's disease, Lou Gehrig's disease, or Huntington's disease, and for acute injuries, such as spinal cord and brain trauma or stoke, are being currently developed and tested. These diverse disorders must be investigated within the contexts of their unique disease processes and treated accordingly with highly adapted cell-based approaches.

Although severe spinal cord injury is an area of intense research, the therapeutic targets are not as clear-cut as in Parkinson's disease. Spinal cord trauma destroys numerous cell types, including the neurons that carry messages between the brain and the rest of the body. In many spinal injuries, the cord is not actually severed, and at least some of the signal-carrying neuronal axons remain intact. However, the surviving axons no longer carry messages because oligodendrocytes, which make the axons' insulating myelin sheath, are lost. Researchers have recently made progress to replenish these lost myelin-producing cells. In one study, scientists cultured human ES cells through several steps to make mixed cultures that contained oligodendrocytes. When they injected these cells into the spinal cords of chemically-demyelinated rats, the treated rats regained limited use of their hind limbs compared with un-grafted rats.19 Researchers are not certain, however, whether the limited increase in function observed in rats is actually due to the remyelination or to an unidentified trophic effect of the treatment.

Getting neurons to grow new axons through the injury site to reconnect with their targets is even more challenging. While myelin promotes normal neuronal function, it also inhibits the growth of new axons following spinal injury. In a recent study to attempt post-trauma axonal growth, Harper and colleagues treated ES cells with a combination of factors that are known to promote motor neuron differentiation.20 The researchers then transplanted these cells into adult rats that had received spinal cord injuries. While many of these cells survived and differentiated into neurons, they did not send out axons unless the researchers also added drugs that interfered with the inhibitory effects of myelin. The growth effect was modest, and the researchers have not yet seen evidence of functional neuron connections. However, their results raise the possibility that signals can be turned on and off in the correct order to allow neurons to reconnect and function properly. Spinal injury researchers emphasize that additional basic and preclinical research must be completed before attempting human trials using stem cell therapies to repair the trauma-damaged nervous system.

Since myelin loss is at the heart of many other degenerative diseases, oligodendrocytes made from ES cells may be useful to treat these conditions as well. For example, scientists recently cultured human ES cells with a combination of growth factors to generate a highly enriched population of myelinating oligodendrocyte precursors.21,22 The researchers then tested these cells in a genetically-mutated mouse that does not produce myelin properly. When the growth factor-cultured ES cells were transplanted into affected mice, the cells migrated and differentiated into mature oligodendrocytes that made myelin sheaths around neighboring axons. These researchers subsequently showed that these cells matured and improved movement when grafted in rats with spinal cord injury.23 Improved movement only occurred when grafting was completed soon after injury, suggesting that some post-injury responses may interfere with the grafted cells. However, these results are sufficiently encouraging to plan clinical trials to test whether replacement of myelinating glia can treat spinal cord injury.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is characterized by a progressive destruction of motor neurons in the spinal cord. Patients with ALS develop increasing muscle weakness over time, which ultimately leads to paralysis and death. The cause of ALS is largely unknown, and there are no effective treatments. Researchers recently have used different sources of stem cells to test in rat models of ALS to test for possible nerve cell-restoring properties. In one study, researchers injected cell clusters made from embryonic germ (EG) cells into the spinal cord fluid of the partially-paralyzed rats.24 Three months after the injections, many of the treated rats were able to move their hind limbs and walk with difficulty, while the rats that did not receive cell injections remained paralyzed. Moreover, the transplanted cells had migrated throughout the spinal fluid and developed into cells that displayed molecular characteristics of mature motor neurons. However, too few cells matured in this way to account for the recovery, and there was no evidence that the transplanted cells formed functional connections with muscles. The researchers suggest that the transplanted cells may be promoting recovery in some other way, such as by producing trophic factors.

This possibility was addressed in a second study in which scientists grew human fetal CNS stem cells in culture and genetically modified them to produce a trophic factor that promotes the survival of cells that are lost in ALS. When grafted into the spinal cords of the ALS-like rats, these cells secreted the desired growth factor and promoted the survival of the neurons that are normally lost in the ALS-like rats.25 While promising, these results highlight the need for additional basic research into functional recovery in ALS disease models.

Stroke affects about 750,000 patients per year in the

U.S. and is the most common cause of disability in adults. A stroke occurs when blood flow to the brain is disrupted. As a consequence, cells in affected brain regions die from insufficient amounts of oxygen. The treatment of stroke with anti-clotting drugs has dramatically improved the odds of patient recovery. However, in many patients the damage cannot be prevented, and the patient may permanently lose the functions of affected areas of the brain. For these patients, researchers are now considering stem cells as a way to repair the damaged brain regions. This problem is made more challenging because the damage in stroke may be widespread and may affect many cell types and connections.

However, researchers from Sweden recently observed that strokes in rats cause the brain's own stem cells to divide and give rise to new neurons.26 However, these neurons, which survived only a couple of weeks, are few in number compared to the extent of damage caused. A group from the University of Tokyo added a growth factor, bFGF, into the brains of rats after stroke and showed that the hippocampus was able to generate large numbers of new neurons.27 The researchers found evidence that these new neurons were actually making connections with other neurons. These and other results suggest that future stroke treatments may be able to coax the brain's own stem cells to make replacement neurons.

Taking an alternative approach, another group attempted transplantation as a means to treat the loss of brain mass after a severe stroke. By adding stem cells onto a polymer scaffold that they implanted into the stroke-damaged brains of mice, the researchers demonstrated that the seeded stem cells differentiated into neurons and that the polymer scaffold reduced scarring.28 Two groups transplanted human fetal stem cells in independent studies into the brains of stroke-affected rodents; these stem cells not only survived but migrated to the damaged areas of the brain.29,30 These studies increase our knowledge of how stem cells are attracted to diseased areas of the brain.

There is also increasing evidence from numerous animal disease models that stem cells are actively drawn to brain damage. Once they reach these damaged areas, they have been shown to exert beneficial effects such as reducing brain inflammation or supporting nerve cells. It is hoped that, once these mechanisms are better understood, this stem cell recruitment can potentially be exploited to mobilize a patient's own stem cells.

Similar lines of research are being considered with other disorders such as Huntington's Disease and certain congenital defects. While much attention has been called to the treatment of Alzheimer's Disease, it is still not clear if stem cells hold the key to its treatment. But despite the fact that much basic work remains and many fundamental questions are yet to be answered, researchers are hopeful that repair for once-incurable nervous system disorders may be amenable to stem cell based therapies.

Considerable progress has been made the last few years in our understanding of stem cell biology and devising sources of cells for transplantation. New methods are also being developed for cell delivery and targeting to affected areas of the body. These advances have fueled optimism that new treatments will come for millions of persons who suffer from neurological disorders. But it is the current task of scientists to bring these methods from the laboratory bench to the clinic in a scientifically sound and ethically acceptable fashion.

Notes:

* Chief, Developmental Neurobiology Program, Molecular, Cellular & Genomic Neuroscience Research Branch, Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, National Institutes of Health, Email: panchisiond@mail.nih.gov

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