A year after the London Patient was introduced to the world as only the second person to be cured of H.I.V., he is stepping out of the shadows to reveal his identity: He is Adam Castillejo.

Six feet tall and sturdy, with long, dark hair and an easy smile, Mr. Castillejo, 40, exudes good health and cheer. But his journey to the cure has been arduous and agonizing, involving nearly a decade of grueling treatments and moments of pure despair. He wrestled with whether and when to go public, given the attention and scrutiny that might follow. Ultimately, he said, he realized that his story carried a powerful message of optimism.

This is a unique position to be in, a unique and very humbling position, he said. I want to be an ambassador of hope.

Last March, scientists announced that Mr. Castillejo, then identified only as the London Patient, had been cured of H.I.V. after receiving a bone-marrow transplant for his lymphoma. The donor carried a mutation that impeded the ability of H.I.V. to enter cells, so the transplant essentially replaced Mr. Castillejos immune system with one resistant to the virus. The approach, though effective in his case, was intended to cure his cancer and is not a practical option for the widespread curing of H.I.V. because of the risks involved.

Only one other individual with H.I.V. Timothy Ray Brown, the so-called Berlin Patient, in 2008 has been successfully cured, and there have been many failed attempts. In fact, Mr. Castillejos doctors could not be sure last spring that he was truly rid of H.I.V., and they tiptoed around the word cure, instead referring to it as a remission.

Still, the news grabbed the worlds attention, even that of President Trump.

And by confirming that a cure is possible, it galvanized researchers.

Its really important that it wasnt a one-off, it wasnt a fluke, said Richard Jefferys, a director at Treatment Action Group, an advocacy organization. Thats been an important step for the field.

For Mr. Castillejo, the experience was surreal. He watched as millions of people reacted to the news of his cure and speculated about his identity. I was watching TV, and its, like, OK, theyre talking about me, he said. It was very strange, a very weird place to be. But he remained resolute in his decision to remain private until a few weeks ago.

For one, his doctors are more certain now that he is virus-free. We think this is a cure now, because its been another year and weve done a few more tests, said his virologist, Dr. Ravindra Gupta of the University of Cambridge.

Mr. Castillejo also tested his own readiness in small ways. He set up a separate email address and telephone number for his life as LP, as he refers to himself, and opened a Twitter account. He began talking weekly with Mr. Brown, the only other person who could truly understand what he had been through. In December, Mr. Castillejo prepared a statement to be read aloud by a producer on BBC Radio 4.

After talking through his decision with his doctors, friends and mother, he decided the time was right to tell his story.

I dont want people to think, Oh, youve been chosen, he said. No, it just happened. I was in the right place, probably at the right time, when it happened.

Mr. Castillejo grew up in Caracas, Venezuela. His father was of Spanish and Dutch descent which later turned out to be crucial and served as a pilot for an ecotourism company. Mr. Castillejo speaks reverently of his father, who died 20 years ago, and bears a strong resemblance to him. But his parents divorced when he was young, so he was primarily raised by his industrious mother, who now lives in London with him. She taught me to be the best I could be, no matter what, he said.

As a young man, Mr. Castillejo made his way first to Copenhagen and then to London in 2002. He was found to have H.I.V., the virus that causes AIDS, in 2003.

I do recall when the person told me and the panic set in, he said. At the time, an H.I.V. diagnosis was often seen as a death sentence, and Mr. Castillejo was only 23. It was a very terrifying and traumatic experience to go through.

With the support of his partner at the time, Mr. Castillejo persevered. He turned the passion for cooking he had inherited from his grandmother into a job as a sous chef at a fashionable fusion restaurant. He adopted an unfailingly healthy lifestyle: He ate well, exercised often, went cycling, running and swimming.

Then, in 2011, came the second blow. Mr. Castillejo was in New York City, visiting friends and brunching on the Upper East Side, when a nurse from the clinic where he went for regular checkups called him. Where are you? she asked. When Mr. Castillejo told her, she would say only that they had some concerns about his health and that he should come in for more tests when he returned to London.

He had been experiencing fevers, and the tests showed that they were the result of a Stage 4 lymphoma. I will never forget my reaction as once again my world changed forever, he said. Once again, another death sentence.

Years of harsh chemotherapy followed. Mr. Castillejos H.I.V. status complicated matters. Each time his oncologists adjusted his cancer treatment, the infectious-disease doctors had to recalibrate his H.I.V. medications, said Dr. Simon Edwards, who acted as a liaison between the two teams.

There is little information about how to treat people with both diseases, and H.I.V.-positive people are not allowed to enter clinical trials. So with each new chemotherapy combination, Mr. Castillejos doctors were venturing further into unchartered territory, Dr. Edwards said.

With each treatment that seemed to work and then didnt, Mr. Castillejo fell into a deeper low. He saw fellow patients at the clinic die and others get better, while he kept returning, his body weakening with each round.

I was struggling mentally, he said. I try to look at the bright side, but the brightness was fading.

In late 2014, the extreme physical and emotional toll of the past few years caught up to Mr. Castillejo, and two weeks before that Christmas he disappeared. His friends and family imagined the worst, and filed a missing persons report. Mr. Castillejo turned up four days later outside London, with no memory of how he had ended up there or what he had done in the interim. He described it as switching off from his life.

Around that same time, he said, he felt so defeated that he also contemplated going to Dignitas, the Swiss company that helps terminally ill people take their own lives: I felt powerless. I needed control, to end my life on my own terms. He made it through that dark period, and emerged with a determination to spend whatever was left of his life fighting.

Still, in the spring of 2015, his doctors told him he would not live to see Christmas. A bone-marrow transplant from a donor is sometimes offered to people with lymphoma who have exhausted their other options, but Mr. Castillejos doctors did not have the expertise to try that, especially for someone with H.I.V.

His close friend, Peter, was not ready to give up, and together they searched online for alternatives. (Peter declined to reveal his last name because of privacy concerns.) They discovered that at a hospital in London was Dr. Ian Gabriel, an expert in bone-marrow transplants for treating cancer, including in people with H.I.V. Because of their last-ditch effort, Mr. Castillejo said, Were here today. You never, never know.

Within a week, he met with Dr. Gabriel, who tried a third and final time to tap Mr. Castillejos own stem cells for a transplant. When that failed, Dr. Gabriel explained that Mr. Castillejos Latin background might complicate the search for a bone-marrow donor who matched the genetic profile of his immune system. To everyones surprise, however, Mr. Castillejo quickly matched with several donors, including a German one perhaps a legacy from his half-Dutch father who carried a crucial mutation called delta 32 that hinders H.I.V. infection. A transplant from this donor offered the tantalizing possibility of curing both Mr. Castillejos cancer and the H.I.V.

When Dr. Gabriel called with the news in the fall of 2015, Mr. Castillejo was on the top deck of one of Londons iconic red buses, on his way to see his general practitioner for a checkup. His thoughts raced alongside the scenery: He had only recently been told he was going to die, and now he was being told he might be cured of both cancer and H.I.V.

I was trying to digest what just happened, he recalled. But after that call, I had a big smile on my face. Thats where the journey began as LP.

With the possibility of an H.I.V. cure, the case immediately took on intense importance for everyone involved. Dr. Edwards, who had cared for Mr. Castillejo since 2012, had, as a young doctor in the early 1990s, seen many men his age die of H.I.V. What a privilege it would be to go from no therapy to a complete cure in my lifetime, he recalled telling Mr. Castillejo. So you have to get better no pressure.

Dr. Edwards involved Dr. Gupta, his former colleague and one of the few virologists in London he knew to be doing H.I.V. research. Dr. Gupta initially was skeptical; the approach had worked only once, 12 years earlier, with Mr. Brown. But Dr. Gupta also knew that the payoff could be huge. Antiretroviral drugs can suppress the virus to undetectable levels, but any interruption in the treatment can bring the virus roaring back, so a cure for H.I.V. is still the ultimate goal.

Dr. Gupta began carefully monitoring Mr. Castillejos H.I.V. status. In late 2015, Mr. Castillejo was preparing to receive the transplant when another major setback arose. His viral load shot back up with H.I.V. that appeared to be resistant to the drugs he had been taking.

This gave Dr. Gupta a rare glimpse at the typically suppressed virus, and allowed him to confirm that the viral strain was one that would be cleared by the transplant. But it also delayed the transplant by several months while the doctors adjusted Mr. Castillejos medications. He eventually received the transplant on May 13, 2016.

The next year was punishing. Mr. Castillejo spent months in the hospital. He lost nearly 70 pounds, contracted multiple infections and underwent several more operations. He had some hearing loss and began wearing a hearing aid. His doctors fretted over how to get his H.I.V. pills into his ulcer-filled mouth by crushing and dissolving them, or by feeding them to him through a tube. One of the doctors came to me and said to me, You must be very special, because I have more than 40 doctors and clinicians discussing your medication, Mr. Castillejo recalled.

Even after he left the hospital, the only exercise he initially was allowed to do was walking, so he walked for hours around the trendy Shoreditch neighborhood. He went to the flower market there every Sunday, treated himself to salted beef beigels to celebrate small successes and admired the colorful murals and vintage clothes.

A year on, as he became stronger, he slowly began thinking about forgoing the H.I.V. medications to see if he was rid of the virus. He took his last set of antiretroviral drugs in October 2017. Seventeen months later, in March 2019, Dr. Gupta announced the news of his cure.

Neither he nor Mr. Castillejo was prepared for what came next. Dr. Gupta found himself presenting the single case to a standing-room-only crowd at a conference, and shaking hands afterward with dozens of people. Mr. Castillejo was overwhelmed by the nearly 150 media requests to reveal his identity, and began to see a role he might play in raising awareness of cancer, bone-marrow transplants and H.I.V.

He has enrolled in several studies to help Dr. Gupta and others understand both diseases. So far, his body has shown no evidence of the virus apart from fragments the doctors call fossils and what seems to be a long-term biological memory of having once been infected.

Others in the H.I.V. community are reassured by this news, but expressed concern for Mr. Castillejos privacy and mental health.

It can be very important for people to have these kinds of beacons of hope, Mr. Jefferys, the Treatment Action Group director, said. At the same time, thats a lot of weight for someone to carry.

Mr. Castillejos friends have similar worries. But he is as ready as he will ever be, he said. He sees LP as his work identity and is determined to live his private life to its fullest. Having lost his lustrous dark hair several times over, he has now grown it to shoulder length. He has always enjoyed adventures, and with careful preparation he has begun traveling again, describing himself to fellow travelers only as a cancer survivor. He celebrated his 40th birthday with a trip to Machu Picchu, in Peru.

But in conversations about his status as the second person ever to be cured of H.I.V., Mr. Castillejo still adamantly refers to himself as LP, not Adam. When you call me LP, it calms me down, he said. LP to my name, that is kind of a big step.

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The London Patient, Cured of H.I.V., Reveals His Identity - The New York Times

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The Age Stop Switzerland product line contains a high concentration of anti-aging elements in well-researched and tested combinations. Some of the innovative ingredients used in these products include bio-mimetic peptides, Swiss Snow Algae, Alpine Flower Stem Cells, hyaluronic acid, oxygen fusion, vitamins, and bio-available precious stone extracts.

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Age Stop Switzerland Creates an Exceptional Range of Skincare Products That Can Repair and Rejuvenate Aging Skin - MENAFN.COM

WARSAW (AFP) Submerged in liquid nitrogen vapour at a temperature of minus 175 degrees Celsius, hundreds of thousands of stem cells from all over Europe bide their time in large steel barrels on the outskirts of Warsaw.

Present in blood drawn from the umbilical cord of a newborn baby, stem cells can help cure serious blood-related illnesses like leukaemia and lymphoma, as well as genetic conditions and immune system deficits.

Polish umbilical cord blood bank PBKM/FamiCord became the industrys leader in Europe after Swiss firm Cryo-Save went bankrupt early last year.

It is also the fifth largest in the world, according to its management, after two companies in the United States (US), a Chinese firm and one based in Singapore.

Since the first cord blood transplant was performed in France in 1988, the sector has significantly progressed, fuelling hopes.

Mum-of-two Teresa Przeborowska has firsthand experience.

At five-years-old, her son Michal was diagnosed with lymphoblastic leukaemia and needed a bone marrow transplant, the entrepreneur from northern Poland said.

The most compatible donor was his younger sister, Magdalena.

When she was born, her parents had a bag of her cord blood stored at PBKM.

More than three years later, doctors injected his sisters stem cells into Michals bloodstream. It was not quite enough for Michals needs but nicely supplemented harvested bone marrow.

As a result, Michal, who is nine, is now flourishing, both intellectually and physically, his mum told AFP.

A cord blood transplant has become an alternative to a bone marrow transplant when there is no donor available, with a lower risk of complications.

Stem cells taken from umbilical cord blood are like those taken from bone marrow, capable of producing all blood cells: red cells, platelets and immune system cells.

When used, stem cells are first concentrated, then injected into the patient. Once transfused, they produce new cells of every kind.

At the PBKM laboratory, each container holds up to 10,000 blood bags. Safe and secure, they wait to be used in the future, its Head Krzysztof Machaj, said.

The bank holds around 440,000 samples, not including those from Cryo-Save, he said.

If the need arises, the blood will be ready to use without the whole process of looking for a compatible donor and running blood tests, the biologist told AFP.

For families who have paid an initial nearly EUR600 (USD675) and then an annual EUR120 euros to have the blood taken from their newborns umbilical cords preserved for around 20 years, it is a kind of health insurance promising faster and more effective treatment if illness strikes.

But researchers also warn against unrealistic expectations.

Bone marrow pioneer in Poland Haematologist Wieslaw Jedrzejczak describes promoters of the treatment as sellers of hope, who make promises that are either impossible to realise in the near future or downright impossible to realise at all for biological reasons.

He compares them to makers of beauty products who swear their cream will rejuvenate the client by 20 years.

Various researches is being done on the possibility of using the stem cells to treat other diseases, notably nervous disorders. But the EuroStemCell scientist network warns that the research is not yet conclusive.

There is a list of almost 80 diseases for which stem cells could prove beneficial, US Haematologist Roger Mrowiec, who heads the clinical laboratory of the cord blood programme Vitalant in New Jersey, told AFP.

But given the present state of medicine, they are effective only for around a dozen of them, like leukaemia or cerebral palsy, he said.

