New Genetic And Stem-Cell Technology To Grow Sheets Of Skin

Somewhere in Germany’s Ruhr valley, a nine-year-old boy is doing what children do: playing football, joking around with friends and going to school. Two years ago, he was confined to a hospital bed, dying of a rare and cruel genetic skin disease. The boy had junctional epidermolysis bullosa, or JEB. He, like other people with the disease, carried a mutation in a gene that controls the integrity of the skin. Doctors could only try to ease his suffering as some 80% of his skin simply fell away.

A team of Italian researchers came to his aid by combining stem-cell techniques with gene therapy. As a young scientist at Harvard Medical School in Boston, Massachusetts, in the 1980s, Michele De Luca — the lead author of the new study — watched pioneers in skin regeneration learn to grow small sheets of skin from cells taken from burns patients, and to use them in grafts. He extended the work in Italy, applying new genetic and stem-cell technologies. He developed ways to generate stem cells from human skin, replace disease-causing genes in them and grow sheets of healthy skin on scaffolds in the lab.

He chose JEB for his first clinical trial, which he registered with the Italian Medicines Agency in 2002. Four years later, he reported his first success, in which he created healthy skin patches from biopsies to replace small areas of sloughed-off skin on the legs of a patient with a form of JEB (F. Mavilio et al. Nature Med. 12, 1397–1402; 2006). New European Commission regulations introduced in 2007 required him to pause the project while he created facilities adhering to ‘good manufacturing practices’ (GMPs) and a spin-off company to meet the demands for strengthened oversight of cell-based therapies.

Having a company refocused his team’s attention on a different type of stem-cell therapy, one likely to yield a product for the market faster. Holoclar, a treatment that replaces the eye’s cornea in a form of blindness, became the world’s first commercial stem-cell therapy in 2015.

A few months later, at the University of Modena, De Luca got a call out of the blue from doctors in Germany who were trying to treat the little boy. Because the therapy had been in a clinical trial, albeit one on hold at the time, and because De Luca could provide GMP services, German regulatory authorities quickly approved the one-off compassionate use of the JEB therapy. Surgeons in Germany sent a skin biopsy to Modena, and two major skin transplants followed. Six months after the initial biopsy, the boy returned to school. During the many months since, he has not had so much as a blister, and loves to show off his ‘new skin’. By their nature, highly personalized treatments using gene therapies and products derived from an individual’s stem cells are likely to be applicable to only a subset of patients.

Scientists and clinicians have presented the details of the recovery in Nature (T. Hirsch et al.Nature http://dx.doi.org/10.1038/nature24487; 2017). This major clinical development was based on decades of basic research. The clinical data gathered during 21 months of follow-up after the boy’s treatment have also led to major insights into human skin biology, as discussed in an accompanying News & Views (M. Aragona and C. Blanpain Naturehttp://dx.doi.org/10.1038/nature24753; 2017). For example, normal regeneration of the epidermis is directed by only a few stem-cell clones that can self-renew.

Source: http://www.nature.com/

Nanogels For Heart Attack Patients

Heart disease and heart-related illnesses are a leading cause of death around the world, but treatment options are limited. Now, one group reports in ACS Nano that encapsulating stem cells in a nanogel could help repair damage to the heart.

Myocardial infarction, also known as a heart attack, causes damage to the muscular walls of the heart. Scientists have tried different methods to repair this damage. For example, one method involves directly implanting stem cells in the heart wall, but the cells often don’t take hold, and sometimes they trigger an immune reaction. Another treatment option being explored is injectable hydrogels, substances that are composed of water and a polymer. Naturally occurring polymers such as keratin and collagen have been used but they are expensive, and their composition can vary between batches. So Ke Cheng, Hu Zhang, Jinying Zhang and colleagues wanted to see whether placing stem cells in inexpensive hydrogels with designed tiny pores that are made in the laboratory would work.

The team encapsulated stem cells in nanogels, which are initially liquid but then turn into a soft gel when at body temperature. The nanogel didn’t adversely affect stem cell growth or function, and the encased stem cells didn’t trigger a rejection response. When these enveloped cells were injected into mouse and pig hearts, the researchers observed increased cell retention and regeneration compared to directly injecting just the stem cells. In addition, the heart walls were strengthened. Finally, the group successfully tested the encapsulated stem cells in mouse and pig models of myocardial infarction.

