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Injured bones reconstructed by gene and stem cell therapies – Medical Xpress

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May 17, 2017 This illustration shows the bone-tissue engineering technique developed by Cedars-Sinai investigators. 'Endogenous MSCs' refers to stem cells from a patient's bone. The 'BMP gene' is a gene that promotes bone repair. Credit: Gazit Group/Cedars-Sinai

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, the pioneering method of combining ultrasound, stem cell and gene therapies could eventually replace grafting as a way to mend severely broken bones.

"We are just at the beginning of a revolution in orthopedics," said Dan Gazit, PhD, DMD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "We're combining an engineering approach with a biological approach to advance regenerative engineering, which we believe is the future of medicine."

Gazit was the principal investigator and co-senior author of the research study, published in the journal Science Translational Medicine.

More than 2 million bone grafts, frequently necessitated by severe injuries involving traffic accidents, war or tumor removal, are performed worldwide each year. Such injuries can create gaps between the edges of a fracture that are too large for the bone to bridge on its own. The grafts require implanting pieces from either the patient's or a donor's bone into the gap.

"Unfortunately, bone grafts carry disadvantages," said Gazit, a professor of surgery at Cedars-Sinai. "There are huge unmet needs in skeleton repair."

One problem is that enough healthy bone is not always available for repairs. Surgeries to remove a bone piece, typically from the pelvis, and implant it can lead to prolonged pain and expensive, lengthy hospitalizations. Further, grafts from donors may not integrate or grow properly, causing the repair to fail.

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The new technique developed by the Cedars-Sinai-led team could provide a much-needed alternative to bone grafts.

In their experiment, the investigators constructed a matrix of collagen, a protein the body uses to build bones, and implanted it in the gap between the two sides of a fractured leg bone in laboratory animals. This matrix recruited the fractured leg's own stem cells into the gap over a period of two weeks. To initiate the bone repair process, the team delivered a bone-inducing gene directly into the stem cells, using an ultrasound pulse and microbubbles that facilitated the entry of the gene into the cells.

Eight weeks after the surgery, the bone gap was closed and the leg fracture was healed in all the laboratory animals that received the treatment. Tests showed that the bone grown in the gap was as strong as that produced by surgical bone grafts, said Gadi Pelled, PhD, DMD, assistant professor of surgery at Cedars-Sinai and the study's co-senior author.

"This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal's own stem cells can effectively be used to treat nonhealing bone fractures," Pelled said. "It addresses a major orthopedic unmet need and offers new possibilities for clinical translation."

The study involved six departments at Cedars-Sinai, plus investigators from Hebrew University in Jerusalem; the University of Rochester in Rochester, New York; and the University of California, Davis.

"Our project demonstrates how scientists from diverse disciplines can combine forces to find solutions to today's medical challenges and help develop treatments for the patients of tomorrow," said Bruce Gewertz, MD, surgeon-in-chief and chair of the Department of Surgery at Cedars-Sinai.

Explore further: Combining adult stem cells with hormone may speed bone fracture healing

More information: DOI: 10.1126/scitranslmed.aal3128 "In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs," Science Translational Medicine (2017). http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aal3128

A combination of adult stem cells and parathyroid hormone significantly increased new bone formation in laboratory animals and may speed the healing process for human bone fractures caused by osteoporosis, a new study shows.

Broken bones do not always repair fully, especially after major trauma such as a car accident. Complications can occur when the bone is broken in several places, the blood flow is reduced or infection sets in. Patients can ...

Stem cells could one day be stimulated to make a special type of cartilage to help repair large, hard-to-heal bone fractures a potential boon for doctors treating big-money athletes, USC researchers say.

The prospect of regenerating bone lost to cancer or trauma is a step closer to the clinic as University of Wisconsin-Madison scientists have identified two proteins found in bone marrow as key regulators of the master cells ...

The range of biomimetic approaches to promote bone growth that are at the core of current bone healing therapies need to more closely emulate natural regenerative mechanisms. A review of biomimetic strategies to help heal ...

Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time ...

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, ...

Type 2 diabetes, a prolific killer, is on a steep ascent. According to the World Health Organization, the incidence of the condition has grown dramatically from 108 million cases in 1980 to well over 400 million today. The ...