Its not true, as its written sometimes, that we can already use them to fight Parkinsons disease or Alzheimers disease or diabetes.

EuroStemCell also cautions against private blood banks that advertise services to parents suggesting they should pay to freeze their childs cord blood in case its needed later in life.

Studies show it is highly unlikely that the cord blood will ever be used for their child, the network said.

It also pointed out that there could be a risk of the childs cells not being useable anyway without reintroducing the same illness.

Some countries, such as Belgium and France, are cautious and ban the storage of cord blood for private purposes. Most European Union (EU) countries however permit it while imposing strict controls.

In the early 2000s, Swiss company Cryo-Save enjoyed rapid growth.

Greeks, Hungarians, Italians, Spaniards and Swiss stored blood from their newborns with the company for 20 years on payment of UER2,500 euros upfront.

When the firm was forced to close in early 2019, clients were left wondering where their stem cells would end up.

Under a kind of back-up agreement, the samples of some 250,000 European families were transferred for storage at PBKM.

The Polish firm, founded in 2002 with PLN2million (around EUR450,000, USD525,000), has also grown quickly.

Present under the FamiCord brand in several countries, PBKM has some 35 per cent of the European market, excluding Cryo-Save assets.

Over the last 15 months, outside investors have contributed EUR63 million to the firm, PBKMs Chief Executive Jakub Baran told AFP.

But the company has not escaped controversy: the Polityka weekly recently published a critical investigative report on several private clinics that offer what was described as expensive treatment involving stem cells held by PBKM.

Read more:
Europe's guardian of stem cells and hopes, real and unrealistic - Borneo Bulletin Online

I think it was around the time I was in high school that I learned that people were using stem cells to repair otherwise diseased organs. Science is crazy, right? But now, I see plant stem cells touted as skin-care ingredients in beauty productsall the timeand immediately my mind goes back to the laboratories. WTF are they actually?

The term stem cells is a generic phrase which refers to a special type of cell in an organism that can develop into many different types of cells, explains cosmetic chemist Perry Romanowski. Embryonic stem cells can be developed into all types of human cells like nerve cells, skin cells, muscle cells, etc. Its important to know that these are human cells that are specific to an individual.

In laymans terms, theyre undifferentiated cells that have not chosen a path as to what cells they are going to be yet, adds Purvisha Patel, MD, board-certified dermatologist and founder of Visha Skincare. More specifically, however, Im looking at plant stem cellswhich are different, but have somewhat similar functions. In plants, these cells live in the meristems of plants, says Dr. Patel. They help and regenerate live plants after they have an injury.

The similarity comes in how the cells act, though. Stem cells have the ability to self renew and self repair, just like human stem cells, says Ginger King, cosmetic chemist. The difference is that the plant ones actually have stronger antioxidant properties than human cells because plants are stationary. They have to protect themselves from the insults of weather.

Thats where the benefits to your skin come into playthese cellular components of plants are packed with antioxidants, which helps your skin to fend off free radicals that might otherwise aim to damage it. Plant stem cell benefits to the skin include anti-aging, antioxidant, and anti-inflammatory properties, says King.

These cellular components of plants are protective, and that translates when you apply one to your face.

But while we use the term stem cell it doesnt necessarily mean theyre alive like in the lab. When in skin-care products, the stem cells are not live, but you get the same benefits of antioxidants, amino acid content, and ability to boost collagen synthesis from these stem cell extracts, says King.

Original studies on plant stem cells on skin came using Swiss apple stem cells, according to Dr. Patel. Stem cell extracts were found to reverse the aging process of cultured fibroblasts, she explains. One of the first specific studies showed a decrease in the appearance of crows feet after extract administration. Other studies have followed, and it seems that the major benefit of plant stem cells is in the repair of the skin. These extracts may be beneficial as an anti-aging agent, especially if mixed with tissue exfoliating agents such as retinol, bakuchiol and alpha-hydroxy acids.

That said, even though experts affirm the skin benefits of plant stem cells, Romanowski says to take it with a grain of salt: In my opinion, stem cells are put into cosmetics because consumers hear the words stem cells and think it must refer to some type of advanced biomedical technology, he says. In reality, theyre just plant extracts, albeit super potent ones in many cases.

To find them on beauty product labels, King says to look for the words cell culture extract. Or the packaging will market it as a main ingredient. Product labels will usually have words stem cell on the product to show that they have the extract in them, says Dr. Patel. Other words such as phyto cells, plant extracts, and fruit extracts may be used on the label as well. Remember as with all skin-care ingredients, not all products are created equal and not all plants show efficacy with their stem cells. Look for brands that have clinical trials and results to back up the claims.

To shop the plant stem cell extracts for your own regimen, Ive rounded up some of the most noteworthy products, below.

Other ingredients to add to your skin-care regimen include some form of retinol, along with a trusty vitamin C serum.

Original post:
The low-down on plant stem cells in skin care | Well+Good

Submerged in liquid nitrogen vapor at a temperature of minus 175 degrees Celsius, hundreds of thousands of stem cells from all over Europe bide their time in large steel barrels on the outskirts of Warsaw.

Present in blood drawn from the umbilical cord of a newborn baby, stem cells can help cure serious blood-related illnesses like leukemias and lymphomas, as well as genetic conditions and immune system deficits.

Polish umbilical cord blood bank PBKM/FamiCord became the industrys leader in Europe after Swiss firm Cryo-Save went bankrupt early last year.

It is also the fifth largest in the world, according to its management, after two companies in the United States, a Chinese firm and one based in Singapore.

Since the first cord blood transplant was performed in France in 1988, the sector has significantly progressed, fuelling hopes.

Health insurance

Mum-of-two Teresa Przeborowska has firsthand experience.

At five years old, her son Michal was diagnosed with lymphoblastic leukemia and needed a bone marrow transplant, the entrepreneur from northern Poland said.

The most compatible donor was his younger sister, Magdalena.

When she was born, her parents had a bag of her cord blood stored at PBKM.

More than three years later, doctors injected his sisters stem cells into Michals bloodstream.

It was not quite enough for Michals needs but nicely supplemented harvested bone marrow.

As a result, Michal, who is nine, is now flourishing, both intellectually and physically, his mum told AFP.

A cord blood transplant has become an alternative to a bone marrow transplant when there is no donor available, with a lower risk of complications.

Stem cells taken from umbilical cord blood are like those taken from bone marrow, capable of producing all blood cells: red cells, platelets and immune system cells.

When used, stem cells are first concentrated, then injected into the patient. Once transfused, they produce new cells of every kind.

At the PBKM laboratory, each container holds up to 10,000 blood bags Safe and secure, they wait to be used in the future, its head, Krzysztof Machaj, said.

The bank holds around 440,000 samples, not including those from Cryo-Save, he said.

If the need arises, the blood will be ready to use without the whole process of looking for a compatible donor and running blood tests, the biologist told AFP.

For families who have paid an initial nearly 600 euros (around P34,000) and then an annual 120 euros (around P7,000) to have the blood taken from their newborns umbilical cords preserved for around 20 years, it is a kind of health insurance promising faster and more effective treatment if illness strikes.

But researchers also warn against unrealistic expectations.

Beauty products

Hematologist Wieslaw Jedrzejczak, a bone marrow pioneer in Poland, describes promoters of the treatment as sellers of hope, who make promises that are either impossible to realize in the near future or downright impossible to realize at all for biological reasons.

He compares them to makers of beauty products who swear their cream will rejuvenate the client by 20 years.

Various research is being done on the possibility of using the stem cells to treat other diseases, notably nervous disorders. But the EuroStemCell scientist network warns that the research is not yet conclusive.

There is a list of almost 80 diseases for which stem cells could prove beneficial, U.S. hematologist Roger Mrowiec, who heads the clinical laboratory of the cord blood program Vitalant in New Jersey, told AFP.

But given the present state of medicine, they are effective only for around a dozen of them, like leukemia or cerebral palsy, he said.

Its not true, as its written sometimes, that we can already use them to fight Parkinsons disease or Alzheimers disease or diabetes.

EuroStemCell also cautions against private blood banks that advertise services to parents suggesting they should pay to freeze their childs cord blood in case its needed later in life.

Studies show it is highly unlikely that the cord blood will ever be used for their child, the network said.

It also pointed out that there could be a risk of the childs cells not being useable anyway without reintroducing the same illness.

Some countries, such as Belgium and France, are cautious and ban the storage of cord blood for private purposes. Most E.U. countries however permit it while imposing strict controls.

Rapid growth

In the early 2000s, Swiss company Cryo-Save enjoyed rapid growth.

Greeks, Hungarians, Italians, Spaniards and Swiss stored blood from their newborns with the company for 20 years on payment of 2,500 euros (around P140,000) upfront.

When the firm was forced to close in early 2019, clients were left wondering where their stem cells would end up.

Under a kind of back-up agreement, the samples of some 250,000 European families were transferred for storage at PBKM.

The Polish firm, founded in 2002 with 2 million zlotys (around P26 million), has also grown quickly.

Present under the FamiCord brand in several countries, PBKM has some 35% of the European market, excluding Cryo-Save assets.

Over the last 15 months, outside investors have contributed 63 million euros to the firm, PBKMs chief executive Jakub Baran told AFP.

But the company has not escaped controversy: the Polityka weekly recently published a critical investigative report on several private clinics that offer what was described as expensive treatment involving stem cells held by PBKM.IB/JB

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View original post here:
Europe's guardian of stem cells and hopes, real and unrealistic - INQUIRER.net

Poland has emerged as Europe's leader in stem cell storage, a billion-dollar global industry that is a key part of a therapy that can treat leukaemias but raises excessive hopes.

Submerged in liquid nitrogen vapour at a temperature of minus 175 degrees Celsius, hundreds of thousands of stem cells from all over Europe bide their time in large steel barrels on the outskirts of Warsaw.

Present in blood drawn from the umbilical cord of a newborn baby, stem cells can help cure serious blood-related illnesses like leukaemias and lymphomas, as well as genetic conditions and immune system deficits.

Polish umbilical cord blood bank PBKM/FamiCord became the industry's leader in Europe after Swiss firm Cryo-Save went bankrupt early last year.

It is also the fifth largest in the world, according to its management, after two companies in the United States, a Chinese firm and one based in Singapore.

Since the first cord blood transplant was performed in France in 1988, the sector has significantly progressed, fuelling hopes.

- Health insurance -

Mum-of-two Teresa Przeborowska has firsthand experience.

At five years old, her son Michal was diagnosed with lymphoblastic leukaemia and needed a bone marrow transplant, the entrepreneur from northern Poland said.

The most compatible donor was his younger sister, Magdalena.

When she was born, her parents had a bag of her cord blood stored at PBKM.

More than three years later, doctors injected his sister's stem cells into Michal's bloodstream.

It was not quite enough for Michal's needs but nicely supplemented harvested bone marrow.

As a result, Michal, who is nine, "is now flourishing, both intellectually and physically," his mum told AFP.

A cord blood transplant has become an alternative to a bone marrow transplant when there is no donor available, with a lower risk of complications.

Stem cells taken from umbilical cord blood are like those taken from bone marrow, capable of producing all blood cells: red cells, platelets and immune system cells.

Story continues

When used, stem cells are first concentrated, then injected into the patient. Once transfused, they produce new cells of every kind.

At the PBKM laboratory, "each container holds up to 10,000 blood bags... Safe and secure, they wait to be used in the future," its head, Krzysztof Machaj, said.

The bank holds around 440,000 samples, not including those from Cryo-Save, he said.

If the need arises, the "blood will be ready to use without the whole process of looking for a compatible donor and running blood tests," the biologist told AFP.

For families who have paid an initial nearly 600 euros ($675) and then an annual 120 euros to have the blood taken from their newborns' umbilical cords preserved for around 20 years, it is a kind of health insurance promising faster and more effective treatment if illness strikes.

But researchers also warn against unrealistic expectations.

- Beauty products -

Haematologist Wieslaw Jedrzejczak, a bone marrow pioneer in Poland, describes promoters of the treatment as "sellers of hope", who "make promises that are either impossible to realise in the near future or downright impossible to realise at all for biological reasons."

He compares them to makers of beauty products who "swear their cream will rejuvenate the client by 20 years."

Various research is being done on the possibility of using the stem cells to treat other diseases, notably nervous disorders. But the EuroStemCell scientist network warns that the research is not yet conclusive.

"There is a list of almost 80 diseases for which stem cells could prove beneficial," US haematologist Roger Mrowiec, who heads the clinical laboratory of the cord blood programme Vitalant in New Jersey, told AFP.

"But given the present state of medicine, they are effective only for around a dozen of them, like leukaemia or cerebral palsy," he said.

"It's not true, as it's written sometimes, that we can already use them to fight Parkinson's disease or Alzheimer's disease or diabetes."

EuroStemCell also cautions against private blood banks that "advertise services to parents suggesting they should pay to freeze their child's cord blood... in case it's needed later in life."

"Studies show it is highly unlikely that the cord blood will ever be used for their child," the network said.

It also pointed out that there could be a risk of the child's cells not being useable anyway without reintroducing the same illness.

Some countries, such as Belgium and France, are cautious and ban the storage of cord blood for private purposes. Most EU countries however permit it while imposing strict controls.

- Rapid growth -

In the early 2000s, Swiss company Cryo-Save enjoyed rapid growth.

Greeks, Hungarians, Italians, Spaniards and Swiss stored blood from their newborns with the company for 20 years on payment of 2,500 euros upfront.

When the firm was forced to close in early 2019, clients were left wondering where their stem cells would end up.

Under a kind of back-up agreement, the samples of some 250,000 European families were transferred for storage at PBKM.

The Polish firm, founded in 2002 with two million zlotys (around 450,000 euros, $525,000), has also grown quickly.

Present under the FamiCord brand in several countries, PBKM has some 35 percent of the European market, excluding Cryo-Save assets.

Over the last 15 months, outside investors have contributed 63 million euros to the firm, PBKM's chief executive Jakub Baran told AFP.

But the company has not escaped controversy: the Polityka weekly recently published a critical investigative report on several private clinics that offer what was described as expensive treatment involving stem cells held by PBKM.

Read the original here:
Europe's guardian of stem cells and hopes, real and unrealistic - Yahoo News

Poland has emerged as Europe's leader in stem cell storage, a billion-dollar global industry that is a key part of a therapy that can treat leukaemias but raises excessive hopes.