Source: https://www.acs.org/
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Brain Cells Found To Control Aging

Scientists at Albert Einstein College of Medicine have found that stem cells in the brain’s hypothalamus govern how fast aging occurs in the body. The finding, made in mice, could lead to new strategies for warding off age-related diseases and extending lifespan. The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 Nature paper, Einstein researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons.

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Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging,” says senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. “But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it’s possible to slow and even reverse various aspects of aging throughout the body.”

The findings have been published online in Nature.

Source: http://www.einstein.yu.edu/
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Artificial Embryo From Stem Cells

Scientists at the University of Cambridge have managed to create a structure resembling a mouse embryo in culture, using two types of stem cells – the body’s ‘master cells’ – and a 3D scaffold on which they can grow. Understanding the very early stages of embryo development is of interest because this knowledge may help explain why a significant number of human pregnancies fail at this time.

Once a mammalian egg has been fertilised by a sperm, it divides multiple times to generate a small, free-floating ball of stem cells. The particular stem cells that will eventually make the future body, the embryonic stem cells (ESCs) cluster together inside the embryo towards one end: this stage of development is known as the blastocyst. The other two types of stem cell in the blastocyst are the extra-embryonic trophoblast stem cells (TSCs), which will form the placenta, and primitive endoderm stem cells that will form the so-called yolk sac, ensuring that the foetus’s organs develop properly and providing essential nutrients.

Using a combination of genetically-modified mouse ESCs and TSCs, together with a 3D scaffold known as an extracellular matrix, Cambridge researchers were able to grow a structure capable of assembling itself and whose development and architecture very closely resembled the natural embryo.  There is a  remarkable degree of communication between the two types of stem cell: in a sense, the cells are telling each other where in the embryo to place themselves.

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We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other,”  says Professor Zernicka-Goetz. “Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn’t take place properly.”

Comparing their artificial ‘embryo’ to a normally-developing embryo, the team was able to show that its development followed the same pattern of development. The stem cells organise themselves, with ESCs at one end and TSCs at the other.

The study has been published in the journal Science.

Source: http://www.cam.ac.uk/

How To Track Stem Cells In The Body

Rice University researchers have synthesized a new and greatly improved generation of contrast agents for tagging and real-time tracking of stem cells in the body. The agent combines ultrashort carbon nanotubes and bismuth clusters that show up on X-rays taken with computed tomography (CT) scanners. The stable compound performs more than eight times better than the first-generation material introduced in 2013, according to the researchers.

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An improved compound of bismuth and carbon nanotubes called Bi4C@US-tubes, developed at Rice University could enhance the ability to track stem cells as they move through the body and target diseases

The primary application will be to track them in stem-cell therapies to see if the cells are attracted to the site of disease — for example, cancer — and in what concentration,” said Rice chemist Lon Wilson of the compound the researchers call Bi4C@US-tubes.

Magnetic resonance imaging is currently used for that purpose and it works quite well, but X-ray technology in the clinic is much more available,” he said. “It’s faster and cheaper, and it could facilitate preclinical studies to track stem cells in vivo.”

Bismuth is used in cosmetics, pigments and pharmaceuticals, notably as the active ingredient in pink bismuth (aka Pepto-Bismol), an antacid. For this application, bismuth nanoclusters developed by the lab of Rice chemist Kenton Whitmire, a co-author of the paper, are combined with carbon nanotubes chemically treated to shorten them to between 20 and 80 nanometers and add defects to their side walls. The nanoclusters, which make up about 20 percent of the compound, appear to strongly attach to the nanotubes via these defects.

When introduced into stem cells, the treated nanotubes become easy to spot, Wilson said. “It’s very interesting to see a cell culture that is opaque to X-rays. They’re not as dark as bone (which X-rays cannot penetrate), but they’re really dark when they’re loaded with these agents.”

The process developed by Wilson’s team and colleagues at CHI St. Luke’s Health-Baylor St. Luke’s Medical Center and Baylor College of Medicine is detailed this month in the American Chemical Society journal ACS Applied Materials and Interfaces.