Researchers at Boston Children's Hospital have, for the first time, generated blood-forming stem cells in the lab using pluripotent stem cells, which can make virtually every cell type in the body. The advance, published ...

Researchers studying the root cause of cystic fibrosis have made a major advance in our understanding of silent gene changes with implications for the complexity of cystic fibrosis. The findings are published today in [16 ...

A study in mice finds that development of age-related macular degeneration (AMD) could be arrested by switching from a high-glycemic diet (starches as are found in white bread) to a low-glycemic (starches found in whole grains). ...

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Injured bones reconstructed by gene and stem cell therapies - Medical Xpress

Cancer therapy may work in unexpected way – Stanford Medical Center Report

By Uncategorized

Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy, said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer, Gordon said.

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, its unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component, Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place, Weissman said. Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.

Other Stanford co-authors of the study are associate professor of pathology Andrew Connolly, MD, PhD; visiting scholar Gregor Hutter, MD, PhD;instructor Rahul Sinha, PhD; postdoctoral scholars Roy Maute, PhD, Daniel Corey, MD, and Melissa McCracken, PhD; graduate students Benjamin Dulken, Benson George and Jonathan Tsai; and former graduate student Aaron Ring, MD, PhD.

The research was supported by the D.K. Ludwig Fund for Cancer Research, the A.P. Giannini Foundation, the Stanford Deans Fellowship, the National Institutes of Health (grant GM07365), the Swiss National Science Foundation and the National Center for Research Resources.

Weissman is a founder of the company Forty Seven Inc., which is sponsoring the clinical trial of the anti-CD47 antibody.

Stanfords departments of Pathology and of Developmental Biology also supported the work.

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Cancer therapy may work in unexpected way - Stanford Medical Center Report

Dr. Kenneth Pettine: Stem cell therapy is here to stay – Becker’s Orthopedic & Spine

By Uncategorized

At the forefront of regenerative medicine, Kenneth Pettine, MD, has participated in three FDA biologic studies. He works with Jeffery Donner, MD, at the Colorado Spine Institute . Dr. Pettine is the founder of the Orthopedic Stem Cell Institute, and is a pioneer in the field, with the only Stem Cell methods patent procedure in the nation.

"I'm convinced your body wants to heal itself," says Dr. Pettine. "The problem in orthopedics and spine is there's a paucity of blood supply to the joints or the disc in your back. If you injure your cartilage or disc, it has very little capacity to heal itself."

The key to regenerative medicine in orthopedics and spine lies in the mesenchymal stem cell, because it has the ability to differentiate into osteoblasts, chondroblasts or fibroblasts.

"This may be the most important stem cell in your body," Dr. Pettine explains. "The MSC is the cell that modulates your immune system through its paracrine ability to release numerous growth factors, cytokines, chemokines and inhibitorsIt's the conductor and your body is the orchestra."

The use of the MSC to treat orthopedic injuries is standard of care in veterinary medicine, with a good amount of Class 1 data proving safety and efficacy. Dr. Pettine believes humans could also potentially benefit from the use of the MSC to treat orthopedic and spine pathology.

Throughout his career, Dr. Pettine has served as principle investigator for 15 FDA IDE studies focused on non-fusion technology.

He helped with the ISTO Technologies FDA phase one study, which was the first biologic study ever conducted in the human spine in the United States. Using juvenile cartilage cells, the study saw significant reduction in patients' back pain and one-year results have been published.

Dr. Pettine also conducted an IRB study similar to the ISTO trial, utilizing autologous bone marrow concentrated cells to treat discogenic low back pain in 26 patients. This treatment has no FDA issues, as autologous bone marrow concentrated (BMC) cell therapy falls under "the practice of medicine" by the FDA under Section 361 of the Public Health Service Act's provisions.

The 30-minute procedure can be performed in an office or ambulatory surgery center with IV sedation or local anesthetic. Dr. Pettine has published one- and two-year results, and plans to publish three-year follow-up results soon.