Submerged in liquid nitrogen vapour at a temperature of minus 175 degrees Celsius, hundreds of thousands of stem cells from all over Europe bide their time in large steel barrels on the outskirts of Warsaw.

Present in blood drawn from the umbilical cord of a newborn baby, stem cells can help cure serious blood-related illnesses like leukaemias and lymphomas, as well as genetic conditions and immune system deficits.

Polish umbilical cord blood bank PBKM/FamiCord became the industry's leader in Europe after Swiss firm Cryo-Save went bankrupt early last year.

It is also the fifth-largest in the world, according to its management, after two companies in the United States, a Chinese firm and one based in Singapore.

Since the first cord blood transplant was performed in France in 1988, the sector has significantly progressed, fuelling hopes.

Mum-of-two Teresa Przeborowska has firsthand experience.

At five years old, her son Michal was diagnosed with lymphoblastic leukaemia and needed a bone marrow transplant, the entrepreneur from northern Poland said.

The most compatible donor was his younger sister, Magdalena.

When she was born, her parents had a bag of her cord blood stored at PBKM.

More than three years later, doctors injected his sister's stem cells into Michal's bloodstream.

It was not quite enough for Michal's needs but nicely supplemented harvested bone marrow.

As a result, Michal, who is nine, "is now flourishing, both intellectually and physically," his mum told AFP.

A cord blood transplant has become an alternative to a bone marrow transplant when there is no donor available, with a lower risk of complications.

Stem cells taken from umbilical cord blood are like those taken from bone marrow, capable of producing all blood cells: red cells, platelets and immune system cells.

When used, stem cells are first concentrated, then injected into the patient. Once transfused, they produce new cells of every kind.

At the PBKM laboratory, "each container holds up to 10,000 blood bags... Safe and secure, they wait to be used in the future," its head, Krzysztof Machaj, said.

The bank holds around 440,000 samples, not including those from Cryo-Save, he said.

If the need arises, the "blood will be ready to use without the whole process of looking for a compatible donor and running blood tests," the biologist told AFP.

For families who have paid an initial nearly 600 euros ($675) and then an annual 120 euros to have the blood taken from their newborns' umbilical cords preserved for around 20 years, it is a kind of health insurance promising faster and more effective treatment if illness strikes.

But researchers also warn against unrealistic expectations.

Haematologist Wieslaw Jedrzejczak, a bone marrow pioneer in Poland, describes promoters of the treatment as "sellers of hope", who "make promises that are either impossible to realise in the near future or downright impossible to realise at all for biological reasons."

He compares them to makers of beauty products who "swear their cream will rejuvenate the client by 20 years."

Various research is being done on the possibility of using the stem cells to treat other diseases, notably nervous disorders. But the EuroStemCell scientist network warns that the research is not yet conclusive.

"There is a list of almost 80 diseases for which stem cells could prove beneficial," US haematologist Roger Mrowiec, who heads the clinical laboratory of the cord blood programme Vitalant in New Jersey, told AFP.

"But given the present state of medicine, they are effective only for around a dozen of them, like leukaemia or cerebral palsy," he said.

"It's not true, as it's written sometimes, that we can already use them to fight Parkinson's disease or Alzheimer's disease or diabetes."

EuroStemCell also cautions against private blood banks that "advertise services to parents suggesting they should pay to freeze their child's cord blood... in case it's needed later in life."

"Studies show it is highly unlikely that the cord blood will ever be used for their child," the network said.

It also pointed out that there could be a risk of the child's cells not being useable anyway without reintroducing the same illness.

Some countries, such as Belgium and France, are cautious and ban the storage of cord blood for private purposes. Most EU countries, however, permit it while imposing strict controls.

In the early 2000s, Swiss company Cryo-Save enjoyed rapid growth.

Greeks, Hungarians, Italians, Spaniards and Swiss stored blood from their newborns with the company for 20 years on payment of 2,500 euros upfront.

When the firm was forced to close in early 2019, clients were left wondering where their stem cells would end up.

Under a kind of back-up agreement, the samples of some 250,000 European families were transferred for storage at PBKM.

The Polish firm, founded in 2002 with two million zlotys (around 450,000 euros, $525,000), has also grown quickly.

Present under the FamiCord brand in several countries, PBKM has some 35 per cent of the European market, excluding Cryo-Save assets.

Over the last 15 months, outside investors have contributed 63 million euros to the firm, PBKM's chief executive Jakub Baran told AFP.

But the company has not escaped controversy: the Polityka weekly recently published a critical investigative report on several private clinics that offer what was described as expensive treatment involving stem cells held by PBKM.

More here:
Europe's guardian of stem cells and hopes, real and unrealistic - Deccan Herald

Warsaw (AFP)

Poland has emerged as Europe's leader in stem cell storage, a billion-dollar global industry that is a key part of a therapy that can treat leukaemias but raises excessive hopes.

Submerged in liquid nitrogen vapour at a temperature of minus 175 degrees Celsius, hundreds of thousands of stem cells from all over Europe bide their time in large steel barrels on the outskirts of Warsaw.

Present in blood drawn from the umbilical cord of a newborn baby, stem cells can help cure serious blood-related illnesses like leukaemias and lymphomas, as well as genetic conditions and immune system deficits.

Polish umbilical cord blood bank PBKM/FamiCord became the industry's leader in Europe after Swiss firm Cryo-Save went bankrupt early last year.

It is also the fifth largest in the world, according to its management, after two companies in the United States, a Chinese firm and one based in Singapore.

Since the first cord blood transplant was performed in France in 1988, the sector has significantly progressed, fuelling hopes.

- Health insurance -

Mum-of-two Teresa Przeborowska has firsthand experience.

At five years old, her son Michal was diagnosed with lymphoblastic leukaemia and needed a bone marrow transplant, the entrepreneur from northern Poland said.

The most compatible donor was his younger sister, Magdalena.

When she was born, her parents had a bag of her cord blood stored at PBKM.

More than three years later, doctors injected his sister's stem cells into Michal's bloodstream.

It was not quite enough for Michal's needs but nicely supplemented harvested bone marrow.

As a result, Michal, who is nine, "is now flourishing, both intellectually and physically," his mum told AFP.

A cord blood transplant has become an alternative to a bone marrow transplant when there is no donor available, with a lower risk of complications.

Stem cells taken from umbilical cord blood are like those taken from bone marrow, capable of producing all blood cells: red cells, platelets and immune system cells.

When used, stem cells are first concentrated, then injected into the patient. Once transfused, they produce new cells of every kind.

At the PBKM laboratory, "each container holds up to 10,000 blood bags... Safe and secure, they wait to be used in the future," its head, Krzysztof Machaj, said.

The bank holds around 440,000 samples, not including those from Cryo-Save, he said.

If the need arises, the "blood will be ready to use without the whole process of looking for a compatible donor and running blood tests," the biologist told AFP.

For families who have paid an initial nearly 600 euros ($675) and then an annual 120 euros to have the blood taken from their newborns' umbilical cords preserved for around 20 years, it is a kind of health insurance promising faster and more effective treatment if illness strikes.

But researchers also warn against unrealistic expectations.

- Beauty products -

Haematologist Wieslaw Jedrzejczak, a bone marrow pioneer in Poland, describes promoters of the treatment as "sellers of hope", who "make promises that are either impossible to realise in the near future or downright impossible to realise at all for biological reasons."

He compares them to makers of beauty products who "swear their cream will rejuvenate the client by 20 years."

Various research is being done on the possibility of using the stem cells to treat other diseases, notably nervous disorders. But the EuroStemCell scientist network warns that the research is not yet conclusive.

"There is a list of almost 80 diseases for which stem cells could prove beneficial," US haematologist Roger Mrowiec, who heads the clinical laboratory of the cord blood programme Vitalant in New Jersey, told AFP.

"But given the present state of medicine, they are effective only for around a dozen of them, like leukaemia or cerebral palsy," he said.

"It's not true, as it's written sometimes, that we can already use them to fight Parkinson's disease or Alzheimer's disease or diabetes."

EuroStemCell also cautions against private blood banks that "advertise services to parents suggesting they should pay to freeze their child's cord blood... in case it's needed later in life."

"Studies show it is highly unlikely that the cord blood will ever be used for their child," the network said.

It also pointed out that there could be a risk of the child's cells not being useable anyway without reintroducing the same illness.

Some countries, such as Belgium and France, are cautious and ban the storage of cord blood for private purposes. Most EU countries however permit it while imposing strict controls.

- Rapid growth -

In the early 2000s, Swiss company Cryo-Save enjoyed rapid growth.

Greeks, Hungarians, Italians, Spaniards and Swiss stored blood from their newborns with the company for 20 years on payment of 2,500 euros upfront.

When the firm was forced to close in early 2019, clients were left wondering where their stem cells would end up.

Under a kind of back-up agreement, the samples of some 250,000 European families were transferred for storage at PBKM.

The Polish firm, founded in 2002 with two million zlotys (around 450,000 euros, $525,000), has also grown quickly.

Present under the FamiCord brand in several countries, PBKM has some 35 percent of the European market, excluding Cryo-Save assets.

Over the last 15 months, outside investors have contributed 63 million euros to the firm, PBKM's chief executive Jakub Baran told AFP.

But the company has not escaped controversy: the Polityka weekly recently published a critical investigative report on several private clinics that offer what was described as expensive treatment involving stem cells held by PBKM.

2020 AFP

Read more:
Europe's guardian of stem cells and hopes, real and unrealistic - FRANCE 24

Swiss pharmaceutical giant Novartis made history as the first company to win FDA approval for a CAR-T therapy in the United States. Novartis announced that its genetically modified autologous (self-derived) immunocellular therapy, Kymriah, will cost $475,000 per treatment course. Shortly thereafter, Kite Pharma announced the approval of its CAR-T therapy, Yescarta, in the U.S. with a list price of $373,000. While these prices are expensive, they are far from trendsetting.

In this article:

Pricing of cell therapies is controversialbecause most cell therapy products are priced exponentially higher than traditional drugs. Unfortunately, most drugs can be manufactured and stockpiled in large quantities for off-the-shelf use, while cell therapies involve living cells that require a different approach to commercial-scale manufacturing, transit, stockpiling, and patient use.

To date, the highest priced treatment has not been a cell therapy, but a gene therapy (Glybera). At the time of its launch, Glybera was the first gene therapy approved in the Western world, launching for sale in Germany at a cost close to $1 million per treatment.[1] The record-breaking price tag got revealed in November 2014, when Uniqure and its marketing partner Chiesi, filed a pricing dossier with German authorities to launch Glybera. Unfortunately, Glybera was later withdrawn from the European market due to lack of sales.

Following the approval of Glybera, Kymriah, Yescarta, and more than a dozen other cell therapies, conversations surrounding pricing and reimbursement have become a focal point within the cell therapy industry.

In contrast to pharmaceutical drugs, cell therapies require a different pricing analysis. Below, price tags are shown for approved cell therapy products that have reached the market (prices in US$) and for which there is standardized market pricing.

Pricing of Approved Cell Therapy Products:

Apligrafby Organogenesis & Novartis AG in USA = $1,500-2,500 per use [2]Carticelby Genzyme in USA = $15,000 to $35,000 [3]Cartistemby MEDIPOST in S. Korea = $19,000-21,000 [4],[5]Cupistemby Anterogen in South Korea = $3,000-5,000 per treatment [6]ChondroCelectby Tigenix in EU = ~ $24,000 (20,000) [7]Dermagraftby Advanced Tissue Science in USA = $1,700 per application [8],[9]Epicelby Vericel in theUnited States = $6,000-10,000 per 1% of total body surface area [10]Hearticellgramby FCB-Pharmicell in South Korea = $19,000 [11]HeartSheetby Terumo in Japan = $56,000 (6,360,000) for HeartSheet A Kit; $15,000 (1,680,000) for HeartSheet B Kit (*Each administration uses one A Kit and 5 B Kits)[12]Holoclarby Chiesi Framaceutici in EU = Unknown (very small patient population)Kymriahby Novartis in USA = $425,000 per treatment[13]Osteocelby NuVasive in USA = $600 per cc [14],[15]Prochymalby Osiris Therapeutics and Mesoblast in Canada = ~ $200,000 [16]Provengeby Dendreon and Valeant Pharma in USA = $93,000 [17], [18]SpheroxbyCO.DON AG in EU = $9,500 $12,000 (8,000 10,000) per treatment[19]Strimvelisby GSK in EU = $665,000 (One of worlds most expensive therapies) [20],[21]Temcellby JCR Pharmaceuticals Co. Ltd. in Japan = $115,000-170,000 [22]*Pricing of TEMCELL is $7,600 (868,680 per bag), with one bag of 72m cells administered twice weekly and 2m cells/kg of body weight required per administration[23]Yescartaby Kite Pharma in USA =$373,000[24]

As shown in the list above, wound care products tend to have the lowest cell therapy pricing, typically costing $1,500 to $2,500 per use. For example, Apligrafis created from cells found in healthy human skin and is used to heal ulcers that do not heal after 3-4 weeks ($1,500-2,500 per use), and Dermagraftis a skin substitute that is placed on your ulcer to cover it and to help it heal ($1,700 per application).

Interestingly, Epicel is a treatment for deep dermal or full thickness burns comprising a total body surface area of greater than or equal to 30%. It has higher pricing of $6,000-10,000 per 1% of total body surface area, because it is not used to treat a single wound site, but rather used to treat a large surface area of the patients body.

Next, cartilage-based cell therapy products tend to have mid-range pricing of $10,000 to $35,000. For example, Carticelis a product that consists of autologous cartilage cells (pricing of $15,000 to $35,000), CARTISTEM is a regenerative treatment for knee cartilage (pricing of $19,000 to $21,000), and ChondroCelectis a suspension for implantation that contains cartilage cells (pricing of $24,000).In July 2017,the EMA in Europe also approved Spheroxas a product for articular cartilage defects of the knee with a pricing of$9,500 $12,000 (8,000 10,000) per treatment.

The next most expensive cell therapy products are the ones that are administered intravenously, which range in price from approximately $90,000 to $200,000. For example, Prochymal is an intravenously administered allogenic MSC therapy derived from the bone marrow of adult donors (pricing of $200,000), Provenge is an intravenously administered cancer immunotherapy for prostate cancer ($93,000), and Temcell is an intravenously administered autologous MSC product for the treatment of acute GVHD after an allogeneic bone marrow transplant (pricing of $115,000-170,000).

