Basis of ‘leaky’ brain blood vessels in Huntington’s disease identified – UCI News

Irvine, Calif., May 16, 2017 By using induced pluripotent stem cells to create endothelial cells that line blood vessels in the brain for the first time for a neurodegenerative disease, University of California, Irvine neurobiologists and colleagues have learned why Huntingtons disease patients have defects in the blood-brain barrier that contribute to the symptoms of this fatal disorder.

Now we know there are internal problems with blood vessels in the brain, said study leader Leslie Thompson, UCI professor of psychiatry & human behavior and neurobiology & behavior. This discovery can be used for possible future treatments to seal the leaky blood vessels themselves and to evaluate drug delivery to patients with HD.

The blood-brain barrier protects the brain from harmful molecules and proteins. It has been established that in Huntingtons and other neurodegenerative diseases there are defects in this barrier adding to HD symptoms. What was not known was whether these defects come from the cells that constitute the barrier or are secondary effects from other brain cells.

To answer that, Thompson and colleagues from UCI, Columbia University, the Massachusetts Institute of Technology and Cedars-Sinai Medical Center reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into brain microvascular endothelial cells those that form the internal lining of blood vessels and prevent leakage of blood proteins and immune cells.

The researchers discovered that blood vessels in the brains of HD patients become abnormal due to the presence of the mutated Huntingtin protein, the hallmark molecule linked to the disease. As a result, these blood vessels have a diminished capacity to form new blood vessels and are leaky compared to those derived from control patients.

The chronic production of the mutant Huntingtin protein in the blood vessel cells causes other genes within the cells to be abnormally expressed, which in turn disrupts their normal functions, such as creating new vessels, maintaining an appropriate barrier to outside molecules, and eliminating harmful substances that may enter the brain.

In addition, by conducting in-depth analyses of the altered gene expression patterns in these cells, the study team identified a key signaling pathway known as the Wnt that helps explain why these defects occur. In the healthy brain, this pathway plays an important role in forming and preserving the blood-brain barrier. The researchers showed that most of the defects in HD patients blood vessels can be prevented when the vessels are exposed to a compound (XAV939) that inhibits the activity of the Wnt pathway.

This is the first induced pluripotent stem cell-based model of the blood-brain barrier for a neurodegenerative disease. The study appears in the journal Cell Reports, with a parallel study from Cedars-Sinai Medical Center in Cell Stem Cell that advances the first model for a neurodevelopmental disease that specifically affects the blood-brain barrier.

These studies together demonstrate the incredible power of iPSCs to help us more fully understand human disease and identify the underlying causes of cellular processes that are altered, said Ryan Lim, a postgraduate research scientist at the Institute for Memory Impairments and Neurological Disorders, or UCI MIND, who initiated the UCI work.

We show a proof-of-concept therapy where we could reverse some of the abnormalities in the blood vessel cells by treating them with a drug, added Thompson, who is affiliated with both UCI MIND and the Sue & Bill Gross Stem Cell Research Center.

The future direction of this study is to develop ways to test how drugs may be delivered to the brain of HD patients and to examine additional treatment strategies using our understanding of the underlying causes of abnormalities in brain blood vessels, said study co-leader Dritan Agalliu, assistant professor of pathology & cell biology at Columbia University Medical Center.

Chris Quan, Andrea M. Reyes-Ortiz, Jie Wu, Jennifer Stocksdale and Malcolm S. Casale of UCI; Amanda J. Kedaigle, Theresa A. Gipson, Ernest Fraenkel and David E. Housman of MIT; Gad D. Vatine and Clive N. Svendsen of Cedars-Sinai; and Sarah E. Lutz of Columbia University also contributed to the study, which was supported in part by the American Heart Association, California Institute for Regenerative Medicine and National Institutes of Health.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 30,000 students and offers 192 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $5 billion annually to the local economy. For more on UCI, visit http://www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

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Basis of 'leaky' brain blood vessels in Huntington's disease identified - UCI News