The one-year results revealed the cell therapy "significantly reduces lumbar discogenic pain," according to Pettine et.al., Stem Cells 2015; 33:146-156. Out of the 26 patients, only six received surgery 36 months post-injection. Dr. Pettine reported a 72 percent average reduction in Oswestry Disability Index scores and 75 percent average decrease in Visual Analog Scales scores at 36 months.

"It seems to be long lasting," says Dr. Pettine. "We only re-injected two of the 26 patients at three-year follow up."

Of 210 patients with cervical degeneration Dr. Pettine has injected with BMC, about 70 percent reported a 65 percent improvement in pain at one year follow up. Any arthritic joint can be injected with BMC.

Although seeing positive results, Dr. Pettine notes this BMC cell therapy is not intended to replace surgery, but rather serve as a treatment for chronic conditions in patients who want an option prior to surgery. He believes this therapy will become more prevalent in the industry within three years to five years.

"I think it's important for surgeons to be more proactive with [stem cell therapy], because I promise this will not go away," cautions Dr. Pettine. "And if surgeons don't get involved in this, it will be taken over by non-surgeons."

More articles on spine: 5 spine surgeons in the headlines Dec. 16, 2016 9 key thoughts on incentives for spine surgeons behavioral economics in healthcare Drs. Richard Kube & Brian Gantwerker on their holiday traditions

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Dr. Kenneth Pettine: Stem cell therapy is here to stay - Becker's Orthopedic & Spine

MS patient reveals he may ‘defer’ assisted suicide to undergo stem cell therapy in Serbia – Herald Scotland

By Stem Cell Treatment

A SCOT with crippling multiple sclerosis who planned to end his life at a Swiss suicide clinic has revealed he is applying to undergo an experimental stem cell treatment abroad in a last ditch attempt to reverse his symptoms and prolong his life.

Colin Campbell, from Inverness, said he would postpone his appointment at the LifeCircle clinic in Basel, where he had expected to end his life on June 15, if he was accepted for the pioneering therapy by medical chain, Swiss Medica. A 12-day course at its facility in Belgrade, Serbia costs around 15-16,000 and floods patients with up to 300 million stem cells which have been shown to restore myelin - a fatty coating around nerve cells destroyed by multiple sclerosis - leading to improved brain function and mobility.

Several clinical trials worldwide are exploring stem cell therapy as a means of "pausing" the degeneration associated with MS, but it cannot cure the condition and the treatment is not available on the NHS or privately in Britain.

Former IT consultant Mr Campbell praised his "very kind" landlord, Robert More, for persuading him to try out the procedure.

Mr Campbell, 56, said: "Robert said 'I don't want you to die - you can go abroad and try this. If it works, great; if it doesn't, it doesn't. There's nothing to lose'. So I would say I've moved into a new territory where I'm a 'deferred' suicide, but not a cancelled suicide.

"I will hopefully get onto the treatment programme, but if not then June 15 goes ahead as planned. So I'm in a limbo situation. I'm still holding on to June 15 because I don't want to knock that back and find that the time passes and I'm thinking 'why didn't I get out when I could?'. I've got no desire to spend another winter in the UK with MS - death would be preferable for me.

"That's the thing about not having [voluntary assisted suicide] in Scotland though. If I could do it here I wouldn't have to be too concerned about a date because it would be available to me whenever I choose, whereas when you have the travel to Switzerland and you've got a progressive illness you probably don't want to plan it too far ahead because you might not be up to the journey."

He added that MS patients were also let down because doctors did not routinely highlight the options for treatment outside the NHS.

He said: It would be nice after a diagnosis if a neurologist would go through your options - if they said look, you cant get this on the NHS at the moment, but you can get this abroad, but they dont even have this discussion with you. You get nothing, and thats the experience I hear from talking to other MS sufferers."MS

Mr Campbell was a keen footballer, swimmer and tennis player before being diagnosed aged 34 with primary progressive MS, a rarer form of the disease which results in a steady deterioration without any periods of remission. He now relies on walking aids to move around his first-floor flat and a wheelchair outdoors.

He revealed his plan to end his life in Switzerland to the Herald's sister paper, the Sunday Herald, in April as part of a campaign calling on MSPs to bring a new Bill on assisted dying to Holyrood. The proposed Bill would bring Scotland into line with Canada and parts of the US and Australia by allowing terminally ill people with less than six months to live the right to be prescribed a lethal dose of medication which they can then self-administer.