Finally, many of the worlds most expensive cell therapies are gene therapies, ranging in price from $500,000 to $1,000,000. For example, Kymriah is the first CAR-T cell therapy to be FDA approved in the United States (pricing of $475,00 per treatment course).Strimvelis isan ex-vivo stem cell gene therapy to treat patients with a very rare disease called ADA-SCID (pricing of $665,000).

Although these generalizations do not hold true for every cell therapy product, they explain the majority of cell therapy pricing and provide a valuable model for estimating cell therapy pricing and reimbursement. This information is summarized in the following table.

TABLE. Pricing Scale for Approved Cell Therapies

Another point of reference is also valuable. The RIKEN Institute launched the worlds first clinical trial involving an iPSC-derived product when it transplanted autologous iPSC-derived RPE cells into a human patient in 2014.While the trial was later suspended due to safety concerns, it resumed in 2016, this time using an allogeneic iPSC-derived cell product.

The research team indicated that by using stockpiled iPS cells, the time needed to prepare for a graft can be reduced from 11 months to as little as one month, and the cost, currently around 100 million ($889,100), can be cut to one-fifth or less.[25]

While many factors contribute to cell therapy pricing, key variables that can be used to predict market pricing include:

Another compounding factor is market size, because wound healing and cartilage replacement therapies have significant patient populations, while several of the more expensive therapies address smaller patient populations.[26]

To learn more about this rapidly expanding industry, view the Global Regenerative Medicine Industry Database Featuring 700+ Companies Worldwide.

What variable do you think influence the cost of cell therapies? Share your thoughts in the comments below.

BioInformant is the first and only market research firm to specialize in the stem cell industry. Our research has been cited by major news outlets that include the Wall Street Journal, Nature Biotechnology, Xconomy, and Vogue Magazine. Serving industry leaders that include GE Healthcare, Pfizer, Goldman Sachs, and Becton Dickinson. BioInformant is your global leader in stem cell industry data.

Footnotes[1] $1-Million Price Tag For Glybera Gene Therapy: Trade Secrets. Available at http://blogs.nature.com/tradesecrets/2015/03/03/1-million-price-tag-set-for-glybera-gene-therapy. Web. 21 Aug. 2017.[2] 2017 Apligraf Medicare Product and Related Procedure Payment, Organogenesis. Available at: http://www.apligraf.com/professional/pdf/PaymentRateSheetHospitalOutpatient.pdf. Web. 3 Mar. 2017.[3] CARTICEL (Autologous Chondrocyte Implantation, Or ACI). Available at: https://www.painscience.com/articles/cartilage-repair-with-carticel-review.php. Web. 3 Aug. 2017.[4] Cartistem?, What. What Is The Cost Of Cartistem? Available at: http://www.stemcellsfreak.com/2015/01/cartistem-price.html. N.p., 2017. Web. 3 Mar. 2017.[5] Cartistem. Kneeguru.co.uk. Available at: http://www.kneeguru.co.uk/KNEEtalk/index.php?topic=59438.0. Web. 3 Aug. 2017.[6] Stem Art, Stem Cell Therapy Pricing. Available at: http://www.stem-art.com/Library/Miscellaneous/SCT%20products%20%20Sheet%201.pdf. Web. 3 Mar. 2017.[7]Are Biosimilar Cell Therapy Products Possible? Presentation by Christopher A Bravery [PDF]. Available at: http://advbiols.com/documents/Bravery-AreBiosimilarCellTherapiesPossible.pdf. Web. 3 Aug. 2017.[8] Artificial Skin, Presentation by Nouaying Kue (BME 281). Available at: http://www.ele.uri.edu/Courses/bme281/F12/NouayingK_1.ppt. Web. 3 Mar. 2017.[9] Allenet, et al. Cost-effectiveness modeling of Dermagraft for the treatment of diabetic foot ulcers in the french context. Diabetic Metab. 2000 Apr;26(2):125-32.[10] Epicel Skin Grafts, Sarah Schlatter, Biomedical Engineering, University of Rhode Island. Available at: http://www.ele.uri.edu/Courses/bme281/F08/Sarah_1.pdf. Web. 31 July. 2017.[11] Nature. (2011). South Koreas stem cell approval. [online] Available at: http://www.nature.com/nbt/journal/v29/n10/full/nbt1011-857b.html. Web. 3 Sept. 2017.[12] Novick, Coline Lee. Translated version of the first two pages of Terumos Conditionally Approved HeartSheet NHI Reimbursement Price. [Twitter Post] Available at:goo.gl/YGCh6z. Web. 21 Sep. 2017.[13] Fortune.com. (2017). Is $475,000 Too High a Price for Novartiss Historic Cancer Gene Therapy? [online] Available at: http://fortune.com/2017/08/31/novartis-kymriah-car-t-cms-price/ Web. 8 Sept. 2017.[14] Skovrlj, Branko et al. Cellular Bone Matrices: Viable Stem Cell-Containing Bone Graft Substitutes. The Spine Journal 14.11 (2014): 2763-2772. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402977/. Web. April 12, 2017.[15] Hiltzik, Michael. Sky-High Price Of New Stem Cell Therapies Is A Growing Concern. Available at: http://www.latimes.com/business/hiltzik/la-fi-hiltzik-20151010-column.html. Web. 1 Sept. 2017.[16] Counting Coup: Is Osiris Losing Faith In Prochymal?, Busa Consulting LLC. Available at: http://busaconsultingllc.com/scsi/organelles/counting_coup_prochymal.php. Web. 3 Aug. 2017.[17] Dendreon Sets Provenge Price At $93,000, Says Only 2,000 People Will Get It In First Year | Xconomy. Available at: http://www.xconomy.com/seattle/2010/04/29/dendreon-sets-provenge-price-at-93000-says-only-2000-people-will-get-it-in-first-year/. Web. 3 Mar. 2017.[18] Dendreon: Provenge To Cost $93K For Full Course Of Treatment | Fiercebiotech. Available at: http://www.fiercebiotech.com/biotech/dendreon-provenge-to-cost-93k-for-full-course-of-treatment. Web. 3 Mar. 2017.[19]Warberg Research.CO.DON (CDAX, Health Care). Available at:http://www.codon.de/fileadmin/assets/pdf/03_Investor/Research_Report/2017_07_24_CO.DON_Note_Warburg_Research_englisch.pdf. Web. 21 Sept. 2017.[20] GSK Inks Money-Back Guarantee On $665K Strimvelis, Blazing A Trail For Gene-Therapy Pricing | Fiercepharma. Available at: http://www.fiercepharma.com/pharma/gsk-inks-money-back-guarantee-665k-strimvelis-blazing-a-trail-for-gene-therapy-pricing. Web. 3 Mar. 2017.[21] Strimvelis. Wikipedia.org. Available at: https://en.wikipedia.org/wiki/Strimvelis. Web. 13 Aug. 2017.[22] MesoblastS Japan Licensee Receives Pricing For TEMCELL HS Inj. For Treatment Of Acute Graft Versus Host Disease. Mesoblast Limited, GlobeNewswire News Room. Available at: https://globenewswire.com/news-release/2015/11/27/790909/0/en/Mesoblast-s-Japan-Licensee-Receives-Pricing-for-TEMCELL-HS-Inj-for-Treatment-of-Acute-Graft-Versus-Host-Disease.html. Web. 3 Mar. 2017.[23]TEMCELL HS Inj. Receives NHI Reimbursement Price Listing, JCR Pharmaceuticals Co., Ltd. News Release, November 26, 2015. Available at: http://www.jcrpharm.co.jp/wp2/wp-content/uploads/2016/01/ir_news_20151126.pdf. Web. 3 Mar. 2017.[24]Kites Yescarta (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy. Business Wire.Web. 19 Oct. 2017.[25]Riken-Linked Team Set To Test Transplanting Eye Cells Using Ips From Donor | The Japan Times. The Japan Times. N.p., 2017. Web. 23 July. 2017.[26]LinkedIn Comment, by David Caron. Available at: https://www.linkedin.com/feed/update/urn:li:activity:6316277496551665664/. Web. 21 Sept. 2017.

Pricing Of Approved Cell Therapy Products Stem Cells, CAR-T, And More

Link:
Pricing Of Approved Cell Therapy Products - BioInformant

We are thrilled to share an excerpt form Dr. Q Schulte aufm Erley's article on Plant Stem Cells. Dr. Q is an entrepreneur, scientist and founder of one of our most loved partners: Shtrands. Shtrands is a beauty industry innovator. They provide a hair care concierge service that brings you curated products and expert advice to match your hair texture, scalp condition and styling needs.

The highly competitive cosmetics industry is always looking for the next best ingredient(s) that can fight the aging process and this led to a sizable increase in the number of anti-aging products on the market. With this is coming an increased number of active ingredients developed for this category; one of these ingredients is stem cell extract.This is an ingredient that must be assessed carefully, as marketing claims often push the limits of the available science.

The concept of stem cells originated at the end of the 19th century as a theoretical postulate to account for the ability of certain tissues (blood, skin, etc.) to renew themselves for the lifetime of organisms even though they are comprised of short-lived cells. Stem cells isolation and identification happened many years later though.

Stem cells have received a fair share of attention in the public debate mostly in connection with their potential for biomedical application and therapies. While the promise of organ regeneration have captured our imagination, it has gone almost unnoticed that plant stem cells represent the ultimate origin of much of the food we eat, the oxygen we breathe, as well the fuels we burn. Thus, plant stem cells may be ranked among the most important cells for human well-being.

A stem cell is a generic cell that can make exact copies of itself (daughters) indefinitely. These daughters can remain stem cells or further undergo differentiation (2). Such that a stem cell has the ability to make specialized cells for various tissues in the body, such as heart muscle, skin tissue, and liver tissue.

Because of their self-renewal functions, stem cells are the most important cells in the skin, as they are the source for continuous regeneration of the epidermis. Stem cell cosmetics are developed based on stem cell technology, which involves using extracts or culture media of stem cells. However, cosmetics containing human stem cells or their extracts have not been released into the market due to legal, ethical, and safety concerns. Meanwhile, plant stem cells, which circumvent these problems, are highly regarded in the cosmetics industry for improving culture technology.

The EUprohibits the use of cells, tissues, or products of human origin in cosmetics; stem cell therapy for anti-aging has not been approved or been deemed safe or effective in USA by the FDA. Furthermore, its use outside of a clinical research trial (which would be listed at http://www.clinicaltrials.gov) is prohibited. Whereas the Korea Food and Drug Association has allowed the use of sources originating from stem cell media in cosmetics since 2009 (3).

So, any cosmetics marketed as containing stem cells found on US market (should) contain stem cells extracted from plants.

A major difference between animal and plant stem cells is that plant stem cells provide cells for complete organs (branches, leaves, etc.), compared with the animal stem cells, which regenerate cells restricted to one tissue type.

Plants have nowhere to run when times get tough, so they must rely on an inner body plan to generate developmental responses to environmental changes.

Research by many labs in the last decades has uncovered a set of independent stem cell systems that fulfill the specialized needs of plant development and growth in four dimensions. In some long-lived plants, such as trees, plant stem cells remain active over hundreds or even thousands of years, revealing the exquisite precision in the underlying control of proliferation, self-renewal and differentiation.

There is some confusion around the term stem cell due to the marketing verbiage used by the cosmetic companies. In topical cosmetics the formulations dont contain stem cells straight out of the plants. They are actually a range ofplant stem cell extracts, which are manufactured using a cell culture technology.This technology consists of many and complicated methods that should ensure growth of plant cells, tissues or organs in the environment with a microbe-free nutrient. The plant cell technologyallows synthesis of the biologically active substances that exist in plants, but are not commonly available in natural environment or are difficult to obtain by chemical synthesis.

The extracts obtained through this technology from the plant stem cells are currently used for production of both common or professional care cosmetics (4).

The beneficial apple properties are known for centuries. Apples are cultivated today only for their taste, but earlier the main criterion of the type selection was the shelf life of the fruits.

One of such apple-tree types isUttwiler Spatlauberwhich is growing in Switzerland. This is a type cultivated solely due to a possible long-time storage of fruits, which remain fresh even for several months.Some trees come from the plant cutting sets planted during the 18th century!!!

The stem cell extracts are made in 2 main steps: first, the tissue material is obtained from apples (collected from a cut surfaces of the apples). Secondly, the material is going through a complicated biotechnological process to make the stem cell extracts that contains certain active ingredients. These are actually the ingredients used in formulations marketed as containing stem cells (5).

Swiss biotech company Mibelle Biochemistry created the product named PhytoCellTecTMMalus Domestica, that is a liposomal formulation (extract) derived from the stem cells of the Uttwiler Spatlauber apples. The company has published in vitro experiments done with hair follicles that showed the ability of theUttwiler Spatlauberstem cell extract to delaying of the tissue atrophy process (6); this ingredient delays hair aging.

At Teadora, we chose to includeMibelle'sPhytoCellTecTM Argan Plant Stem Cells in our ButterandBrazilian Glow Oiland here are the details from Mibelle that helped to convince us this ingredient was a must have companion to the huge list of active superfruits we crafted into our products, read on, it's pretty cool:

Deep-Seated Rejuvenation of the Skin:In order to maintain the skin in a healthy condition,cutaneous tissue is being continuously regenerated.This regenerative capacity relies on adult stem cells inthe skin. While considerable research has been done onepidermal stem cells, dermal stem cells were identifiedonly in 2009. The dermis is the middle layer of the skinand gives it tensile strength and elasticity, therefore it isalso the site where wrinkles originate.

PhytoCellTec Argan was developed to improvethe regenerative capacity of dermal stem cells therebyachieving deep-seated rejuvenation of the skin.

PhytoCellTec Argan is a powder based on stem cellsof the argan tree, one of the oldest tree species in theworld.In order to evaluate which active ingredient effectivelypromotes dermal stem cell activity, a stable humandermal papilla cell line was used as a new test system:stem cell activity is assessed based on the expression ofthe Sox2 gene, which is an established stem cell marker.Furthermore, the characteristic property of stem cells togrow in three-dimensional spherical colonies serves asa second observable indicator of stem cell viability inthis assay.