Basis of ‘leaky’ brain blood vessels in Huntington’s Disease identified – Science Daily

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Basis of 'leaky' brain blood vessels in Huntington's Disease identified Science Daily To answer that, Thompson and colleagues from UCI, Columbia University, the Massachusetts Institute of Technology and Cedars-Sinai Medical Center reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into ... Team creates self-renewing hematopoietic stem cells for transplantationMedical Xpress Approaching a decades-old goal: Making blood stem cells from patients' own cellsEurekAlert (press release) all 21 news articles »

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Basis of 'leaky' brain blood vessels in Huntington's Disease identified - Science Daily

Press Release: New Stem Cell Collection Center Opens in Boston – The Scientist

Press Release: New Stem Cell Collection Center Opens in Boston The Scientist StemExpress expands to the East Coast with the launch of a new Stem Cell Collection Center to meet the growing demand of its products. This new donation center, located in Arlington Massachusetts, will expand the company's ability to collect and ...

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Press Release: New Stem Cell Collection Center Opens in Boston - The Scientist

Stem cell transplants may advance ALS treatment by repair of blood-spinal cord barrier – Medical Xpress

May 15, 2017 An MRI with increased signal in the posterior part of the internal capsule which can be tracked to the motor cortex consistent with the diagnosis of ALS. Credit: Frank Gaillard/Wikipedia

Researchers at the University of South Florida show in a new study that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with the disease Amyotrophic Lateral Sclerosis (ALS) by repairing damage to the blood-spinal cord barrier.

In a study recently published in the journal Scientific Reports, researchers in USF's Center of Excellence for Aging and Brain Repair say the results of their experiment are an early step in pursuing stem cells for potential repair of the blood-spinal cord barrier, which has been identified as key in the development of ALS. USF Health Professor Svitlana Garbuzova-Davis, PhD, led the project.

Previous studies in development of various therapeutic approaches for ALS typically used pre-symptomatic mice.

"This is the first study advancing barrier repair that treats symptomatic mice, which more closely mirrors conditions for human patients," Dr. Garbuzova-Davis said.

Using stem cells harvested from human bone marrow, researchers transplanted cells into mice modeling ALS and already showing disease symptoms. The transplanted stem cells differentiated and attached to vascular walls of many capillaries, beginning the process of blood-spinal cord barrier repair.

The stem cell treatment delayed the progression of the disease and led to improved motor function in the mice, as well as increased motor neuron cell survival, the study reported.

ALS is a progressive neurodegenerative disease that affects neuronal cells in the brain and the spinal cord, which send signals to control muscles throughout the body. The progressive degeneration of motor neuron cells leads to death from ALS. More than 6,000 Americans each year are diagnosed with the disease.

Because stem cells have the ability to develop into many different cell types in the body, researchers at USF's Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair have focused on using stem cells to restore function lost through neurodegenerative disorders or injuries.

Damage to the barrier between the blood circulatory system and the central nervous system has been recently recognized as a factor in ALS development, leading researchers to work on targeting the barrier for repair as a potential strategy for ALS therapy.

In this study, the ALS mice were given intravenous treatments of one of three different doses of the bone marrow stem cells. Four weeks after treatment, the scientists determined improved motor function and enhanced motor neuron survival. The mice receiving the higher doses of stem cells fared better in the study, the researcher noted.

The transplanted stem cells had differentiated into endothelial cells - which form the inner lining of a blood vessel, providing a barrier between blood and spinal cord tissueand attached to capillaries in the spinal cord. Furthermore, the researchers observed reductions in activated glial cells, which contribute to inflammatory processes in ALS.

Explore further: Discovery offers new hope to repair spinal cord injuries

More information: Svitlana Garbuzova-Davis et al, Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair, Scientific Reports (2017). DOI: 10.1038/s41598-017-00993-0

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Researchers at the University of South Florida show in a new study that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with the disease Amyotrophic Lateral Sclerosis ...

