DAVID GRANOVSKY

TZAP! GOES THE TELOMERE FUSE

In STEM CELLS IN THE NEWS on January 21, 2017 at 9:44 am

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EVERY TIME A CELL DIVIDES, A TELOMERE LOSES IT’S WINGS

  • The length of a telomere controls cell age.
  • Each time a cell splits, the telomere gets smaller.
  • Too long and cancer risk increases.
  • Too short and no more cell division.

Scripps Research Institute discovered the TZAP that controls telomere length.  “TZAP: a Telomere-Associated Protein involved in telomere length control”

Master regulator of cellular aging discovered

Date: January 12, 2017 – Source: Scripps Research Institute – Summary: Scientists have discovered a protein that fine-tunes the cellular clock involved in aging.
Cell culture under microscope (stock image).
Credit: © sinitar / Fotolia
 Scientists at The Scripps Research Institute (TSRI) have discovered a protein that fine-tunes the cellular clock involved in aging.

This novel protein, named TZAP, binds the ends of chromosomes and determines how long telomeres, the segments of DNA that protect chromosome ends, can be. Understanding telomere length is crucial because telomeres set the lifespan of cells in the body, dictating critical processes such as aging and the incidence of cancer.

“Telomeres represent the clock of a cell,” said TSRI Associate Professor Eros Lazzerini Denchi, corresponding author of the new study, published online today in the journal Science. “You are born with telomeres of a certain length, and every time a cell divides, it loses a little bit of the telomere. Once the telomere is too short, the cell cannot divide anymore.”

Naturally, researchers are curious whether lengthening telomeres could slow aging, and many scientists have looked into using a specialized enzyme called telomerase to “fine-tune” the biological clock. One drawback they’ve discovered is that unnaturally long telomeres are a risk factor in developing cancer.

“This cellular clock needs to be finely tuned to allow sufficient cell divisions to develop differentiated tissues and maintain renewable tissues in our body and, at the same time, to limit the proliferation of cancerous cells,” said Lazzerini Denchi.

In this new study, the researcher found that TZAP controls a process called telomere trimming, ensuring that telomeres do not become too long.

“This protein sets the upper limit of telomere length,” explained Lazzerini Denchi. “This allows cells to proliferate — but not too much.”

For the last few decades, the only proteins known to specifically bind telomeres is the telomerase enzyme and a protein complex known as the Shelterin complex. The discovery TZAP, which binds specifically to telomeres, was a surprise since many scientists in the field believed there were no additional proteins binding to telomeres.

“There is a protein complex that was found to localize specifically at chromosome ends, but since its discovery, no protein has been shown to specifically localize to telomeres,” said study first author Julia Su Zhou Li, a graduate student in the Lazzerini Denchi lab.

“This study opens up a lot of new and exciting questions,” said Lazzerini Denchi.

In addition to Lazzerini Denchi and Li, authors of the study, “TZAP: a telomere-associated protein involved in telomere length control,” were Tatevik Simavorian, Cristina Bartocci and Jill Tsai of TSRI; Javier Miralles Fuste of the Salk Institute for Biological Studies and the University of Gothenburg; and Jan Karlseder of the Salk Institute for Biological Studies.

The study was supported by the American Cancer Society (grant RSG-14-186-01), the Swedish Research Council International (grant D0730801) and the National Institutes of Health (grant R01GM087476 and R01CA174942).


Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.


Journal Reference:

  1. Julia Su Zhou Li, Javier Miralles Fuste, Tatevik Simavorian, Cristina Bartocci, Jill Tsai, Jan Karlseder, Eros Lazzerini Denchi. TZAP: A telomere-associated protein involved in telomere length control. Science, 2017; DOI: 10.1126/science.aah6752

MOSES, STEM CELL PATHWAYS AND MAYBE METASTATIC CANCERS

In ALL ARTICLES, DISEASE INFO, SCIENCE & STEM CELLS, STEM CELLS IN THE NEWS on January 20, 2017 at 9:32 am

When white blood cells leave a vessel through the vessel wall, they contort their shape to pass through.  But when stem cells exit a blood vessel, they don’t change their shape.  They just pass on through the wall and the endothelial cells lining the vessel do the work by stretching around them and then actively expelling them.   In other words, the stem cells are the Moses to the parting of the cells of the blood vessels:
“…when we looked at therapeutic stem cells… the endothelial cells not only changed their shape in order to surround the stem cell, they actually pushed the stem cells out of the blood vessel. We’ve named this process angiopellosis, and it represents an alternative way for cells to leave blood vessels.”  Which begs the question…is this how cancer cells move around too?

Stem Cell Finding May Improve Understanding of Metastatic Cancers

  • A stem cell exits the bloodstream through angiopellosis. [Alice MacGregor Harvey, North Carolina State University]

  • Researchers at North Carolina State University have discovered that therapeutic stem cells exit the bloodstream in a different manner than was previously thought. This process, called angiopellosis by the researchers, has implications for improving our understanding of not only intravenous stem cell therapies, but also metastatic cancers.

    When white blood cells need to get to the site of an infection, they can exit the bloodstream via a process known as diapedesis. In diapedesis, the white blood cell changes its shape to squeeze between or through the epithelial cells that form the walls of the blood vessel. Diapedesis is a well-understood process, and researchers believed that other types of cells, like therapeutic stem cells or even metastatic cancer cells, exited blood vessels in a similar way, with the cells pushing or squeezing themselves out.

    But a group of researchers led by Ke Cheng, Ph.D., associate professor of molecular biomedical sciences at NC State with a joint appointment in the NC State/University of North Carolina (UNC)-Chapel Hill Department of Biomedical Engineering, found that these stem cells behaved differently. Their study (“Angiopellosis as an Alternative Mechanism of Cell Extravasation”) appears online in Stem Cells.