Clinical studies performed on healthy volunteers showedthat PhytoCellTec Argan:

effectively stimulates the regeneration of dermalconnective tissue, thereby increasing skin density

helps the skin to regain its firmness

significantly reduces wrinkle depth in crows feet area.

PhytoCellTec Argan is the very first active ingredientthat is capable of both protecting and vitalizing humandermal stem cells. This will not only help to acceleratethe skins natural repair process but also fights skin agingright at the root. Here are some of the amazing benefits:

Vitalizes and protects dermal stem cells Reduces wrinkles Tightens and tones skin tissues Increases skin firmness and density Deep-seated rejuvenation of the skinFirst cosmetic active with proven results forprotecting and vitalizing dermal stem cells

See more here:
Benefits of Plant Stem Cells for Skin & Hair Teadora

Brigham and Women's Hospital in Boston.

BRIAN SNYDER/REUTERS/Newscom

By Kelly ServickApr. 27, 2017 , 5:00 PM

A research misconduct investigation of a prominent stem cell lab by the Harvard Universityaffiliated Brigham and Womens Hospital (BWH) in Boston has led to a massive settlement with the U.S. government over allegations of fraudulently obtained federal grants. As Retraction Watch reports, BWH and its parent health care system have agreed to pay $10 million to resolve allegations that former BWH cardiac stem cell scientist Piero Anversa and former lab members Annarosa Leri and Jan Kajstura relied on manipulated and fabricated data in grant applications submitted to the U.S. National Institutes of Health (NIH).

A statement from the U.S. Attorneys Office for the District of Massachusetts released today notes that it was BWH itself that shared the allegations against Anversas lab with the government. The hospital had been conducting its own probe into the Anversa lab since at least 2014, when a retraction published in the journal Circulation revealed the ongoing investigation. The hospital has not yet released any findings.

In 2014, Anversa and Leri sued Harvard and BWHalong with BWH President Elizabeth Nabel and Gretchen Brodnicki, Harvards dean for faculty and research integrityfor launching and publicizing the investigation that they claimed wrongfully damaged their careers. In their complaint, they acknowledged fabricated data in the Circulation paper and altered figures in a 2011 paper for whichThe Lancethas published an expression of concern. But they claimed that Kajstura had altered data without their knowledge. (Anversa and Leris recent papers list their institution as Swiss Institute for Regenerative Medicine, Retraction Watch notes.)

In July 2015, a federal district court judge dismissed the lawsuit, ruling that the plaintiffs had to first air their grievances with the federal Office of Research Integrity, which handles misconduct investigations at NIH-funded labs.

Grant fraud cases against universities rarely involve research misconduct, and most are brought by whistleblowers who stand to claim a share of any returned funds. Despite the high penalty, BWH gets praise from the Department of Justice in todays announcement for self-disclosing the allegations and for taking steps to prevent future recurrences of such conduct.

But the result is confusing and potentially discouraging, says Ferric Fang, a microbiologist at the University of Washington in Seattle, who has published several analyses of retractions, misconduct, and the scientific enterprise. It sounds as if the researchers themselves were found to have engaged in improper practices, but the institution is on the hook for the settlement. The decision deserves greater clarification, he says, or it could discourage other institutions from being as forthcoming in the future.

The rest is here:
$10 million settlement over alleged misconduct in Boston heart stem cell lab - Science Magazine

Suspended from a tree in the wilds of Tennessee, the remains of his hang-glider entangled in the branches above, his lower left leg pulverised and his chest badly bruised from his dramatic fall into the forest canopy, Alan Mackay-Sim felt hyper-alert from the electricity of adrenalin, the clarity of shock. Only the wind was audible, softly rustling the branches around him as he sucked in the forest air, perfumed with poplar and sweet-gum.

Knowing that the adrenalin coursing through his veins would soon give way to an agonising and possibly debilitating pain, the 28-year-old used these precious minutes to assess his predicament, to figure it out coolly like a man of science.

A broken leg, no doubt shattered in multiple places. Possibly hours before his fellow hang-gliding friends would be able to locate him; if they didn't reach him by nightfall, he could be dangling here until the next morning. Unfastening his harness and climbing down to the ground five metres below was not an option, at least, not without incurring further injury. To prevent blood from pooling and to save his leg, he quickly concluded, he'd have to carefully oh-so carefully free the hang-glider's stirrup bar and one of the ropes from his harness, create a splint for his injured left leg, secure it to his right leg and hoist up both limbs while hanging there like a gammy fruit bat.

Mackay-Sim had only arrived in the US a few weeks before, a post-doctoral researcher from the University of Sydney eager to extend his studies into the olfactory system specifically, what the nose tells the brain at the University of Philadelphia. But on that blustery October day back in 1979, when a freak wind gust whooshing around Lookout Mountain near Chattanooga sent a promising young Australian scientist nosediving into the forest, before a rescue team found himhanging in the tree just before sunset, both legs securely elevated, Mackay-Sim was set to gain some useful insights that would become valuable to him in his later life. Insights that would be peculiarly relevant to his work as a pioneering stem cell researcher specialising in the treatment of spinal cord injuries.

So badly broken was his leg that Mackay-Sim spent more than six months in a wheelchair, and many more months afterwards receiving intensive physiotherapy.

"It gave me some insight into what life's like in a wheelchair, and it stayed with me," says Mackay-Sim, settling into a chair in his office at the Institute for Drug Discovery at Griffith University, just down the corridor from the laboratory where he spent years toiling over petri dishes of nasal stem cells, in his life's mission to treat spinal injuries, hereditary spastic paraplegia and diseases like Parkinson's.

A photo of the late actor Christopher Reeve is pinned on a noticeboard behind him. "I met Christopher in 2003 when he came out for a conference; he was interested in our clinical trials," Mackay-Sim says, looking at the photo. "Then in the following year I spent some time at his home in New York, and we talked a lot about spinal cord injury repair, and his own personal story."

As Mackay-Sim explains, the higher up the spinal cord an injury is, the more severe the effects. "As we know, Christopher fell off a horse and became a full paraplegic on a respirator, but in fact he suffered only a small injury; the problem was that the bleed went straight into his spinal cord. It only takes a very small injury to stop transmission; you can have large injuries to the chest and not suffer long-term repercussions but here, in the neck, a small event can change your life."

Back in the late 1980s, after he started at Griffith University, Mackay-Sim became interested in a set of extraordinary busy-bee cells in the human nose called olfactory ensheathing cells nerve cells that regenerate every single day to recreate our sense of smell. If these wonder cells are continually regenerating, he kept asking himself, could they not be transplanted to another part of the body where cells don't regenerate, like the spinal cord?

Years of scientific slog followed until 2002, when Mackay-Sim was the first researcher in the world to remove cells from the nose of a patient paralysed in a car accident, grow them in a cell culture and then, with the help of surgeons at Brisbane's Princess Alexandra Hospital, implant them in the same patient's spinal cord. "By the time Christopher died in 2006, we'd transferred stem cells from the nose into three patients and shown it was safe to do so," he says. "One of the patients recovered some sensation above the injury, which was hopeful, but one person does not make real scientific evidence."

For Mackay-Sim, the importance of scientific breakthroughs in the treatment of life-threatening illnesses is deeply personal. In 2014, he was diagnosed with multiple myeloma, an incurable form of leukaemia. As a result of the illness, which breaks down bones in an advanced form of osteoporosis, and the punishing series of treatments that followed his diagnosis, involving radiation, chemotherapy and stem cell therapy (albeit a very different form from the one the scientist was researching), Mackay-Sim lost nine centimetres in height and shed more than 15 kilograms of body weight. "I became extremely sick from the chemotherapy just prior to the bone marrow transplant," the 65-year-old recalls. "It was the worst experience of my life."

There was also the initial shock of the diagnosis, and grief for the loss of his health after a highly active life, from football and rowing in his teens to distance cycling, scuba diving and hang-gliding, which he took up while atuniversity. "Both my parents lived into their 80s and 90s and I'd been cycling up to 200 kilometres a week for decades, so I wasn't anticipating something like this."

Still, as a scientist he couldn't help but observe the trajectory of his illness with stricken fascination. "I had some good conversations with my oncologist," he smiles. "As a biologist examining my own biology, it did demystify lots of things. One minute I was a grieving patient, the next an interested scientist."

Above all, Mackay-Sim refuses to sentimentalise his battle with the illness and asks that I don't embroider it in this story by turning it into some kind of triumph of personal will power over disease. "My survival is determined by the vagaries of the particular cancer I've got," he says matter-of-factly. "Some people have nasty genetic diseases that mean they die earlier. For the moment, I feel very healthy."

Surely his extreme fitness at least helped him to survive the ravages of chemo? "I think being fit and active all my life has given me a higher quality of life after treatment," he acknowledges. "But one doctor put it to me that I probably would have sought out treatment earlier if I wasn't so fit, because I dismissed the symptoms as simple back pain from the cycling. It took two years after the chemo and radiation for the pain to go away. 2016 was a year of normality for me my back became stable enough for me to get on a road bike again."

The diagnosis added poignancy to the evening in Canberra in late January when Mackay-Sim, out of 3000- plus nominations, was crowned Australian of the Year. Sitting alongside him were his American-born wife of nearly 34 years, Lisa Peine, a retired primary school teacher, their 28-year-old daughter Matilda, a trainee psychiatrist, and 25-year-old son Callum, an engineer.

Mackay-Sim with wife Lisa Peine in North Queensland in 1983. Photo: Courtesy of Alan Mackay-Sim

Perhaps no Australian of the Year is better placed to recognise just how precious a year can be, and more determined to seize the moment to put science and innovation at the top of the national conversation. A former Queenslander of the Year, Mackay-Sim sees science as vital to our future national wellbeing, especially after the recent wake-up call in international school education rankings, which placed Australia behind Kazakhstan and Slovenia in maths and science.

Mackay-Sim agrees unequivocally with Michelle Simmons, professor of quantum physics at the University of NSW, who drew headlines recently when she declared that the "feminised" nature of Australia's high school physics curriculum (emphasising the sociology of science with essays and theory instead of rigorous lab experiments and mathematical problem-solving) had been an unmitigated failure. Introduced in the 1980s, the approach had resulted in a long, slow decline in standards.

"Scientific understanding comes from learning the processes; it can be hard work but is absolutely essential," Mackay-Sim insists. "The key to a good science education in schools is to get well-trained teachers." (Mackay-Sim has been deeply encouraged by some of the science teachers he's met since winning the award.)

The choice of Mackay-Sim the first scientist honoured as Australian of the Year since immunologist Ian Frazer in 2006 was met with near-universal applause by Australia's scientific community, who no doubt feel dispirited in this post-truth world of climate-change denial, cuts to the CSIRO and the growing view by government agencies that basic research isn't worth it.

"We need to invest in young scientists," Mackay-Sim declared in his acceptance speech, adding that the discovery of new medical treatments can reduce the strain on health budgets. "More than 10,000 Australians live with a spinal cord injury a new person is added to this tally every day." But politicians need to take a long-term view of the benefits of basic research, he tells me, "a view much longer than the political horizon".

The announcement also gave the image of the Australian of the Year awards a much-needed polish. The 2016 winner, Lieutenant-General David Morrison, drew criticism for charging up to $15,000 a pop forpublic speaking engagements, as well as grandstanding about sexism in the military despite his own handling of the army's "Jedi Council" sex scandal, in which demeaning sex videos of women were distributed among a group of soldiers. (It was revealed that Morrison's office knew of the scandal 11 months prior to the former Chief of Army releasing a now-famous condemnation on YouTube of those involved.)

Will Mackay-Sim accept speakers' fees? "I knew nothing about speakers' fees when I accepted the award," he says crisply. "I'm not pursuing money after all, I've spent my life doing public research."

Although he hasn't received any fees to date, Mackay-Sim insists that if they are offered, the funds will be donated to the Hereditary Spastic Paraplegia Research Foundation, his charity of choice.

Mackay-Sim only had a day or so to bask in the glow of being named Australian of the Year before there was a claim his scientific achievements had beenoverstated in the application. A Polish scientist, Professor Pawel Tabakow, after being approached by an Australian journalist in Europe, declared that Mackay-Sim had nothing to do with the world-first surgery using olfactory stem cells that enabled a Polish paraplegic, Darek Fidyka, to walk again. "It is not our business who should be Australian of the Year," Tabakow told The Weekend Australian. "But it is our business when his work is being linked to the surgery of Fidyka. He has no link whatsoever."

The scientific hullaballoo arose from the submission to the Australia Day Council (ADC), which states that Mackay-Sim's research "helped play a central role in proving the safety of science that was a precursor to Dr Tabokow in Poland undertaking the first successful restoration of mobility in a quadriplegic man".

Although Mackay-Sim didn't write the submission to the ADC, doesn't know who did, and never claimed to be involved in Tabokow's work, an artificial straight line was drawn between the two scientists, especially when the word "precursor" was dropped from condensed versions of the ADC's quote in multiple news stories (we'll examine the fallout from the controversy a little later).

Padding amiably about his large, multi-room laboratory, past refrigerator-sized storage cabinets containing cell cultures, past white-coated scientists peering into microscopes, Mackay-Sim seems to be in his element, with every second person saying "Hi", "Hello", or "How are you?" If stem cells are indeedthe microscopic building blocks of the world, this is the tiny universe the scientist feels most comfortable in. But it's a laboratory that now has to hum along without him Mackay-Sim retired late last year, his duties now limited to popping into the university once a week as an emeritus professor.

Later in the day, Professor George D. Mellick, head of Clinical Neurosciences at Griffith, tells me that Mackay-Sim has always set aside time to mentor younger scientists, and to explain sometimes hideously complicated science to a lay audience, but would be the last person to crow about his own scientific achievements.

"One of the things that isn't highlighted very much about Alan's work is his research into Parkinson's. We've been able to learn a lot about Parkinson's by studying cells from people with the disease, and the information coming out of this research will hopefully lead to better treatments."

Back in his office, Mackay-Sim gives me a quick rundown, 101-style, on the human nose. No, the human sense of smell doesn't necessarily decline with age, unless illness or disease set in, and it is astonishingly adept at distinguishing hundreds of thousands of different odours. Yes, women do have a superior sense of smell to men, but the difference is surprisingly only slight. Yes, the first symptom of Parkinson's, before the typical tremors set in, is a reduced sense of smell, as it is with those sufferers who will go on to develop dementia. And yes paws down dogs do have a vastly more powerful sense of smell than humans, although it's impossible to quantify by exactly how much (Mackay-Sim has been known to hide from his spoodle Henry, to measure how long it takes for the dog to find him).