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Stem cell transplants may advance ALS treatment by repair of blood-spinal cord barrier - Medical Xpress

Skin Cell Discovery Could Lead to Possible Treatments for Balding, Hair Graying – Sci-News.com

A team of scientists at the University of Texas Southwestern Medical Center has identified the cells that directly give rise to hair as well as the mechanism that causes hair to turn gray. The research is published in the journal Genes & Development.

Layers of the skin. Image credit: M.Komorniczak / Madhero / CC BY-SA 3.0.

With this knowledge, we hope in the future to create a topical compound or to safely deliver the necessary gene to hair follicles to correct these cosmetic problems, said senior author Dr. Lu Le, an associate professor of dermatology with the Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center.

Dr. Le and colleagues found that a protein called KROX20 (also termed EGR2), more commonly associated with nerve development, turns on in skin cells that become the hair shaft.

These hair precursor cells then produce a protein called stem cell factor (SCF) that the researchers showed is essential for hair pigmentation.

When the authors deleted the SCF gene (KITLG gene) in the hair progenitor cells in mouse models, the animals hair turned white.

When they deleted the KROX20-producing cells, no hair grew and the mice became bald.

We uncovered this explanation for balding and hair graying while studying a disorder called Neurofibromatosis Type 1, a rare genetic disease that causes tumors to grow on nerves, Dr. Le said.

Scientists already knew that stem cells contained in a bulge area of hair follicles are involved in making hair and that SCF is important for pigmented cells.

What they did not know in detail is what happens after those stem cells move down to the base, or bulb, of hair follicles and which cells in the hair follicles produce SCF or that cells involved in hair shaft creation make the KROX20 protein.

If cells with functioning KROX20 and SCF are present, they move up from the bulb, interact with pigment-producing melanocyte cells, and grow into pigmented hairs.

But without SCF, the hair in mouse models was gray, and then turned white with age. Without KROX20-producing cells, no hair grew.

We will now try to find out if the KROX20 in cells and the SCF gene stop working properly as people age, leading to the graying and hair thinning seen in older people as well as in male pattern baldness, Dr. Le said.

_____

Chung-Ping Liao et al. Identification of hair shaft progenitors that create a niche for hair pigmentation. Genes & Development, published online May 2, 2017; doi: 10.1101/gad.298703.117

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Skin Cell Discovery Could Lead to Possible Treatments for Balding, Hair Graying - Sci-News.com

New lung ‘organoids’ in a dish mimic features of full-size lung – Phys.Org

May 12, 2017 Bright-field images of day 50 LBO-derived Matrigel colonies from RUES2 cells. Representative of six independent experiments. Scale bars, 500?m. Credit: Snoeck lab/Columbia University Medical Center

New lung "organoids"tiny 3-D structures that mimic features of a full-sized lunghave been created from human pluripotent stem cells by researchers at Columbia University Medical Center (CUMC). The team used the organoids to generate models of human lung diseases in a lab dish, which could be used to advance our understanding of a variety of respiratory diseases.

A paper detailing the discovery was published in the April 24 online issue of Nature Cell Biology.

Organoids are 3-D structures containing multiple cell types that look and function like a full-sized organ. By reproducing an organ in a dish, researchers hope to develop better models of human diseases, and find new ways of testing drugs and regenerating damaged tissue.

"Researchers have taken up the challenge of creating organoids to help us understand and treat a variety of diseases," said Hans-Willem Snoeck, PhD, professor of medicine (in Microbiology & Immunology) at CUMC and lead investigator of the study. "But we have been tested by our limited ability to create organoids that can replicate key features of human disease."

The lung organoids created in Dr. Snoeck's lab are the first to include branching airway and alveolar structures, similar to human lungs.

To demonstrate their functionality, the researchers showed that the organoids reacted in much the same way as a real lung does when infected with respiratory syncytial virus (RSV). Additional experiments revealed that the organoids also responded as a human lung would when carrying a gene mutation linked to pulmonary fibrosis.