Mr More, who has rented a flat to Mr Campbell for three years, said: "He's a decent man and, quite frankly, he was depressed with his condition and all he was getting was tea and sympathy. There's nobody doing anything to really help him. Nobody is giving him options and in those situations there are always options.

"There was a 36-year-old woman that was at this [Swiss Medica] clinic and she went in in a wheelchair and when she came out her only complaint was she got tired after long walks. Stem cell therapy doesn't offer a cure, but it might make his life better and that's what I want for the man."

Mr More said he felt compelled to help after his own experience 32 years ago when his youngest daughter was diagnosed with spina bifida and the family were told she would never walk again.

He said: "If someone tells me that I try to do something about it so I took her to the Peto Institute in Budapest. I took her there for four years running and when she came out she could walk. So just because people tell you it's a death sentence, I don't believe it. She's alive and well - the Hungarians did a magnificent job with her."

Mr Campbell said he had also been boosted after being contacted by a fellow MDS sufferer, Rona Tynan, who encouraged him to test out a mobility scooter after seeing reports about his plans to end his life.

He said: "This has given me some kind of optimism which I definitely didn't have - so I owe that to Rona."

Mrs Tynan said: "What alarmed me about Colin was, I felt he was more able than myself."

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MS patient reveals he may 'defer' assisted suicide to undergo stem cell therapy in Serbia - Herald Scotland

Scientists get closer to making personalized blood cells by using patients’ own stem cells – Los Angeles Times

By Stem Cell Treatment

New research has nudged scientists closer to one of regenerative medicines holy grails: the ability to create customized human stem cells capable of forming blood that would be safe for patients.

Advances reported Wednesday in the journal Nature could not only give scientists a window on what goes wrong in such blood cancers as leukemia, lymphoma and myeloma. They could also improve the treatment of those cancers, which affect some 1.2 million Americans.

The stem cells that give rise to our blood are a mysterious wellspring of life. In principle, just one of these primitive cells can create much of a human beings immune system, not to mention the complex slurry of cells that courses through a persons arteries, veins and organs.

While the use of blood-making stem cells in medicine has been common since the 1950s, it remains pretty crude. After patients with blood cancers have undergone powerful radiation and chemotherapy treatments to kill their cancer cells, they often need a bone-marrow transplant to rebuild their white blood cells, which are destroyed by that treatment.

The blood-making stem cells that reside in a donors bone marrow and in umbilical cord blood that is sometimes harvested after a babys birth are called hematopoietic, and they can be life-saving. But even these stem cells can bear the distinctive immune system signatures of the person from whom they were harvested. As a result, they can provoke an attack if the transplant recipients body registers the cells as foreign.

This response, called graft-versus-host disease, affects as many as 70% of bone-marrow transplant recipients in the months following the treatment, and 40% develop a chronic version of the affliction later. It can overwhelm the benefit of a stem cell transplant. And it kills many patients.

Rather than hunt for a donor whos a perfect match for a patient in need of a transplant a process that can be lengthy, ethically fraught and ultimately unsuccessful doctors would like to use a patients own cells to engineer the hematopoietic stem cells.

The patients mature cells would be reprogrammed to their most primitive form: stem cells capable of becoming virtually any kind of human cell. Then factors in their environment would coax them to become the specific type of stem cells capable of giving rise to blood.

Once reintroduced into the patient, the cells would take up residence without prompting rejection and set up a lifelong factory of healthy new blood cells.

If the risk of deadly rejection episodes could be eliminated, physicians might also feel more confident treating blood diseases that are painful and difficult but not immediately deadly diseases such as sickle cell disease and immunological disorders with stem cell transplants.

The two studies published Wednesday demonstrate that scientists may soon be capable of pulling off the sequence of operations necessary for such treatments to move ahead.

One of two research teams, led by stem-cell pioneer Dr. George Q. Daley of Harvard Medical School and the Dana Farber Cancer Institute in Boston, started their experiment with human pluripotent stem cells primitive cells capable of becoming virtually any type of mature cell in the body. Some of them were embryonic stem cells and others were induced pluripotent stem cells, or iPS cells, which are made by converting mature cells back to a flexible state.