As he relays all this, Mackay-Sim's eyes twinkle and a smile lights up his face: it's easy to see how he'd be the perfect academic for Griffith to call on to schmooze a government minister or potential philanthropist and secure desperately sought-after funding. I ask him about his trademark moustache, which he's had since the early 1990s, when he shaved off a beard. "My wife wouldn't recognise me without it," he jokes. "She says that a small mammal could roost beneath my mouth."

Mackay-Sim, whose double-barrelled surname comes from his paternal grandfather, grew up in middle-class Roseville, on Sydney's leafy North Shore, the third of four brothers. His mother Lois was a nurse during World War II and later a full-time mum while his father Malcolm ran a hardware importing and distributing business, Macsim Distributors (now Macsim Fasteners, owned by Alan's eldest brother, Fraser). At North Sydney Boys' High he was "the opposite of a shit-stirrer. I was vice captain, head of the cadets, played football, was in the rowing team, had a shot at athletics, sang in the choir I did it all."

With wife, Lisa Peine, in Sulawesi, Indonesia, 2007. Photo: Courtesy of Alan Mackay-Sim

After graduating with honours in science from Macquarie University, Mackay-Sim picked up tutoring work in the department of physiology at the University of Sydney, where he completed a PhD on the brain's visual system. Two academic stints in the US followed, first at the University of Pennsylvania from 1979 until 1981, followed by two years at the University of Wyoming, during which time he met his wife Lisa, then living in northern Colorado.

The pair married in 1984, by which time Mackay-Sim had been offered a research role in the department of physiology at the University of Adelaide. He started at Griffith University in 1987, where his research concentrated on the biology of nasal cells.

At the height of the heated moral debate over the use of embryonic stem cells whether the therapeutic potential of stem cells could justify destroying human embryos to extract them Mackay-Sim met Pope Benedict XVI at a Vatican conference in 2005. The Pope congratulated him on his exclusive use of adult stem cells.

"I wasn't avoiding embryonic stem cells for religious reasons," Mackay-Sim explains. "It just so happenedthat I was working with adult stem cells at the time and the conference was looking at alternatives to using embryonic stem cells. But it was a scientific conference and I was impressed with its calibre; the only difference was that men in purple robes were sitting at the back asking questions."

Later in the same trip, Mackay-Sim was invited, along with a host of others, to the Apostolic Palace at Castel Gandolfo the Vatican summer palace. "You feel the history of the Roman Catholic Church, with the Pope coming in with his cardinals and the Swiss Guards," he says. "I'm not a believer, but it was a very powerful experience."

In 2006, the debate over embryonic stem cells virtually vanished when scientist Shinya Yamanaka from Japan's Kyoto University stunned the world by proving that stem cells needn't come from human embryos adult cells can be reprogrammed to act like stem cells, to be returned to an embryo-like state (Yamanaka's discovery won him the Nobel Prize in 2012). "Yamanaka worked out how to genetically engineer any cells so that they had the properties of embryonic stem cells," says Mackay-Sim, who nonetheless continued to focus on adult stem cells only.

Mackay-Sim accomplished his own world first in 2002 when, with the assistance of doctors at Brisbane's Princess Alexandra Hospital, he transplanted olfactory stem cells into the spinal cord of a man crippled in a car accident. The procedure was repeated with two other paraplegic patients at the same hospital and the study wrapped up in 2007.

While the procedures didn't result in any of the patients regaining useful movement in their legs, the results of Mackay-Sim's clinical trials, published in 2005 and 2008, paved the way for further development of olfactory stem cell transplantation.

One researcher who followed Mackay-Sim's trials closely was Geoffrey Raisman from University College London, who visited the Australian team shortly after the first operation in Brisbane to study their work. Raisman later led the British team who worked with Polish surgeon Tabakow on Darek Fidyka in 2012.

Tabakow deployed 100 separate micro-injections of olfactory sheathing cells above and below Fidyka's spinal injury, with the hope these cells would provide a skeleton for nerve fibres to grow and reconnect. A former volunteer firefighter, Fidyka had become paralysed in 2010 after a severe knife attack by the jealous ex-husband of his girlfriend. The repeated stab wounds to Fidyka's back severed his spinal cord, paralysing from the waistdown. (Fidyka's attacker, a fellow firefighter, committed suicide shortly afterwards.)

There's no doubt Tabakow's work was a major advance on Mackay-Sim's research. Tabakow's strategy was to extract ensheathing cells specifically from the olfactory bulbs in Fidyka's nose, grow them in a culture, while also extracting nerve cells from his ankle in a multi-pronged attempt at spinal cord reconstruction. After a series of operations, Fidyka can walk with the assistance of a frame, has regained some bladder control and sexual function, and can ride a tricycle.

Raisman described their new stem cell procedure as "more impressive than man walking on the moon", but it will have be tested on other paraplegics, including those with more severe injuries than Fidyka's, such as car accident victims who have had more of their spinal cord damaged, before it can be declared a reliable method of restoring mobility. As impressive as Tabakow's achievement is, it has still only worked on one patient.

Nobody, however, disputes Mackay-Sim's immense contribution to stem cell transplantation; his work is unimpeachable. If nothing else, he was at the forefront of the science showing that restoring the ability to walk to paraplegics is no longer science fiction. "What I've always said is that we did the first phase of clinicaltrials with olfactory stem cells, and the aim of those trials was to show they were safe," says Mackay-Sim. "That was the first important step."

Mackay-Sim wrote to Tabakow shortly after the controversy blew up, explaining that he didn't write the submission to the Australia Day Council, and was in no way claiming credit for Fidyka's remarkable recovery. "He wrote back a very nice email," says Mackay-Sim. "I believe I've given credit to other scientists in every interview I've given to journalists. I feel comfortable in my behaviour and ethics."

With Prime Minister Turnbull in January this year. Photo: Elesa Kurtz

Mackay-Sim can remember the day when he felt something was wrong terribly wrong. He'd been suffering back pain for months, but dismissed it as old age, or strain from bending over on his bicycle on long rides, and stocked up his pantry with painkillers. "I was in Colorado with Lisa visiting her family, and the pain became so bad I couldn't walk very far. I found the pain eased when I got on my bicycle. I flew home a week before she did; the plane trip back was absolute hell."

What followed was a swift diagnostic journey from his GP to specialists at Brisbane's Wesley Hospital, resulting in a devastating diagnosis. "They suspected something cancerous quite quickly. I didn't realise how ill I was; by this stage, my kidneys weren't coping at all with the antibodies released from my white blood cells, which were going berserk trying to fight the disease. I was at risk of kidney failure and my bones were becoming very fragile. I started therapy almost immediately, in June 2014. Then began the cycles of chemotherapy and stem cell treatment in December."

Since the beginning of last year, however, Mackay-Sim's health has dramatically improved, and even though he's retired to his beachside home in Currimundi on the Sunshine Coast, he is still active in university affairs. He concedes that his health may prevent him from being as active as Rosie Batty, perhaps our most vigorous Australian of the Year to date. But he's already spoken at functions in Brisbane, Sydney and Perth, and will be attending the national March for Science on April 22, which coincides with Earth Day. He moves with the speed and fluidity of a man 10 or 15 years younger.

"I feel very healthy, very energised at the moment," says Mackay-Sim, who is planning a bicycle ride in Italy's Dolomites in July with a couple of mates. (Last year he and his wife went on the Great Victorian Bike Ride, a seven-day ride averaging 85 kilometres a day.)

"I do need to be selective with the number of invitations around Australian of the Year," he concedes, "but I'll do everything I can. After all, what more exciting time could you have to talk about science?"

Original post:
Australian of the Year Alan Mackay-Sim on the advantage of being 'an interested scientist' - The Sydney Morning Herald

Suspended from a tree in the wilds of Tennessee, the remains of his hang-glider entangled in the branches above, his lower left leg pulverised and his chest badly bruised from his dramatic fall into the forest canopy, Alan Mackay-Sim felt hyper-alert from the electricity of adrenalin, the clarity of shock. Only the wind was audible, softly rustling the branches around him as he sucked in the forest air, perfumed with poplar and sweet-gum.

Knowing that the adrenalin coursing through his veins would soon give way to an agonising and possibly debilitating pain, the 28-year-old used these precious minutes to assess his predicament, to figure it out coolly like a man of science.

A broken leg, no doubt shattered in multiple places. Possibly hours before his fellow hang-gliding friends would be able to locate him; if they didn't reach him by nightfall, he could be dangling here until the next morning. Unfastening his harness and climbing down to the ground five metres below was not an option, at least, not without incurring further injury. To prevent blood from pooling and to save his leg, he quickly concluded, he'd have to carefully oh-so carefully free the hang-glider's stirrup bar and one of the ropes from his harness, create a splint for his injured left leg, secure it to his right leg and hoist up both limbs while hanging there like a gammy fruit bat.

Mackay-Sim had only arrived in the US a few weeks before, a post-doctoral researcher from the University of Sydney eager to extend his studies into the olfactory system specifically, what the nose tells the brain at the University of Philadelphia. But on that blustery October day back in 1979, when a freak wind gust whooshing around Lookout Mountain near Chattanooga sent a promising young Australian scientist nosediving into the forest, before a rescue team found himhanging in the tree just before sunset, both legs securely elevated, Mackay-Sim was set to gain some useful insights that would become valuable to him in his later life. Insights that would be peculiarly relevant to his work as a pioneering stem cell researcher specialising in the treatment of spinal cord injuries.

So badly broken was his leg that Mackay-Sim spent more than six months in a wheelchair, and many more months afterwards receiving intensive physiotherapy.

"It gave me some insight into what life's like in a wheelchair, and it stayed with me," says Mackay-Sim, settling into a chair in his office at the Institute for Drug Discovery at Griffith University, just down the corridor from the laboratory where he spent years toiling over petri dishes of nasal stem cells, in his life's mission to treat spinal injuries, hereditary spastic paraplegia and diseases like Parkinson's.

A photo of the late actor Christopher Reeve is pinned on a noticeboard behind him. "I met Christopher in 2003 when he came out for a conference; he was interested in our clinical trials," Mackay-Sim says, looking at the photo. "Then in the following year I spent some time at his home in New York, and we talked a lot about spinal cord injury repair, and his own personal story."

As Mackay-Sim explains, the higher up the spinal cord an injury is, the more severe the effects. "As we know, Christopher fell off a horse and became a full paraplegic on a respirator, but in fact he suffered only a small injury; the problem was that the bleed went straight into his spinal cord. It only takes a very small injury to stop transmission; you can have large injuries to the chest and not suffer long-term repercussions but here, in the neck, a small event can change your life."

Back in the late 1980s, after he started at Griffith University, Mackay-Sim became interested in a set of extraordinary busy-bee cells in the human nose called olfactory ensheathing cells nerve cells that regenerate every single day to recreate our sense of smell. If these wonder cells are continually regenerating, he kept asking himself, could they not be transplanted to another part of the body where cells don't regenerate, like the spinal cord?

Years of scientific slog followed until 2002, when Mackay-Sim was the first researcher in the world to remove cells from the nose of a patient paralysed in a car accident, grow them in a cell culture and then, with the help of surgeons at Brisbane's Princess Alexandra Hospital, implant them in the same patient's spinal cord. "By the time Christopher died in 2006, we'd transferred stem cells from the nose into three patients and shown it was safe to do so," he says. "One of the patients recovered some sensation above the injury, which was hopeful, but one person does not make real scientific evidence."

For Mackay-Sim, the importance of scientific breakthroughs in the treatment of life-threatening illnesses is deeply personal. In 2014, he was diagnosed with multiple myeloma, an incurable form of leukaemia. As a result of the illness, which breaks down bones in an advanced form of osteoporosis, and the punishing series of treatments that followed his diagnosis, involving radiation, chemotherapy and stem cell therapy (albeit a very different form from the one the scientist was researching), Mackay-Sim lost nine centimetres in height and shed more than 15 kilograms of body weight. "I became extremely sick from the chemotherapy just prior to the bone marrow transplant," the 65-year-old recalls. "It was the worst experience of my life."

There was also the initial shock of the diagnosis, and grief for the loss of his health after a highly active life, from football and rowing in his teens to distance cycling, scuba diving and hang-gliding, which he took up while atuniversity. "Both my parents lived into their 80s and 90s and I'd been cycling up to 200 kilometres a week for decades, so I wasn't anticipating something like this."

Still, as a scientist he couldn't help but observe the trajectory of his illness with stricken fascination. "I had some good conversations with my oncologist," he smiles. "As a biologist examining my own biology, it did demystify lots of things. One minute I was a grieving patient, the next an interested scientist."

Above all, Mackay-Sim refuses to sentimentalise his battle with the illness and asks that I don't embroider it in this story by turning it into some kind of triumph of personal will power over disease. "My survival is determined by the vagaries of the particular cancer I've got," he says matter-of-factly. "Some people have nasty genetic diseases that mean they die earlier. For the moment, I feel very healthy."

Surely his extreme fitness at least helped him to survive the ravages of chemo? "I think being fit and active all my life has given me a higher quality of life after treatment," he acknowledges. "But one doctor put it to me that I probably would have sought out treatment earlier if I wasn't so fit, because I dismissed the symptoms as simple back pain from the cycling. It took two years after the chemo and radiation for the pain to go away. 2016 was a year of normality for me my back became stable enough for me to get on a road bike again."

The diagnosis added poignancy to the evening in Canberra in late January when Mackay-Sim, out of 3000- plus nominations, was crowned Australian of the Year. Sitting alongside him were his American-born wife of nearly 34 years, Lisa Peine, a retired primary school teacher, their 28-year-old daughter Matilda, a trainee psychiatrist, and 25-year-old son Callum, an engineer.

Mackay-Sim with wife Lisa Peine in North Queensland in 1983. Photo: Courtesy of Alan Mackay-Sim

Perhaps no Australian of the Year is better placed to recognise just how precious a year can be, and more determined to seize the moment to put science and innovation at the top of the national conversation. A former Queenslander of the Year, Mackay-Sim sees science as vital to our future national wellbeing, especially after the recent wake-up call in international school education rankings, which placed Australia behind Kazakhstan and Slovenia in maths and science.