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RSV is a major cause of lower respiratory tract infection in infants and has no vaccine or effective antiviral therapy. Idiopathic pulmonary fibrosis, a condition that causes scarring in the lungs, causes 30,000 to 40,000 deaths in the U.S. each year. A lung transplant is the only cure for this condition.

"Organoids, created with human pluripotent or genome-edited embryonic stem cells, may be the best, and perhaps only, way to gain insight into the pathogenesis of these diseases," Dr. Snoeck says.

Explore further: New study makes strides towards generating lung tissue

More information: Ya-Wen Chen et al, A three-dimensional model of human lung development and disease from pluripotent stem cells, Nature Cell Biology (2017). DOI: 10.1038/ncb3510

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Stem cell therapy holds promise for treating most severe cases of … – Medical Xpress

May 11, 2017

An analysis of data from the entire development program consisting of three trials assessing the feasibility of using a stem cell therapy (CD34+ cells) to treat patients with the most severe cases of angina, refractory angina (RA), showed a statistically significant improvement in exercise time as well as a reduction in mortality. Results from "CD34+ Stem Cell Therapy Improves Exercise Time and Mortality in Refractory Angina: A Patient Level Meta-Analysis" were presented today as a late-breaking clinical trial at the Society for Cardiovascular Angiography and Interventions (SCAI) 2017 Scientific Sessions in New Orleans.

One of the warning signs of coronary artery disease is angina, or chest pain, which occurs when the heart muscle does not receive enough blood. Unlike angina pectoris or "stable angina," which can often be treated with medication, RA can be incapacitating, impacting quality of life. In the most severe cases, those with class III or IV angina, treatment options are exhausted, and patients remain severely debilitated. Unfortunately, one of the untoward consequences of the improved survival of patients with chronic ischemic heart disease is more patients with refractory angina.

A meta-analysis of three trials that each showed promising results looked at injecting RA patients with autologous CD34+ cellswhich have been shown to increase blood flowand the therapy's effect on mortality and total exercise time (TET), an important predictor of long-term mortality.

Data from 304 patients was extracted and analyzed from phase 1 (24 patients), ACT-34 and ACT-34 extension studies (168 patients), and RENEW (112 patients), which was prematurely terminated by the sponsor due to financial considerations.

"The goal of this meta-analysis was to combine patient level data from three very similar trials to try understand what it would tell us," said lead investigator Tom Povsic, MD, FSCAI, associate professor at the Duke Clinical Research Institute (DCRI) and an interventional cardiologist at Duke University School of Medicine.

Results showed that patients treated with CD34+ cell therapy (n=187) improved TET by 80.5 12.1, 101.8 13.7, and 90.5 14.7 seconds at three months, six months, and 12 months compared with 28.1 15.7, 48.8 18.2, and 39.5 20.3 seconds for the placebo group (n=89), resulting in treatment effects of 52.5 (p=0.002), 52.9 (p=0.009) and 50.9 (p=0.027) seconds.

The relative risk of angina was 0.90 (p=0.40), 0.81 (p=0.14), and 0.79 (p=0.17) at three months, six months, and 12 months in CD34+ treated patients.

CD34+ treatment decreased mortality by 24 months (2.6 percent vs. 11.8 percent, p=0.003). In addition, major adverse cardiac events were less frequent (29.8 percent for CD34+ patients vs. 40.0 percent for the placebo group, p=0.08).

"Therapies for these patients are direly needed," said Povsic, "and results from our meta-analysis are very compelling. Most importantly, the number of patients in our meta-analysis approximates those who were targetedfor enrollment in RENEW, the prematurely terminated phase III study. These results suggest that had RENEW been completed, a regenerative therapy for these patients might meet criteria for approval. I still think this therapy has a lot of promise."

Timothy Henry, MD, chief of cardiology at Cedars-Sinai Medical Center in Los Angeles, agrees "CD34+ cell therapy appears to be an extremely safe and effective therapy for this growing and challenging patient population with limited options."