The scientists then programmed those pluripotent stem cells to become endothelial cells, which line the inside of certain blood vessels. Past research had established that those cells are where blood-making stem cells are born.

Here, the process needed a nudge. Using suppositions gleaned from experiments with mice, Daley said his team confected a special sauce of proteins that sit on a cells DNA and program its function. When they incubated the endothelial cells in the sauce, they began producing hematopioetic stem cells in their earliest form.

Daleys team then transferred the resulting blood-making stem cells into the bone marrow of mice to see if they would take. In two out of five mice who got the most promising cell types, they did. Not only did the stem cells establish themselves, they continued to renew themselves while giving rise to a wide range of blood cells.

A second research team, led by researchers from Weill Cornell Medicines Ansary Stem Cell Institute in New York, achieved a similar result using stem cells from the blood-vessel lining of adult mice. After programming those cells to revert to a more primitive form, the scientists also incubated those stem cells in a concoction of specialized proteins.

When the team, led by Raphael Lis and Dr. Shahin Rafii, transferred the resulting stem cells back into the tissue lining the blood vessels of the mice from which they came, that graft also took. For at least 40 weeks after the incubated stem cells were returned to their mouse owners, the stem cells continued to regenerate themselves and give rise to many blood-cell types without provoking immune reactions.

In addition to making a workhorse treatment for blood cancers safer, the new advances may afford scientists a unique window on the mechanisms by which blood diseases take hold and progress, said Lee Greenberger, chief scientific officer for the Leukemia and Lymphoma Society.

From a research point of view you could now actually begin to model diseases, said Greenberger. If you were to take the cell thats defective and make it revert to a stem cell, you could effectively reproduce the disease and watch its progression from the earliest stages.

That, in turn, would make it easier to narrow the search for drugs that could disrupt that disease process early. And it would speed the process of discovering which genes are implicated in causing diseases. With gene-editing techniques such as CRISPR-Cas9, those offending genes could one day be snipped out of hematopoietic stem cells, then be returned to their owners to generate new lines of disease-free blood cells.

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Scientists get closer to making personalized blood cells by using patients' own stem cells - Los Angeles Times

Encouraging results after Jonathan Pitre’s transplant, mother says – CTV News

By Stem Cell Treatment

Nick Wells, CTVNews.ca Published Wednesday, May 17, 2017 7:04AM EDT Last Updated Wednesday, May 17, 2017 12:28PM EDT

An Ottawa-area boy who suffers from a rare and painful blistering skin disease is recovering in a Minneapolis hospital, after undergoing a second potentially life-changing transplant.

Jonathan Pitre, known as the "Butterfly Boy" because of his delicate, blistering skin, received a second transfusion of his mother Tina Boileaus stem cells in April.

In a Facebook post Tuesday, Boileau said the donor study tests are showing that her son is officially growing her cells.

Pitre was born with a severe form of epidermolysis bullosa (EB), an incurable genetic collagen disorder. The condition causes a never-ending series of raw and painful blisters -- some of which hes had for years.

His mother told CTV News on Wednesday that the positive turn in Pitres long and painful treatment was exactly what we needed.

Boileau said her son has had infections on top of infections and endured much pain over the past year. The second stem cell transplant has been really hard on his body, she said, but there now seems to be light at the end of the tunnel.

Yesterday was just the greatest day. We were speechless. Jonathan hugged me and we were like, We did it, she said in an interview from the hospital.

Boileau said that even some of the nurses were crying when Pitre received the good news.

Its finally now feeling like its all been worth it.

However, she pointed out that if Pitre is unable to grow his own cells, he could be diagnosed with Graft vs. Host disease a condition where the donor's cells take over the host's organs and bodily functions, leading to complications.

We still have a long road ahead of us, but you know what, this is definitely what weve been waiting for, Boileau said.

The $1.5-million transplant procedure Pitre is undergoing is currently only performed as a University of Minnesota clinical trial.