Mackay-Sim agrees unequivocally with Michelle Simmons, professor of quantum physics at the University of NSW, who drew headlines recently when she declared that the "feminised" nature of Australia's high school physics curriculum (emphasising the sociology of science with essays and theory instead of rigorous lab experiments and mathematical problem-solving) had been an unmitigated failure. Introduced in the 1980s, the approach had resulted in a long, slow decline in standards.

"Scientific understanding comes from learning the processes; it can be hard work but is absolutely essential," Mackay-Sim insists. "The key to a good science education in schools is to get well-trained teachers." (Mackay-Sim has been deeply encouraged by some of the science teachers he's met since winning the award.)

The choice of Mackay-Sim the first scientist honoured as Australian of the Year since immunologist Ian Frazer in 2006 was met with near-universal applause by Australia's scientific community, who no doubt feel dispirited in this post-truth world of climate-change denial, cuts to the CSIRO and the growing view by government agencies that basic research isn't worth it.

"We need to invest in young scientists," Mackay-Sim declared in his acceptance speech, adding that the discovery of new medical treatments can reduce the strain on health budgets. "More than 10,000 Australians live with a spinal cord injury a new person is added to this tally every day." But politicians need to take a long-term view of the benefits of basic research, he tells me, "a view much longer than the political horizon".

The announcement also gave the image of the Australian of the Year awards a much-needed polish. The 2016 winner, Lieutenant-General David Morrison, drew criticism for charging up to $15,000 a pop forpublic speaking engagements, as well as grandstanding about sexism in the military despite his own handling of the army's "Jedi Council" sex scandal, in which demeaning sex videos of women were distributed among a group of soldiers. (It was revealed that Morrison's office knew of the scandal 11 months prior to the former Chief of Army releasing a now-famous condemnation on YouTube of those involved.)

Will Mackay-Sim accept speakers' fees? "I knew nothing about speakers' fees when I accepted the award," he says crisply. "I'm not pursuing money after all, I've spent my life doing public research."

Although he hasn't received any fees to date, Mackay-Sim insists that if they are offered, the funds will be donated to the Hereditary Spastic Paraplegia Research Foundation, his charity of choice.

Mackay-Sim only had a day or so to bask in the glow of being named Australian of the Year before there was a claim his scientific achievements had beenoverstated in the application. A Polish scientist, Professor Pawel Tabakow, after being approached by an Australian journalist in Europe, declared that Mackay-Sim had nothing to do with the world-first surgery using olfactory stem cells that enabled a Polish paraplegic, Darek Fidyka, to walk again. "It is not our business who should be Australian of the Year," Tabakow told The Weekend Australian. "But it is our business when his work is being linked to the surgery of Fidyka. He has no link whatsoever."

The scientific hullaballoo arose from the submission to the Australia Day Council (ADC), which states that Mackay-Sim's research "helped play a central role in proving the safety of science that was a precursor to Dr Tabokow in Poland undertaking the first successful restoration of mobility in a quadriplegic man".

Although Mackay-Sim didn't write the submission to the ADC, doesn't know who did, and never claimed to be involved in Tabokow's work, an artificial straight line was drawn between the two scientists, especially when the word "precursor" was dropped from condensed versions of the ADC's quote in multiple news stories (we'll examine the fallout from the controversy a little later).

Padding amiably about his large, multi-room laboratory, past refrigerator-sized storage cabinets containing cell cultures, past white-coated scientists peering into microscopes, Mackay-Sim seems to be in his element, with every second person saying "Hi", "Hello", or "How are you?" If stem cells are indeedthe microscopic building blocks of the world, this is the tiny universe the scientist feels most comfortable in. But it's a laboratory that now has to hum along without him Mackay-Sim retired late last year, his duties now limited to popping into the university once a week as an emeritus professor.

Later in the day, Professor George D. Mellick, head of Clinical Neurosciences at Griffith, tells me that Mackay-Sim has always set aside time to mentor younger scientists, and to explain sometimes hideously complicated science to a lay audience, but would be the last person to crow about his own scientific achievements.

"One of the things that isn't highlighted very much about Alan's work is his research into Parkinson's. We've been able to learn a lot about Parkinson's by studying cells from people with the disease, and the information coming out of this research will hopefully lead to better treatments."

Back in his office, Mackay-Sim gives me a quick rundown, 101-style, on the human nose. No, the human sense of smell doesn't necessarily decline with age, unless illness or disease set in, and it is astonishingly adept at distinguishing hundreds of thousands of different odours. Yes, women do have a superior sense of smell to men, but the difference is surprisingly only slight. Yes, the first symptom of Parkinson's, before the typical tremors set in, is a reduced sense of smell, as it is with those sufferers who will go on to develop dementia. And yes paws down dogs do have a vastly more powerful sense of smell than humans, although it's impossible to quantify by exactly how much (Mackay-Sim has been known to hide from his spoodle Henry, to measure how long it takes for the dog to find him).

As he relays all this, Mackay-Sim's eyes twinkle and a smile lights up his face: it's easy to see how he'd be the perfect academic for Griffith to call on to schmooze a government minister or potential philanthropist and secure desperately sought-after funding. I ask him about his trademark moustache, which he's had since the early 1990s, when he shaved off a beard. "My wife wouldn't recognise me without it," he jokes. "She says that a small mammal could roost beneath my mouth."

Mackay-Sim, whose double-barrelled surname comes from his paternal grandfather, grew up in middle-class Roseville, on Sydney's leafy North Shore, the third of four brothers. His mother Lois was a nurse during World War II and later a full-time mum while his father Malcolm ran a hardware importing and distributing business, Macsim Distributors (now Macsim Fasteners, owned by Alan's eldest brother, Fraser). At North Sydney Boys' High he was "the opposite of a shit-stirrer. I was vice captain, head of the cadets, played football, was in the rowing team, had a shot at athletics, sang in the choir I did it all."

With wife, Lisa Peine, in Sulawesi, Indonesia, 2007. Photo: Courtesy of Alan Mackay-Sim

After graduating with honours in science from Macquarie University, Mackay-Sim picked up tutoring work in the department of physiology at the University of Sydney, where he completed a PhD on the brain's visual system. Two academic stints in the US followed, first at the University of Pennsylvania from 1979 until 1981, followed by two years at the University of Wyoming, during which time he met his wife Lisa, then living in northern Colorado.

The pair married in 1984, by which time Mackay-Sim had been offered a research role in the department of physiology at the University of Adelaide. He started at Griffith University in 1987, where his research concentrated on the biology of nasal cells.

At the height of the heated moral debate over the use of embryonic stem cells whether the therapeutic potential of stem cells could justify destroying human embryos to extract them Mackay-Sim met Pope Benedict XVI at a Vatican conference in 2005. The Pope congratulated him on his exclusive use of adult stem cells.

"I wasn't avoiding embryonic stem cells for religious reasons," Mackay-Sim explains. "It just so happenedthat I was working with adult stem cells at the time and the conference was looking at alternatives to using embryonic stem cells. But it was a scientific conference and I was impressed with its calibre; the only difference was that men in purple robes were sitting at the back asking questions."

Later in the same trip, Mackay-Sim was invited, along with a host of others, to the Apostolic Palace at Castel Gandolfo the Vatican summer palace. "You feel the history of the Roman Catholic Church, with the Pope coming in with his cardinals and the Swiss Guards," he says. "I'm not a believer, but it was a very powerful experience."

In 2006, the debate over embryonic stem cells virtually vanished when scientist Shinya Yamanaka from Japan's Kyoto University stunned the world by proving that stem cells needn't come from human embryos adult cells can be reprogrammed to act like stem cells, to be returned to an embryo-like state (Yamanaka's discovery won him the Nobel Prize in 2012). "Yamanaka worked out how to genetically engineer any cells so that they had the properties of embryonic stem cells," says Mackay-Sim, who nonetheless continued to focus on adult stem cells only.

Mackay-Sim accomplished his own world first in 2002 when, with the assistance of doctors at Brisbane's Princess Alexandra Hospital, he transplanted olfactory stem cells into the spinal cord of a man crippled in a car accident. The procedure was repeated with two other paraplegic patients at the same hospital and the study wrapped up in 2007.

While the procedures didn't result in any of the patients regaining useful movement in their legs, the results of Mackay-Sim's clinical trials, published in 2005 and 2008, paved the way for further development of olfactory stem cell transplantation.

One researcher who followed Mackay-Sim's trials closely was Geoffrey Raisman from University College London, who visited the Australian team shortly after the first operation in Brisbane to study their work. Raisman later led the British team who worked with Polish surgeon Tabakow on Darek Fidyka in 2012.

Tabakow deployed 100 separate micro-injections of olfactory sheathing cells above and below Fidyka's spinal injury, with the hope these cells would provide a skeleton for nerve fibres to grow and reconnect. A former volunteer firefighter, Fidyka had become paralysed in 2010 after a severe knife attack by the jealous ex-husband of his girlfriend. The repeated stab wounds to Fidyka's back severed his spinal cord, paralysing from the waistdown. (Fidyka's attacker, a fellow firefighter, committed suicide shortly afterwards.)

There's no doubt Tabakow's work was a major advance on Mackay-Sim's research. Tabakow's strategy was to extract ensheathing cells specifically from the olfactory bulbs in Fidyka's nose, grow them in a culture, while also extracting nerve cells from his ankle in a multi-pronged attempt at spinal cord reconstruction. After a series of operations, Fidyka can walk with the assistance of a frame, has regained some bladder control and sexual function, and can ride a tricycle.

Raisman described their new stem cell procedure as "more impressive than man walking on the moon", but it will have be tested on other paraplegics, including those with more severe injuries than Fidyka's, such as car accident victims who have had more of their spinal cord damaged, before it can be declared a reliable method of restoring mobility. As impressive as Tabakow's achievement is, it has still only worked on one patient.

Nobody, however, disputes Mackay-Sim's immense contribution to stem cell transplantation; his work is unimpeachable. If nothing else, he was at the forefront of the science showing that restoring the ability to walk to paraplegics is no longer science fiction. "What I've always said is that we did the first phase of clinicaltrials with olfactory stem cells, and the aim of those trials was to show they were safe," says Mackay-Sim. "That was the first important step."

Mackay-Sim wrote to Tabakow shortly after the controversy blew up, explaining that he didn't write the submission to the Australia Day Council, and was in no way claiming credit for Fidyka's remarkable recovery. "He wrote back a very nice email," says Mackay-Sim. "I believe I've given credit to other scientists in every interview I've given to journalists. I feel comfortable in my behaviour and ethics."

With Prime Minister Turnbull in January this year. Photo: Elesa Kurtz

Mackay-Sim can remember the day when he felt something was wrong terribly wrong. He'd been suffering back pain for months, but dismissed it as old age, or strain from bending over on his bicycle on long rides, and stocked up his pantry with painkillers. "I was in Colorado with Lisa visiting her family, and the pain became so bad I couldn't walk very far. I found the pain eased when I got on my bicycle. I flew home a week before she did; the plane trip back was absolute hell."

What followed was a swift diagnostic journey from his GP to specialists at Brisbane's Wesley Hospital, resulting in a devastating diagnosis. "They suspected something cancerous quite quickly. I didn't realise how ill I was; by this stage, my kidneys weren't coping at all with the antibodies released from my white blood cells, which were going berserk trying to fight the disease. I was at risk of kidney failure and my bones were becoming very fragile. I started therapy almost immediately, in June 2014. Then began the cycles of chemotherapy and stem cell treatment in December."

Since the beginning of last year, however, Mackay-Sim's health has dramatically improved, and even though he's retired to his beachside home in Currimundi on the Sunshine Coast, he is still active in university affairs. He concedes that his health may prevent him from being as active as Rosie Batty, perhaps our most vigorous Australian of the Year to date. But he's already spoken at functions in Brisbane, Sydney and Perth, and will be attending the national March for Science on April 22, which coincides with Earth Day. He moves with the speed and fluidity of a man 10 or 15 years younger.

"I feel very healthy, very energised at the moment," says Mackay-Sim, who is planning a bicycle ride in Italy's Dolomites in July with a couple of mates. (Last year he and his wife went on the Great Victorian Bike Ride, a seven-day ride averaging 85 kilometres a day.)

"I do need to be selective with the number of invitations around Australian of the Year," he concedes, "but I'll do everything I can. After all, what more exciting time could you have to talk about science?"

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Australian of the Year Alan Mackay-Sim on the advantage of being 'an interested scientist' - The Age

OSAKA, Japan & LEUVEN, Belgium--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE:4502) (Takeda) and TiGenix NV (Euronext Brussels and Nasdaq:TIG) (TiGenix) today announced new data from the Phase 3 ADMIRE-CD clinical trial, which indicated that investigational compound Cx601, a suspension of allogeneic expanded adipose-derived stem cells (eASC), maintained long-term remission of treatment refractory complex perianal fistulas in patients with Crohns disease over 52 weeks.1 Results were presented at the 12th Congress of the European Crohns and Colitis Organisation (ECCO).

The ADMIRE-CD trial is a randomized, double-blind, controlled, Phase 3 trial, designed to investigate the efficacy and safety of the investigational compound Cx601 for the treatment of complex perianal fistulas in patients with Crohns disease.2 Patients were randomized to a single administration of Cx601 cells or placebo (control), both added to standard of care.1 A significantly greater proportion of patients in the Cx601 group versus the control group achieved clinical and radiological combined remission* (56.3% and 38.6%; p=0.010), and clinical remission (59.2% and 41.6%; p=0.013) at week 52 in the modified intention-to-treat population (mITT).1 Of those mITT patients who had shown combined remission at week 24, a greater number in the Cx601 group versus the control group reported no relapse at week 52 (75.0% and 55.9%).1 The rates and types of treatment related adverse events (non-serious and serious) and discontinuations due to adverse events were indicated to be similar in both groups (Cx601: 20.4%; control: 26.5%).1

Crohns disease is a chronic inflammatory disease of the gastrointestinal tract, which is thought to affect up to 1.6 million people in Europe.3 Complex perianal fistulas are a complication for people living with Crohns disease and there are limited treatment options. Recognizing the rare and debilitating nature of the disorder, and lack of treatment options, in 2009 the European Commission granted Cx601 orphan designation for the treatment of anal fistula. In March 2016, TiGenix announced that it submitted the Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Cx601, and a decision by the EMA is expected in 2017. Additionally, in September 2016 orphan drug status was received from the Swiss Agency for Therapeutic Products (Swissmedic) regarding Cx601 for the rare disease complex perianal fistulas in Crohns disease.4

Perianal fistulizing Crohns disease is difficult to treat with currently available therapies and often leads to pain, swelling, infection and incontinence, said Dr. Asit Parikh, Head of Takedas Gastroenterology Therapeutic Area Unit. Existing therapies are limited and associated with complications and a high failure rate. Cx601 may offer patients an alternative treatment option.