Explore further: Stem cell therapy shows potential for difficult-to-treat RA patient population

More information: Povsic presented "CD34+ Stem Cell Therapy Improves Exercise Time and Mortality in Refractory Angina: A Patient Level Meta-Analysis" on Thursday, May 11, 2017 11:30 a.m. CDT

A study using a stem cell therapy to treat challenging refractory angina (RA) patients demonstrated promising results, including improved exercise time, reduced angina and reduced mortality. The RENEW results were presented ...

A two-year, multi-center clinical study with 167 patients with class III-IV refractory angina randomized to low and high dose CD34+ cells or placebo has revealed that patients who received either a high or low dose of CD34a ...

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A new pilot study reports that Mexican-American stroke survivors are less likely to receive inpatient rehabilitation than non-Hispanic whites.

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Sniffing out stem cell fates in the nose – UC Berkeley

Adult stem cells have the ability to transform into many types of cells, but tracing the path individual stem cells follow as they mature and identifying the molecules that trigger these fateful decisions are difficult in a living animal.

Neurons (green) derived from a single stem cell in the olfactory epithelium of the nose. The magenta cells are support cells called sustentacular cells. (Russell Fletcher image)

UC Berkeley neuroscientists have now combined new techniques for sequencing the RNA in single cells with detailed statistical analysis to more easily track individual stem cells in the nose, uncovering clues that someday could help restore smell to those who have lost it.

The results are published this week in the journal Cell Stem Cell.

A stem cells job is twofold: to replace or recreate mature cells that are lost over time, both through normal aging and after injury, and to replace themselves so that the process can continue over the life of the animal, said senior author John Ngai, the Coates Family Professor of Neuroscience and a member of UC Berkeleys Helen Wills Neuroscience Institute and the Berkeley Stem Cell Center. We are getting closer to understanding how mature sensory neurons are generated from olfactory stem cells, an understanding thats key for an eventual stem cell therapy to restore function.

Ngai noted that perhaps one-quarter of all people over the age of 50 have some loss of smell, yet doctors have little understanding why, and no treatments for most cases. Theres not even a standardized test for loss of smell, as there is for vision or hearing loss, in spite of widespread reports of suffering by patients who have lost their sense of smell.

Some cases of anosmia the loss of the sense of smell are due to traumatic injury, and there is generally not a whole lot you can do about that, he said. But some are age-related, or occur for reasons we dont quite know. In the case of age-related anosmias, it could be because the stem cells are just not doing their job replacing the cells that are naturally lost over time. One idea is that if we could harness the very stem cells that are in the noses of people who are losing smell, maybe we can figure out a way to restore function, by getting them to regenerate the cells that are lost.

Tracking cell fate Ngai, who directs the Functional Genomics Laboratory in UC Berkeleys California Institute for Quantitative Biosciences, focuses on the cells and regulatory molecules involved in our sense of smell. Olfactory cells in the nose are unusual in that they are part of the bodys outer layer, or epithelium, but also part of the nervous system, incorporating neurons that connect directly with the smell centers in the brain.

The nose is lined with sensory tissue, the olfactory epithelium, that contains various types of cells, all of which arise from olfactory stem cells (green). Among these are smell-sensing neurons (orange), progenitor cells (cyan) and support cells (magenta sustentacular cells and blue microvillous cells). (Russell Fletcher image)

His group has been working with adult olfactory stem cells that give rise to the neurons that sense odors and other cells, such as sustentacular cells, that support the neurons. A new technique for sequencing the RNA in a single cell has been revolutionary, Ngai said, allowing researchers to trace which stem cells in a densely packed tissue become specialized, based on the mRNA present in the cell, which indicates which genes are being expressed. Nevertheless, it is difficult to follow stem cells that can potentially differentiate into different types of cells.

Ngais group teamed up with UC Berkeley statisticians and computer scientists led by Sandrine Dudoit, a professor of biotstatistics and statistics, Elizabeth Purdom, a professor of statistics, and Nir Yosef, a professor of electrical engineering and computer sciences to develop a way to analyze the experimental data and identify cells with similar RNA profiles, indicative of specific cell types and developmental states.

