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How skeletal stem cells form the blueprint of the face

  |   Stem Cells and Bone   |   No comment
University of Southern California – Health Sciences
Timing is everything when it comes to the development of the vertebrate face. In a new study, researchers have identified the roles of key molecular signals that control this critical timing.
A three-day-old zebrafish head skeleton with newly differentiated cartilage cells (magenta) emerges from a pool of skeletal progenitor cells (green).
Credit: Lindsey Barske/Crump Lab
Timing is everything when it comes to the development of the vertebrate face. In a new study published in PLoS Genetics, USC Stem Cell researcher Lindsey Barske from the laboratory of Gage Crump and her colleagues identify the roles of key molecular signals that control this critical timing.

Previous work from the Crump and other labs demonstrated that two types of molecular signals, called Jagged-Notch and Endothelin1 (Edn1), are critical for shaping the face. Loss of these signals results in facial deformities in both zebrafish and humans, revealing these as essential for patterning the faces of all vertebrates.


Using sophisticated genetic, genomic and imaging tools to study zebrafish, the researchers discovered that Jagged-Notch and Edn1 work in tandem to control where and when stem cells turn into facial cartilage. In the lower face, Edn1 signals accelerate cartilage formation early in development. In the upper face, Jagged-Notch signals prevent stem cells from making cartilage until later in development. The authors found that these differences in the timing of stem cells turning into cartilage play a major role in making the upper and lower regions of the face distinct from one another.


“We’ve shown that the earliest blueprint of the facial skeleton is set up by spatially intersecting signals that control when stem cells turn into cartilage or bone. Logically, therefore, small shifts in the levels of these signals throughout evolution could account for much of the diversity of shapes we see within the skulls of different animals, as well as the wonderful array of facial shapes seen in humans,” said Barske, lead author and A.P. Giannini postdoctoral research fellow.


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Researchers identify key factor for reprogramming adult cells into stem cells

  |   Stem Cells   |   No comment

Provided by Houston Methodist.

In a new Cell Reports paper, a team led by John P. Cooke, M.D., Ph.D., of the Houston Methodist Research Institute, has identified and characterized a biological factor critical to the transformation of adult somatic cells (cells that are not sperm or egg cells) into stem cells.

“Think about the cartoon Transformers, where trucks and cars change into robots. We’re manipulating genes in the cell nucleus to produce specific proteins, changing the normal recipe for growth and maturation, and transforming adult cells into a new type of cell with the ability to morph into any other cell type,” said Cooke, senior author and chair of the Department of Cardiovascular Sciences.


Called induced pluripotent stem cells (iPSCs), these cells can be differentiated into any somatic cell type, making them a potentially valuable weapon against numerous diseases. Cooke and his colleagues discovered that reactive oxygen species (ROS, also known as oxygen-derived free radicals), play a critical role in nuclear reprogramming. Using a variety of methods to induce somatic cells to become iPSCs, the researchers first found that in the early stages of reprogramming, the transformation was consistently accompanied by an increase in ROS generation.


“When we used genetic tools to knock out the enzymes controlling ROS generation, or we tied up any generated ROS with antioxidants, we observed a marked reduction in iPSC colony formation,” said Cooke. “Conversely, the overproduction of ROS impaired stem cell formation, meaning that optimal iPSC production occurs within a ‘Goldilock’s zone’ of free radical generation–too little or too much and reprogramming shuts down.”


Finally, the researchers discovered that ROS generation subsided as the iPSCs matured, and these mature stem cell colonies survive best in a cellular environment with low levels of ROS. This work is an extension of a 2012 paper in the journal Cell, where Cooke showed that the viruses used to deliver the reprogramming genes were more than just vehicles.


“What we learned is that the viral vectors played a role in reprogramming. Their activation of innate immune signaling caused epigenetic changes that were absolutely necessary for the transformation of somatic cells into iPSCs,” explained Cooke, who holds the Joseph C. “Rusty” Walter and Carole Walter Looke Presidential Distinguished Chair in Cardiovascular Disease Research.


Innate immune signaling is known to stimulate ROS production, which participates in cell defense. Cooke said the team is developing methods to manipulate innate immune signaling of ROS to maximize the production of iPSCs and better direct their differentiation.


A better understand of the mechanism by which somatic cells are reprogrammed into pluripotent cells is critical to ongoing work to understand and to treat disease. For example, one can take skin cells come from people with Alzheimer’s, revert them to iPSCs, and then differentiate them to neurons so that scientists can study that individual’s brain cells. Thus, iPSCs are useful in understanding different disease processes and might also be used to develop regenerative therapies.


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Platelet production on large scale steps closer with new stem cell method

  |   Stem Cells   |   No comment

Researchers have taken a significant step toward the mass production of platelets for transfusion. They have found a way to create platelet-producing cells from stem cells faster and more efficiently than before.