    Therapeutic stem cells share the same ability to exit the bloodstream and target particular tissues that white blood cells do. But the precise way that they did so was not well understood, so Dr. Cheng and his team used a zebrafish model to study the process. The genetically modified zebrafish embryos were transparent and had fluorescently marked green blood vessels. Researchers injected the embryos with white blood cells and cardiac stem cells from humans, rats, and dogs. These cells had all been marked with a red fluorescent protein.

    Through time-lapse, three-dimensional, light sheet microscopic imaging, Dr. Cheng and his team could trace the progress of these cells as they left the blood vessel. The white blood cells exited via diapedesis, as expected. When stem cells exited the blood vessel, however, the endothelial cells lining the vessel actively expelled them. Membranes surrounding the endothelial cells on either side of the stem cell stretched themselves around the stem cell, then met in the middle to push the stem cell out of the vessel.

    “When you’re talking about diapedesis, the white blood cell is active because it changes its shape in order to exit. The endothelial cells in the blood vessel are passive,” Dr. Cheng says. “But when we looked at therapeutic stem cells, we found the opposite was true—the stem cells were passive—and the endothelial cells not only changed their shape in order to surround the stem cell, they actually pushed the stem cells out of the blood vessel. We’ve named this process angiopellosis, and it represents an alternative way for cells to leave blood vessels.”

    The researchers found two other key differences between angiopellosis and diapedesis: one, that angiopellosis takes hours, rather than minutes, to occur and two, that angiopellosis allows more than one cell to exit at a time.

    “Angiopellosis is really a group ticket for cells to get out of blood vessels,” notes Dr. Cheng. “We observed clusters of cells passing through in this way. Obviously, this leads us to questions about whether other types of cells, like metastatic cancer cells, may be using this more effective way to exit the bloodstream, and what we may need to do to stop them.”

 

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STEM CELL ‘LIVING BANDAGE’ FOR KNEE INJURIES

In SCIENCE & STEM CELLS, STEM CELLS IN THE NEWS, ALL ARTICLES on January 19, 2017 at 4:31 pm

Can we regrow a meniscus with stem cells?  Yes, of course.

  1. stem cells are harvested from the patient’s bone marrow
  2. cells are grown for 2 weeks
  3. cells are seeded onto a membrane scaffold
  4. the manufactured cell bandage is surgically implanted into the tear
  5. the cartilage is sewn up around the bandage to keep it in place

    All five patients had an intact meniscus 12 months post implantation

Stem cell ‘living bandage’ for knee injuries trialled in humans

December 16, 2016
Stem cell ‘living bandage’ for knee injuries trialled in humans
Credit: University of Bristol

A ‘living bandage’ made from stem cells, which could revolutionise the treatment and prognosis of a common sporting knee injury, has been trialled in humans for the first time by scientists at the Universities of Liverpool and Bristol.

Meniscal tears are suffered by over one million people a year in the US and Europe alone and are particularly common in contact sports like football and rugby. 90 per cent or more of tears occur in the white zone of meniscus which lacks a blood supply, making them difficult to repair. Many professional sports players opt to have the torn tissue removed altogether, risking osteoarthritis in later life.

The cell bandage has been developed by Bristol University spin-out company Azellon, and is designed to enable the meniscal tear to repair itself by encouraging cell growth in the affected tissue.

A prototype version of the cell bandage was trialled in five patients, aged between 18 and 45, with white-zone meniscal tears. The trial received funding support from Innovate UK and the promising results have been published today in the journal Stem Cells Translational Medicine.

The procedure involved taking , harvested from the patient’s own bone marrow, which were then grown for two weeks before being seeded onto a membrane scaffold that helps to deliver the cells into the injured site. The manufactured cell bandage was then surgically implanted into the middle of the tear and the cartilage was sewn up around the bandage to keep it in place.

All five patients had an intact meniscus 12 months post implantation. By 24 months, three of the five patients retained an intact meniscus and had returned to normal knee functionality whilst the other two patients required surgical removal of the damaged meniscus due to a new tear or return of symptoms.

Professor Anthony Hollander, formerly of Bristol and now Chair of Stem Cell Biology at the University of Liverpool and Founder and Chief Scientific Officer of Azellon, said: “The cell bandage trial results are very encouraging and offer a potential alternative to surgical removal that will repair the damaged tissue and restore full knee function.

“We are currently developing an enhanced version of the cell bandage using donor stem cells, which will reduce the cost of the procedure and remove the need for two operations.”

The cell bandage was produced by the Advanced Therapies Unit at the NHS Blood & Transplant facility in Speke, Liverpool and implanted into patients at Southmead Hospital in Bristol, under the supervision of Professor Ashley Blom, Head of Orthopaedic Surgery at the University of Bristol.

Professor Blom, from Bristol’s School of Clinical Sciences, commented: “The cell bandage offers an exciting potential new treatment option for surgeons that could particularly benefit younger patients and athletes by reducing the likelihood of early onset osteoarthritis after meniscectomy.”

A spokesperson for Innovate UK said: “Turning into clinical and commercial reality requires close collaboration between businesses, universities, and Hospitals. It’s great to see this inter-disciplinary approach has led to such an exciting outcome from this first-in-human trial.”

Explore further: Pioneering stem cell bandage receives approval for clinical trial

More information: Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study, , DOI: 10.1002/sctm.16-0199, http://onlinelibrary.wiley.com/doi/10.1002/sctm.16-0199/abstract

Read more at: https://medicalxpress.com/news/2016-12-stem-cell-bandage-knee-injuries.html#jCp

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