Source: http://news.rice.edu/

Stem Cells Boost Bones Repair

A recent study, affiliated with UNIST (South Korea) has developed a new method of repairing injured bone using stem cells from human bone marrow and a carbon material with photocatalytic properties, which could lead to powerful treatments for skeletal system injuries, such as fractures or periodontal disease. In the study, the research team reported that the use of human bone marrow-derived mesenchymal stem cells (hBMSCs) has been tried successfully in fracture treatment due to their potential to regenerate bone in patients who have lost large areas of bone from either disease or trauma. Recently, many attempts have been made to enhance the function of stem cells using carbon nanotubes, graphenes, and nano-oxides.

Professor Kim and Professor Suh (UNIST) examined the C₃N₄sheets. They discovered that this material absorbs red light and then emits fluorescence, which can be used to speed up bone regeneration. Professor Suh conducted a biomedical application of this material. After two days of testing, the material showed no cytotoxicity, making it useful as biomaterials.

bone-repairUpper left) Chemical bonding and physical structure of C₃N₄4 sheets. (Lower left) In a liquid state, red light is transmitted at a maximum of 450nm and emitted at a wavelength of 635 nm. (Right) After 4 weeks of loading C₃N₄4 sheets into the skull-damaged mice, the skull was regenerated by more than 90%.

This research has opened up the possibility of developing a new medicine that effectively treats skeletal injuries, such as fractures and osteoporosis,” said Professor Young-Kyo Seo. “It will be a very useful tool for making artificial joints and teeth with the use of 3D printing. This is an important milestone in the analysis of biomechanical functions needed for the development of biomaterials, including adjuvants for hard tissues such as damaged bones and teeth.”

This research has been jointly conducted by Professor Youngkyo Seo of Life Sciences and Dr. Jitendra N. Tiwari of Chemistry in collaboration with Professor Kwang S. Kim of Natural Science, Professor Pann-Ghill Suh of Life Sciences, and seven other researchers from UNIST.  The results of the study has been published in the January issue of ACS Nano journal.

Source: https://news.unist.ac.kr/

Damaged teeth can be regrown naturally

A way to naturally regrow damaged teeth has been discovered by scientists in a breakthrough that could significantly reduce the need for fillings. Researchers at King’s College London (KCL) found that a drug designed to treat Alzheimer’s disease was able to stimulate the tooth to create new dentine capable of filling in large cavitiesTeeth can already cope with small areas of damage using the same process, but when the holes become too large a dentist must insert artificial cements or the tooth will be lost.

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The simplicity of our approach makes it ideal as a clinical dental product for the natural treatment of large cavities, by providing both pulp protection and restoring dentine,” said Professor Paul Sharpe, lead author of a paper in the journal Scientific Reports.  “In addition, using a drug that has already been tested in clinical trials for Alzheimer’s disease provides a real opportunity to get this dental treatment quickly into clinics.”

If a tooth is damaged or infected, the soft inner pulp can become exposed, risking further infection. When this happens, a band of dentine, the hard material that makes up most of the tooth, will attempt to bridge the gap and seal off the pulp. But the researchers found that the natural repair mechanism could be boosted if the drug  Tideglusib was used. Previously it has been trialled as a treatment for various neurological disorders, including Alzheimer’s. It works by stimulating stem cells, which can turn into any type of tissue in the body, already present in the pulp to create new dentine.

The drug and a substance called glycogen synthase kinase were applied to the tooth on a biodegradable sponge made from collagen. As the sponge degraded, it was replaced by dentineleading to complete, natural repair”, according to a statement about the research issued by KCL.

Source: http://www.independent.co.uk/

How To Grow Mini Human Brains

A*STAR’s Scientists in Singapore have made a big leap on research on the ‘mini-brain’. These advanced mini versions of the human midbrain will help researchers develop treatments and conduct other studies into Parkinson’s Disease  (PD) and ageing-related brain diseases. These mini midbrain versions are three-dimensional miniature tissues that are grown in the laboratory and they have certain properties of specific parts of the human brains. This is the first time that the black pigment neuromelanin has been detected in an organoid model. The study also revealed functionally active dopaminergic neurons.

The human midbrain, which is the information superhighway, controls auditory, eye movements, vision and body movements. It contains special dopaminergic neurons that produce dopamine – which carries out significant roles in executive functions, motor control, motivation, reinforcement, and reward. High levels of dopamine elevate motor activity and impulsive behaviour, whereas low levels of dopamine lead to slowed reactions and disorders like PD, which is characterised by stiffness and difficulties in initiating movements.