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Encouraging results after Jonathan Pitre's transplant, mother says - CTV News

Researchers Are Using Stem Cell Tech to End Neurological Disorders – Futurism

By Stell Cell Research

In Brief

The human body is a melding of different systems designed to function well together. In some cases, however, a mechanism that protects the body can also cause it harm, like with the specializedshield of endothelial cells called the blood-brain barrier that keeps toxins in the blood from entering the brain.

Due to a genetic defect, the blood-brain barrier could prevent essential biomolecules needed for normal brain development from passing through. An example is the Allan-Herndon-Dudley syndrome (AHDS), which is a psychomotor disease resulting from a defective gene that controls the influx of thyroid hormones to the brain. This rare but severe disorder is also unique to humans, making it very difficult to develop treatments that could be lab tested on animals.

So, to study this unique disorder, scientists from the University of Wisconsin-Madison and Cedars-Sinai in Los Angeles used the cells of AHDS patients to recreate the patients blood-brain barriers via induced pluripotent steam (iPS) cellstechnology. What they learned using the model gave the researchers some leads on potential therapies for the disease. They published their study in the journal Cell Stem Cell.

The researchers managed to make a laboratory model for AHDS. This is the first demonstration of using a patients cells to model a blood-brain barrier defect, senior author, Eric Shusta, explained in a press release. If we had just the (compromised) neural cells available, we wouldnt have been able to identify this key characteristic of AHDS.

Thanks so their innovation, theres now a framework to develop new treatmentsthat could prevent or mitigate the debilitating effects of AHDS, according to senior author Clive Svendsen from Cedars-Sinai.

Furthermore, the research could also apply to other neurological disorders that may also have roots in a dysfunctional blood-brain barrier, like Alzheimers disease and Huntingtons disease. The significance of this study expands beyond the limits of AHDS research, to the possibility of stem cell modeling the blood-brain barrier component in many other neurological diseases, said Gad Vatine, lead author for the study, in the press release.

The study is another proof of how stem cells can revolutionize the future of medicine.

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Researchers Are Using Stem Cell Tech to End Neurological Disorders - Futurism

Lab-grown blood stem cells produced at last – Nature.com

By Stell Cell Research

Rio Sugimura

Researchers made these blood stem cells and progenitor cells from human induced pluripotent stem cells.

After 20 years of trying, scientists have transformed mature cells into primordial blood cells that regenerate themselves and the components of blood. The work, described today in Nature1, 2, offers hope to people with leukaemia and other blood disorders who need bone-marrow transplants but cant find a compatible donor. If the findings translate into the clinic, these patients could receive lab-grown versions of their own healthy cells.

One team, led by stem-cell biologist George Daley of Boston Childrens Hospital in Massachusetts, created human cells that act like blood stem cells, although they are not identical to those found in nature1. A second team, led by stem-cell biologist Shahin Rafii of Weill Cornell Medical College in New York City, turned mature cells from mice into fully fledged blood stem cells2.

For many years, people have figured out parts of this recipe, but theyve never quite gotten there, says Mick Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, who was not involved with either study. This is the first time researchers have checked all the boxes and made blood stem cells.

Daleys team chose skin cells and other cells taken from adults as their starting material. Using a standard method, they reprogrammed the cells into induced pluripotent stem (iPS) cells, which are capable of producing many other cell types. Until now, however, iPS cells have not been morphed into cells that create blood.

The next step was the novel one: Daley and his colleagues inserted seven transcription factors genes that control other genes into the genomes of the iPS cells. Then they injected these modified human cells into mice to develop. Twelve weeks later, the iPS cells had transformed into progenitor cells capable of making the range of cells found in human blood, including immune cells. The progenitor cells are tantalizingly close to naturally occurring haemopoetic blood stem cells, says Daley.

Bhatia agrees. Its pretty convincing that George has figured out how to cook up human haemopoetic stem cells, he says. That is the holy grail.

By contrast, Rafiis team generated true blood stem cells from mice without the intermediate step of creating iPS cells. The researchers began by extracting cells from the lining of blood vessels in mature mice. They then inserted four transcription factors into the genomes of these cells, and kept them in Petri dishes designed to mimic the environment inside human blood vessels. There, the cells morphed into blood stem cells and multiplied.