The study is a major step forward toward the goal to make transfusion blood cells in the laboratory instead of relying solely on donation.


Platelets are small, colorless cell fragments whose main function is to interact with clotting proteins to stop or prevent bleeding by forming clots. They are produced in bone marrow by precursor cells called megakaryocytes.


The researchers, including a team from the British National Health Service (NHS) and the University of Cambridge in the UK, describe their new method of creating megakaryocytes from stem cells in a paper published in Nature Communications.


Senior author Cedric Ghevaert, senior lecturer in transfusion medicine and consultant hematologist at NHS Blood and Transplant at Cambridge, says:


“Making megakaryocytes and platelets from stem cells for transfusion has been a long-standing challenge because of the sheer numbers we need to produce to make a single unit for transfusion.”


He adds that their study represents “a major step forward towards our goal to one day make blood cells in the laboratory to transfuse to patients.”


When patients receive blood, they are given either whole blood or specific components, depending on the condition they are being treated for.


Up to four components can be derived from donated blood: red cells, white cells, plasma and platelets. Each component serves a different medical need, allowing several patients to benefit from a single unit of donation.


Platelet transfusions are given to patients with life-threatening bleeding due to injury or surgery. They may also be given to patients having treatments for cancer or leukemia, or with blood disorders where they cannot make enough platelets of their own.


Study ‘paves way for manufacturing platelets for transfusion’


In their paper, the researchers describe a new way of chemically reprogramming human pluripotent stem cells (hPSCs) – called “forward programming” – so that they become megakaryocytes (MKs) a lot faster and more efficiently than previous methods. The researchers note:


“Critically, the forward programmed MKs (fopMKs) matured into platelet-producing cells that could be cryopreserved, maintained and amplified in vitro for over 90 days showing an average yield of 200,000 MKs per input hPSC.”


The chemical “switches” they used to reprogram the hPSCs use three “transcription” factors: GATA1, FLI1 and TAL1. Transcription factors are proteins that help to regulate gene expression.


Previously, attempts to make mature megakaryocytes from hPSCs have used a more laborious approach called “directed differentiation,” which takes longer and yields fewer stable, mature megakaryocytes per hPSC.


The researchers note that they now need to improve the laboratory culture systems to enable the next step – production of platelets from the megakaryocytes.


Dr. Ghevaert and his team are already developing bioreactors that show promise for scaling up platelet production.


Mass production of platelets in the laboratory could overcome not only the difficulties of supply but also lead to a more advanced product that would suit patients of all blood types, carry no risk of infection and could be more effective than platelets recovered from blood.


Dr. Edwin Massey, Associate Medical Director for Diagnostic and Therapeutic Services at NHS Blood and Transplant, says that the study paves the way for manufacturing platelets for transfusion, but adds:


“It will, however, be many years before a process for the large-scale production of platelets is developed.”


NHS Blood and Transplant note that around 60% of platelets go to help treat people with cancer, and expect demand to rise as the population ages.


Platelet transfusions are often needed to supplement cancer treatment because the chemotherapy – as well as the disease itself – can damage bone marrow, thereby reducing platelets and increasing the risk of bleeding.


Last year, Medical News Today learned how coating drugs in the membranes of platelets could make them more effective against cancer.


Written by Catharine Paddock PhD

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Growing skin in the lab

  |   Stem Cells   |   No comment

Using reprogrammed induced pluripotent stem cells (iPSCs), a group of scientists in Japan has successfully grown complex skin tissue—complete with hair follicles and sebaceous glands—in the laboratory. They were then able to implant these three-dimensional tissues into living mice, and the tissues formed proper connections with other organ systems such as nerves and muscle fibers.


This work opens a path to creating functional skin transplants for burn and other patients who require new skin.


Research into bioengineered tissues has led to important achievements in recent years, with a number of different tissue types being created, but there are still obstacles to be overcome. In the area of skin tissue, epithelial cells have been successfully grown into implantable sheets, but they did not have the proper appendages—the oil secreting and sweat glands—that would allow them to function as normal tissue.


To perform the work, published in Science Advances, the team of researchers from RIKEN Center for Developmental Biology (CDB), Tokyo University of Science and other Japanese institutions took cells from mouse gums and used chemicals to transform them into stem cell-like iPSCs. In culture, the cells properly developed into what is called an embryoid body (EB) — a three-dimensional clump of cells that partially resembles the developing embryo in an actual body. The researchers created EBs from iPSCs using Wnt10b signaling and then implanted multiple EBs into immune-deficient mice, where they gradually changed into differentiated tissue, following the pattern of an actual embryo.