DIFFERENCIATION OF HUMAN EMBRIONIC

Also causing PD is the dramatic reduction in neuromelanin production, leading to the degenerative condition of patients, which includes tremors and impaired motor skills. This creation is a key breakthrough for studies in PD, which affects an estimated seven to 10 million people worldwide. Furthermore, there are people who are affected by other causes of parkinsonism. Researchers now have access to the material that is affected in the disease itself, and different types of studies can be conducted in the laboratory instead of through simulations or on animals. Using stem cells, scientists have grown pieces of tissue, known as brain organoids, measuring about 2 to 3 mm long. These organoids contain the necessary hallmarks of the human midbrain, which are dopaminergic neurons and neuromelanin.

Assistant Prof Shawn Je from Duke-NUS Medical School’s Neuroscience & Behavioural Disorders Programme said, “It is remarkable that our midbrain organoids mimic human midbrain development. The cells divide, cluster together in layers, and become electrically and chemically active in three-dimensional environment like our brain. Now we can really test how these mini brains react to existing or newly developed drugs before treating patients, which will be a game changer for drug development.”

Jointly led by Prof Ng Huck Hui from A*STAR’s Genome Institute of Singapore (GIS) and Assistant Prof Shawn Je from Duke-NUS Medical School, this collaborative research between GIS, Duke-NUS, and the National Neuroscience Institute (NNI) is funded by the National Medical Research Council’s Translational Clinical Research (TCR) Programme In Parkinson’s disease (PD) and A*STAR. Other collaborators are from the Lieber Institute for Brain Development, the Johns Hopkins University School of Medicine, and the Nanyang Technological University.

Source: https://www.a-star.edu.sg/

Nanodentistry Regenerates Your Teeth

Salvatore Sauro, professor of Dentistry at the Universidad CEU Cardenal Herrera in Valencia (Spain), has collaborated with experts from the College of Dental Medicine at Georgia Regents University in Augusta, US, and the Brazilian Universidade Federal do Ceará and Universidade Estadual de Campinas, on an exhaustive study of  nanomaterials and their clinical applications within “nanodentistry.” A detailed overview was published in Trends in Biotechnology, analyzing the cutting-edge properties of polymeric, metallic and inorganic nano-based materials and their potential use in therapeutic and restorative dental care.

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One of the most promising features of these nanomaterials is their capacity to imitate the natural physicochemical, mechanic and aesthetic properties of dentine and dental enamel, underlines Sauro. “This is what is meant by biomimetic: human-made materials that imitate nature and natural processes. “For instance, nanoceramic materials have yielded good results in dental restoration, imitating the aesthetic properties of dental enamel.”

Some dental resins and composites used today to treat tooth loss have already been given the “nano treatment,” incorporating ceramic or silica-rich nanoparticles which, aside from imitating the natural aesthetics of teeth, they are stronger, harder and more resistant to decay. Stronger still are new nanomaterials based on sapphires and diamonds, which have proven twenty times as strong as their ceramic-based counterparts. “The field of dental materials is one that will feel the benefit of advances in nanotechnology on the short-term,” adds Sauro, meaning the door is wide open to restorative dental materials that are even more natural-looking, long-lasting and easier to work with in the clinic setting.

Another area of development is that of remineralising and regenerating dental tissue, whose natural capacity for regeneration in adults is very limited. Nanomaterials are being used in conjunction with stem cells to regenerate dentin, dental cement and even enamel, the tissue least able to regenerate naturally. Incorporated into composites and injectable biomaterials, this is a promising approach to dental tissue repair which harnesses biological responses. However, Sauro warns that further testing is required to ascertain the toxicity of these materials, which may also affect the healthy cells in the treated tissue.

Source: http://ruvid.org/wordpress
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How To Repair Nerve Tissue Injuries

Regenerative medicine using stem cells is an increasingly promising approach to treat many types of injury. Transplanted stem cells can differentiate into just about any other kind of cell, including neurons to potentially reconnect a severed spinal cord and repair paralysis.