As a result, the team was able to trace the paths that cells take as they turn into sustentacular cells which seems to be the default fate for olfactory stem cells and into neurons and other types of cells. They also were able to identify a signaling pathway known as Wnt that triggers the olfactory stem cell to become a sensory neuron.

Ngai cautions that the immediate implications of the work are limited to animal models, which provide the necessary foundation for eventually addressing human anosmias. But with this information, we now have a window into what controls the process and therefore a window into manipulating or coopting that process to stimulate regeneration he said. There has been a lot of work on Wnt signaling pathways, for example, so there are a lot of small-molecule drugs that could be tested to trigger a stem cell to mature into a neuron.

The sequencing and statistical techniques the team developed can also be used by others studying regulation of stem cells in other tissues, organ systems or organisms, he said.

The work was spearheaded by senior postdoctoral researcher Russell Fletcher and graduate student Diya Das, and was funded by the National Institute on Deafness and Other Communications Disorders, the National Institute of Mental health, the National Institute on Aging, National Human Genome Research Institute, the National Center for Research Resources, the National Institute of General Medical Sciences, the California Institute of Regenerative Medicine and the Berkeley Siebel Stem Cell Center.

Other co-authors include Levi Gadye, Kelly Street, Ariane Baudhuin, Allon Wagner, Michael Cole, Quetzal Flores, Yoon Gi Choi and Davide Risso.

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Sniffing out stem cell fates in the nose - UC Berkeley

New Lung "Organoids" in a Dish Mimic Features of Full-Size Lung – Newswise (press release)

Newswise (press release)

New Lung "Organoids" in a Dish Mimic Features of Full-Size Lung Newswise (press release) Newswise New York, NY (May 11, 2017)New lung organoidstiny 3-D structures that mimic features of a full-sized lunghave been created from human pluripotent stem cells by researchers at Columbia University Medical Center (CUMC). The team ... and more »

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New Lung "Organoids" in a Dish Mimic Features of Full-Size Lung - Newswise (press release)

Study Identifies Root Cause of Gray, Balding Hair – NBC 10 Philadelphia

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Scientists in North Texas have identified the cells that cause hair to turn gray and to go bald findings that could one day help identify possible treatments.

Researchers from the University of Texas Southewestern Medical Center accidentally stumbled upon the discovery while studying a rare genetic disease that causes tumors to grow on nerves.

"When we saw the mice that we were expecting to form a tumor turned gray, we were really excited!" said Dr. Lu Le, an associate professor of dermatology at UT Southwestern.

The researchers found that a protein called KROX20, more commonly associated with nerve development, switches on in skin cells that become the hair shaft.

These hair cells then produce another protein called stem cell factor (SCF).In mice, these two proteins turned out to be important for baldness and graying.

When researchers deleted theSCF gene in mice,the animals' hair turned white; when they deleted the cells that produce KROX20, the mice stopped growing hair and eventually went bald, according to the study.

"We were really excited because as a dermatologist, I treat patients with hair disease, so when we found the root cause of why hair turns gray and hair loss, we just cannot let it go," Le said.

More research is needed to understand if the process works similarly in humans, and Le and his colleagues plan to start studying it in people.

Le hopes that, armed with this knowledge, scientists can develop a topical compound or transplant the necessary gene to hair follicles to correct these cosmetic problems.

Researchers say the findings could one day also provide answers about why humans age in general as hair graying and hair loss are among the first signs of aging.

At Hair Revival Studio in Dallas, clients say the possibility of a treatment for gray hair and baldness sounds remarkable.

"Everyone wants to have a good head of hair. There's a lot of confidence that comes with that," said Brandon Stewart.

Published at 8:55 AM EDT on May 11, 2017 | Updated at 9:54 AM EDT on May 11, 2017

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Study Identifies Root Cause of Gray, Balding Hair - NBC 10 Philadelphia