Once the tissue had differentiated, the scientists transplanted them out of those mice and into the skin tissue of other mice, where the tissues developed normally as integumentary tissue — the tissue between the outer and inner skin that is responsible for much of the function of the skin in terms of hair shaft eruption and fat excretion. Critically, they also found that the implanted tissues made normal connections with the surrounding nerve and muscle tissues, allowing it to function normally.


One important key to the development was that treatment with the signaling molecule Wnt10b resulted in a larger number of hair follicles, making the bioengineered tissue closer to natural tissue.


Takashi Tsuji, Ph.D., head of the CDB’s Laboratory for Organ Regeneration, led the study. “Up until now,” he said, “artificial skin development has been hampered by the fact that the skin lacked the important organs, such as hair follicles and exocrine glands, which allow the skin to play its important role in regulation. With this new technique, we have successfully grown skin that replicates the function of normal tissue.


“We are coming ever closer to the dream of being able to recreate actual organs in the lab for transplantation, and also believe that tissue grown through this method could be used as an alternative to animal testing of chemicals.”


Learn more:
DOI: 10.1126/sciadv.1500887

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Stem cell anticancer drug clinical trials begin

  |   Stem Cells and Cancer   |   No comment

Clinical trials have begun to test a stem cell drug with the potential to significantly increase the lifespan and survival rates of cancer patients, its manufacturer says.


The trial of BNC101, a metastatic colorectal cancer drug produced by South Australian biopharmaceutical company Bionomics, will take place at specialist centers across Australia. Up to 60 patients will be enrolled in the 15-month trial, designed to test the safety and efficacy of the drug.


“We’ve got data that shows BNC101 could potentially be used in other cancers like pancreatic cancer, breast cancer and lung cancer so we do believe there is broad applicability,” said Deborah Rathjen, Bionomics chief executive officer and managing director Deborah Rathjen, Ph.D.


BNC101 is a highly specific monoclonal antibody to LGR5 that targets cancer stem cells by blocking key stem cell survival signals downstream of LGR5. The clinical strategy is to use BNC101 in combination with standard-of-care chemotherapy to inhibit cancer stem cell activity and/or directly eliminate cancer stem cells.


As a result, BNC101 is proposed to significantly increase the duration of response and survival compared to current standard-of-care therapies for colorectal cancer.


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Stem cells used to successfully regenerate damage in corticospinal injury

  |   Stem Cells, Uncategorized   |   No comment

For first time, researchers show functional benefit in animal model of key motor control system

Date: March 28, 2016
Source: University of California – San Diego
Summary: Researchers have successfully directed stem cell-derived neurons to regenerate lost tissue in damaged corticospinal tracts of rats, resulting in functional benefit, a new article reports.

Writing in the March 28, 2016 issue of Nature Medicine, researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System, with colleagues in Japan and Wisconsin, report that they have successfully directed stem cell-derived neurons to regenerate lost tissue in damaged corticospinal tracts of rats, resulting in functional benefit.

“The corticospinal projection is the most important motor system in humans,” said senior study author Mark Tuszynski, MD, PhD, professor in the UC San Diego School of Medicine Department of Neurosciences and director of the UC San Diego Translational Neuroscience Institute. “It has not been successfully regenerated before. Many have tried, many have failed — including us, in previous efforts.”


“The new thing here was that we used neural stem cells for the first time to determine whether they, unlike any other cell type tested, would support regeneration. And to our surprise, they did.”


Specifically, the researchers grafted multipotent neural progenitor cells into sites of spinal cord injury in rats. The stem cells were directed to specifically develop as a spinal cord, and they did so robustly, forming functional synapses that improved forelimb movements in the rats. The feat upends an existing belief that corticospinal neurons lacked internal mechanisms needed for regeneration.


Previous studies have reported functional recovery in rats following various therapies for spinal cord injury, but none had involved regeneration of corticospinal axons. In humans, the corticospinal tract extends from the cerebral cortex in the upper brain down into the spinal cord.

“We humans use corticospinal axons for voluntary movement,” said Tuszynski. “In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.”


Nonetheless, the road to testing and treatment in people remains long and uncertain.


“There is more work to do prior to moving to humans,” Tuszynski said. We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”

Story Source:

The above post is reprinted from materials provided by University of California – San Diego. The original item was written by Scott LaFee. Note: Materials may be edited for content and length.

Journal Reference:

  1. Ken Kadoya, Paul Lu, Kenny Nguyen, Corinne Lee-Kubli, Hiromi Kumamaru, Lin Yao, Joshua Knackert, Gunnar Poplawski, Jennifer N Dulin, Hans Strobl, Yoshio Takashima, Jeremy Biane, James Conner, Su-Chun Zhang, Mark H Tuszynski. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regenerationNature Medicine, 2016; DOI: 10.1038/nm.4066

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