A variety of agents have been shown to induce transplanted stem cells to differentiate into neurons.  Tufts University biomedical engineers recently published the first report of a promising new way to induce human mesenchymal stem cells (or hMSCs, which are derived from bone marrow) to differentiate into neuron-like cells:  treating them with exosomes.

exosome2Exosomes are very small, hollow particles that are secreted from many types of cells. They contain functional proteins and genetic materials and serve as a vehicle for communication between cells. In the nervous system, exosomes guide the direction of nerve growth, control nerve connection and help regenerate peripheral nerves.

In a series of experiments reported in PLOS ONE in August, the Tufts researchers showed that exosomes from PC12 cells (neuron-like progenitor cells derived from rats) at various stages of their own differentiation could, in turn, cause hMSCs to become neuron-like cells. Exosomes had not previously been studied as a way to induce human stem cell differentiation.

The biomedical engineers also showed that the exosomes contain miRNAs—tiny pieces of RNA that regulate cell behavior and are known to play a role in neuronal differentiation. The researchers hypothesize that the exosomes caused the hMSCs to differentiate by delivering miRNA into the stem cells. The researchers plan future studies to determine the exact mechanism.

“In combination with synthetic nanoparticles that my laboratory is developing, we may ultimately be able to use these identified miRNAs or proteins to make synthetic exosomes, thereby avoiding the need to use any kind of neural progenitor cell line to induce neuron growth,” said the paper’s senior and corresponding author Qiaobing Xu, assistant professor of biomedical engineering at Tufts School of Engineering.

Source: http://now.tufts.edu/

Engineered Cells Cure Spinal Cord Injuries

Iranian researchers produced a laboratorial sample of cell culture scaffold in their research to cure spinal cord injury (SCI).. Many people across the world suffer from injuries on their spinal cord due to diseases or accidents. Neural cell tissues are not able to recover the injury by themselves. Therefore, it is necessary to produce cellular engineered structures to cure neural injuries.

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This research tries to study the ability of mesenchymal stem cells of human bone marrow to convert into cells similar to motor nerve cells. Motor nerve cells transfer movement order from the spinal cord to the muscles.

Nano-sized electrospun gelatin has been used in this study as a scaffold to culture stem cells. Gelatin is considered as an appropriate option in tissue engineering for the treatment of neural injuries due to its structural similarity to in-vivo matrix protein parts.

Results showed that mesenchymal stem cells turn into cells similar to motor nerve cells on electrospun gelatin, and they express the unique properties of these cells on the surface of gene and protein.

The achievement of the research proves that the engineered cellular structure is a good choice to be transplanted into animal sample to study the treatment of spinal cord injury. Therefore, studies are being carried out at the moment on injured animal samples to use the scaffold containing stem cells.

Results of the research have been published in Journal of Molecular Neuroscience.

Source: http://english.farsnews.com/

Liver Cancer: NanoDiamonds Eliminate Resistant Stem Cells

A study led by the National University of Singapore (NUS) found that attaching chemotherapy drug Epirubicin to nanodiamonds effectively eliminates chemoresistant cancer stem cells. The findings were first published online in ACS Nano, the official journal of the American Chemical Society.
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The research team, led by Assistant Professor Edward Chow, Junior Principal Investigator at the Cancer Science Institute of Singapore (CSI Singapore) at NUS, demonstrated the use of nanotechnology to repurpose existing chemotherapy drugs as effective agents against chemoresistant cancer stem cells. Chemoresistance, which is the ability of cancer cells to escape chemotherapy treatment, is a primary cause of treatment failure in cancer. Cancer stem cells, a type of cancer cell which initiates the formation of tumours, are commonly found to be more resistant to chemotherapy than the rest of the bulk tumour, which can lead to cancer recurrence following chemotherapy treatment. As such, there is intense interest in developing new drugs or treatment strategies that overcome chemoresistance, particularly in cancer stem cells.

In this study, widely-used chemotherapy drug Epirubicin was attached to nanodiamonds, carbon structures with a diameter of about five nanometres, to develop a nanodiamond-Epirubicin drug delivery complex (EPND). The researchers found that while both standard Epirubicin as well as EPND were capable of killing normal cancer cells, only EPND was capable of killing chemoresistant cancer stem cells and preventing secondary tumour formation in xenograft models of liver cancer.

Source: http://news.nus.edu.sg/