When the researchers injected these stem cells into mice that had been treated with radiation to kill most of their blood and immune cells, the animals recovered. The stem cells regenerated the blood, including immune cells, and the mice went on to live a full life more than 1.5 years in the lab.

Because he bypassed the iPS-cell stage, Rafii compares his approach to a direct aeroplane flight, and Daleys procedure to a flight that takes a detour to the Moon before reaching its final destination. Using the most efficient method to generate stem cells matters, he adds, because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumours if they are implanted into people.

But Daley and other researchers are confident that the method he used can be made more efficient, and less likely to spur tumour growth and other abnormalities in modified cells. One possibility is to temporarily alter gene expression in iPS cells, rather than permanently insert genes that encode transcription factors, says Jeanne Loring, a stem-cell researcher at the Scripps Research Institute in La Jolla, California. She notes that iPS cells can be generated from skin and other tissue that is easy to access, whereas Rafiis method begins with cells that line blood vessels, which are more difficult to gather and to keep alive in the lab.

Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells. A lot of people have become jaded, saying that these cells dont exist in nature and you cant just push them into becoming anything else, Bhatia says. I hoped the critics were wrong, and now I know they were.

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Lab-grown blood stem cells produced at last - Nature.com

Route to cancer stem cell death ironed out – Chemical & Engineering News

By Stell Cell Research

Cancer stem cells are bad actors. They enable cancers to metastasize, or spread, and help revive cancers after the malignancies go dormant. One of the few agents that can effectively attack them is a small molecule called salinomycin. But scientists havent understood how the compound kills the cells.

Now, researchers have discovered salinomycins mechanism (Nat. Chem. 2017, DOI: 10.1038/nchem.2778). The findings reveal a key weakness of cancer stem cells that could lead to the design of other drugs to help fight the cells.

To discover the mechanism, Raphal Rodriguez of Institut Curie and Frances National Center for Scientific Research, Maryam Mehrpour of Institut Necker Enfants Malades and INSERM, and coworkers first tried to create a more potent version of salinomycin by modifying it with groups of varying polarity and charge. The most potent was ironomycin, in which one of salinomycins hydroxyl groups was replaced by a short amine-alkyne chain. Ironomycin has an order of magnitude greater potency than salinomycin at killing breast cancer stem cells, both in culture and in mice.

They then used in vivo click chemistry on ironomycins alkyne group to label the compound with a fluorescent dye, enabling them to track where the compound goes when in cancer stem cells. They had expected it to distribute evenly throughout the cells and were surprised when it instead localized in lysosomes, which are cellular compartments with enzymes that break down certain molecules.

This led them to the mechanism: Salinomycin, or ironomycin, binds cellular iron and sequesters it in lysosomes. The high concentration of lysosomal iron then triggers a process called ferroptosisin which iron catalyzes the so-called Fenton reaction, producing reactive oxygen species that break lysosomal membranes, oxidize cell lipids, and cause cell death. The mechanism is not specific to cancer stem cells, Rodriguez says, but these cells are more susceptible to salinomycins or ironomycins activity because they are more dependent on iron and may be less efficient at scavenging free radicals than conventional cells.

The study is the first to characterize salinomycins mechanism of action at a molecular level, which is in itself a major step forward and an impressive feat, given the structural complexity of this compound, says Piyush Gupta of the Whitehead Institute and MIT, who discovered salinomycins activity against cancer stem cells. It is also the first to convincingly show that iron plays an unusually important role in regulating the malignant properties of cancer stem cells. These are both important contributions that will guide the development of new therapies targeting the most malignant of cancer cells.

Selective mechanisms for killing cancer stem cells have been a long-standing goal of cancer drug discovery, but few mechanisms have been identified, says Brent R. Stockwell of Columbia University, who discovered ferroptosis. This paper suggests that iron sequestration in lysosomes could be one such effective mechanism for targeting cancer stem cells.

One possible drawback to a cancer-stem-cell-targeting compound is that other cells in the tumor might still survive, he adds. So you would likely need a combination of drugs targeting cancer stem cells and non-stem-cell tumor cells. And there might be toxicity to normal stem cells, so this would need to be evaluated as research on stem-cell-targeted agents progresses.

Read the rest here:
Route to cancer stem cell death ironed out - Chemical & Engineering News

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