These data highlight that the efficacy and safety of a single administration of Cx601 were maintained during one year of follow up, said Dr. Marie Paule Richard, Chief Medical Officer at TiGenix. It is important to also note that the definition of combined remission used in the ADMIRE-CD study, which includes both clinical and radiological assessment by MRI, is more stringent than the criteria commonly used in previous large scale, randomized clinical trials evaluating perianal fistulas in Crohns disease, based only on clinical assessment.

A global pivotal Phase 3 trial for U.S. registration with Cx601 for the treatment of complex perianal fistulas is expected to be initiated by TiGenix in 2017. In the U.S., TiGenix intends to apply for fast track designation from the U.S. Food and Drug Administration (FDA), which would facilitate and expedite the development and review process in the U.S.

Takedas Commitment to Gastroenterology

Takeda is a global leader in gastroenterology. With expertise spanning more than 25 years, the companys dedication to innovation continues to evolve and have a lasting impact. ENTYVIO (vedolizumab) demonstrates Takedas global capabilities and expansion into the specialty care market in gastroenterology and biologics. Designed and developed specifically to target the gastrointestinal (GI) tract, ENTYVIO was launched in 2014 for the treatment of adults with moderate to severe ulcerative colitis and Crohns disease. TAKECAB (vonoprazan fumarate) is Takeda's potassium-competitive acid blocker and was launched in Japan in 2015. Takeda also markets motility agent AMITIZA (lubiprostone), which originally launched in 2006 for the treatment of chronic idiopathic constipation, and received subsequent approval to treat irritable bowel syndrome with constipation and opioid-induced constipation. Preceding these notable launches, Takeda pioneered gastroenterological breakthroughs in proton pump inhibitors beginning in the 1990s with lansoprazole.Through specialized and strategic in-house development, external partnerships, in-licensing and acquisitions, Takeda currently has a number of promising early stage GI assets in development, and remains committed to delivering innovative, therapeutic options for patients with gastrointestinal and liver diseases.

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.

About TiGenix

TiGenix NV (Euronext Brussels and Nasdaq: TIG) is an advanced biopharmaceutical company focused on developing and commercializing novel therapeutics from its proprietary platforms of allogeneic, or donor-derived, expanded stem cells. Our lead product candidate from the adipose-derived stem cell technology platform is Cx601, which is in registration with the EMA for the treatment of complex perianal fistulas in Crohns disease patients. Our adipose-derived stem cell product candidate Cx611 has completed a Phase I sepsis challenge trial and a Phase I/II trial in rheumatoid arthritis. Effective July 31, 2015, TiGenix acquired Coretherapix, whose lead cellular product candidate, AlloCSC-01, is currently in a Phase II clinical trial in acute myocardial infarction. In addition, the second product candidate from the cardiac stem cell-based platform acquired from Coretherapix, AlloCSC-02, is being developed in a chronic indication. On July 4, 2016, TiGenix entered into a licensing agreement with Takeda, a large pharmaceutical company active in gastroenterology, under which Takeda acquired the exclusive right to develop and commercialize Cx601 for complex perianal fistulas outside the United States. TiGenix is headquartered in Leuven (Belgium) and has operations in Madrid (Spain).

About Cx601

Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASC) locally injected. Cx601 is an investigational compound being developed in Crohns disease for the treatment of complex perianal fistulas showing inadequate response to at least one conventional or biologic therapy including antibiotics, immunosuppressants, or anti-TNF agents. Crohns disease is a chronic inflammatory disease of the intestine and, as a complication of it, patients can suffer from complex perianal fistulas, for which there is currently no effective treatment. In 2009, the European Commission granted Cx601 orphan designation for the treatment of anal fistulas, recognizing the debilitating nature of the disease and the lack of treatment options. Cx601 has met the primary end-point in the Phase 3 ADMIRE-CD study, a randomized, double-blind, controlled trial run in Europe and Israel and designed to comply with the requirements laid down by the EMA. Madrid Network issued a soft loan to help finance this Phase 3 study, which was funded by the Secretary of State for Research, Development and Innovation (Ministry of Economy and Competitiveness) within the framework of the INNTEGRA plan. In this trial, patients were randomized to a single administration of Cx601 cells or placebo (control), both added to standard of care. The studys primary endpoint was combined remission, defined as clinical assessment at week 24 of closure of all treated external openings draining at baseline despite gentle finger compression, and absence of collections >2cm confirmed by MRI. In the ITT population (n=212), Cx601 achieved statistically significant superiority (p=0.024) on the primary endpoint with 50% combined remission at week 24 compared to 34% in the control arm. Efficacy results were robust and consistent across all statistical populations. Treatment emergent adverse events (non-serious and serious) and discontinuations due to adverse events were comparable between Cx601 and control arms. The 24-week results have been published by The Lancet, one of the most highly regarded and well known medical journals in the world. The Phase 3 study has completed a follow-up analysis at 52 weeks confirming its sustained efficacy and safety profile. Top line follow-up data showed that in the ITT population Cx601 achieved statistical superiority (p=0.012) with 54% combined remission at week 52 compared to 37% in the control arm. Long-term results also showed that, of patients with combined remission at week 24, a higher proportion of patients treated with Cx601 had no relapse at week 52 (75.0% vs. 55.9%). Based on the positive 24-weeks Phase 3 study results, TiGenix has submitted a Marketing Authorization Application to the EMA in early 2016. TiGenix is preparing to develop Cx601 in the U.S. after having reached an agreement with the FDA through a special protocol assessment procedure (SPA) in 2015. On July 4, 2016, TiGenix entered into a licensing agreement with Takeda, a pharmaceutical company leader in gastroenterology, whereby Takeda acquired an exclusive right to develop and commercialize Cx601 for complex perianal fistulas in Crohns patients outside of the U.S.

-Ends-

____________

* defined as clinical assessment of closure of all treated external openings draining at baseline, despite gentle finger compression, and absence of collections >2cm confirmed by MRI

References

1 Pans, J, Garca-Olmo, D, Van Assche, G, et al., Long-term efficacy and safety of Cx601, allogeneic expanded adipose-derived mesenchymal stem cells, for complex perianal fistulas in Crohns Disease: 52-week results of a phase III randomized controlled trial. ECCO 2017; Barcelona: Abstract OP009.

2 Clinicaltrials.gov. Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease (ADMIRE-CD). https://clinicaltrials.gov/ct2/show/NCT01541579?term=cx601&rank=2. Published February 2012. Accessed February 9, 2017.

3 Burisch, J, Jess, T, Martinato, M, et al., on behalf of ECCO EpiCom. The burden of inflammatory bowel disease in Europe. J Crohns Colitis. 2013; 7: 322-337.

4 Swissmedic. About us Collaboration National collaboration Patients and Users. Available at https://www.swissmedic.ch/ueber/01398/01400/03296/index.html?lang=en. Accessed February 9, 2017.

Original post:
Takeda and TiGenix Report New Data Highlighting Maintenance of ... - Business Wire (press release)

Clinical trials using neural stem cells

Neural stem cells (mouse)

StemCell Inc In December 2010 the Swiss regulatory agency for therapeutic products gave the go-ahead for aStemCell, Inc.-SponsoredPhase I/II clinical trial on chronic spinal cord injuryat the Balgrist University Hospital in Zurich (Switzerland). This trial had been inspired by the preclinical evidence of direct oligodendrocyte cell replacement through human neural stem cell (NSC) transplants in early chronic SCI in a particular mouse model. The trial uses a type of stem cell derived from human brain tissue and can make any of the three major kinds of neural cells found in the central nervous system. A single donor can provide eough cells for several transplanted patients). A single dose (20 x 106cells) of HuCNS-SC is directly implanted through multiple injections into thethoracicspinal cord of patients with chronic thoracic (T2T11) SCI, and immune suppression administered for 9 months after transplantation. This trial had enrolled patients 312 months after complete and incomplete cord injuries. The estimated completion date of this study is March 2016 (clinicaltrials.govidentifier no. NCT01321333). Interim analysis of clinical data to May 2014, presented at the Annual Meeting of the American Spinal Injury Association in San Antonio, Texas has shown that the significant post-transplant gains in sensory function first reported in two patients have now been observed in two additional patients.

The next group of patients currently being recruited in North America (University of Calgary) as well as in Switzerland has included some with incomplete injuries (ie some retained sensory or motor function) (clinicaltrials.govidentifier no. NCT01725880).

Earlier last year, the same company completed enrollment in multicentre open-label Phase I/II clinical titled "Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury" (Pathway Study website;clinicaltrials.govidentifier no. NCT02163876). The Pathway Study is the first clinical study designed to evaluate both the safetyandefficacy of transplanting stem cells. A total of 52 patients with traumatic injury to the cervical spinal cord are enrolled in the trial. The trial will be conducted as a randomized, controlled, single blind study and efficacy will be primarily measured by assessing motor function according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The primary efficacy outcome will focus on change in upper extremity strength as measured in the hands, arms, and shoulders. The trial will follow the patients for one year from the time of enrollment.

The hope is that when transplanted into the injured spinal cord, these cells may re-establish some of the circuitries important for the network of nerves that carry information around the body.

Neuralstem Neuralstembegan surgeries in a Phase I safety trial of its NSI-566 neural stem cells for chronic spinal cord injury (cSCI) at the University of California, San Diego School of Medicine, with support from the UC San Diego Sanford Stem Cell Clinical Center, in September 2014 (clinicaltrials.govidentifier no. NCT01772810). The FDA amended the Phase I trial protocol to include a total of four patients, as the safety of the same cells and a similar procedure were proven in Neuralstems NSI-566/ALS trials. The four cSCI patients, with thoracic spinal cord injuries (T2-T12), have an American Spinal Injury Association (AIS) grade A level of impairment one-to-two years post-injury. This means that they have no motor or sensory function in the relevant segments at or below the injury, and are considered to be completely paralysed.

All patients in the trial will receive six injections in, or around, the injury site, using the same cells and similar procedure as the companys Amyotrophic Lateral Sclerosis (ALS) trials (the first FDA-approved neural stem cell trial for the treatment of ALS). All patients will also receive physical therapy post-surgery to guide newly formed nerves to their proper connections and functionality. The patients will also receive immunosuppressive therapy, which will be for three months, as tolerated. The trial study period will end six months post-surgery of the last patient, with a one-year Phase I completion goal. An NSI-566/acute spinal cord injury Phase I/II trial is expected to commence in the first quarter of 2015 in Seoul, South Korea.

The Miami Project to Cure Paralysis The Miami Projectclinical researchers currently have several clinical trials and clinical studies available for people who have had a spinal cord injury; some are for acute injuries and some are for chronic injuries. The clinical trials are testing the safety and efficacy of different cellular, neuroprotective, reparative, or modulatory interventions. These include Phase I clinical trials with the patients own (peripheral nerve-derived) Schwann cells in bothsubacute thoracicandchronic cervical and thoracicSCIs and a multicenter Phase II clinical trial withHuCNS-SC in chronic cervical SCIs(as above). All these Miami Project cell therapy trials are recruiting patients (more info on clinicaltrials.gov).

Mesenchymal/stromal stem cellsare being investigated as possible treatments for spinal cord injuries. Clinical Trials (clinicaltrials.gov) identifies at present total of 9 trials tagged as MSC trials in spinal cord injuries. These include studies that investigate the safety and efficacy of MSCs derived from the patients own bone marrow (5), adipose tissue (fat) (3) or cord blood (1). MSCs are injected in a number of different ways in these trials - including directly into the spinal cord or the lesion itself, intravenously, or even just in the skin, in patients with chronic cervical to thoracic injuries showingASIA/ISCoS scoresbetween A (complete lack of motor and sensory function below the level of injury) and C (some muscle movement is spared below the level of injury, but 50 percent of the muscles below the level of injury cannot move against gravity).

The hope is that when transplanted into the injured spinal cord, these cells may provide tissue protective molecules/factors and help (indirectly from cell integration and differentiation) to re-establish some of the circuitries important for the network of nerves that carry information around the body.

California based biotech Geronhad a widely reported clinical trial under way for a treatment the first of its kind involving the injection of cells derived from human embryonic stem cells. The injected cells were precursors of oligodendrocytes, the cells that form the insulating myelin sheath around axons. Researchers hoped that these cells, once injected into the spinal cord, would mature and form a new coating on the nerve cells, restoring the ability of signals to cross the spinal cord injury site.

After treating four patients with these cells in a phase one (safety) trial, and reporting no serious adverse effects, Geron announced in November 2011 it was discontinuing its stem cell programme. The company said stem cells continue to hold great promise, but cited financial reasons for shifting focus to other areas of research.

Asterias Biotherapeutics Following up on the cellular technology initially developed by Geron, Asterias Biotherapeutics has developed a program that focuses on the development of a kind of nerve cell, oligodendrocyte progenitor cells (OPCs) for spinal cord injury. These cells, known as AST-OPC1, are produced from human embryonic stem (ES) cells.

In aPhase 1 clinical trial, five patients with neurologically complete, thoracic spinal cord injury were administered two million hES cell-derived OPCs at the spinal cord injury site 7-14 days post-injury. The subjects received low levels immunosuppression for the next 60 days. Delivery of OPCs was successful in all five subjects with no serious adverse events associated with the administration of the cells or the immunosuppressive regimen. In four of the five subjects, serial MRI scans suggested reduction of the volume of injury in the spinal cord

A second follow up (dose escalation)Phase I/II trialwith AST-OPC1 in acute (14-30 days after injury) sensorimotor complete cervical spinal cord injuries (SCI) is currently recruiting participants.

The hope is that when acutely transplanted into the injured spinal cord, OPCs may remyelinate and restore lost functions.

Read more:
Spinal cord injuries: how could stem cells help ...

Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotentiMSC, also called an induced multipotent progenitor celliMPC) or unipotent(iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

Three techniques are widely recognized:[1]

In 1895 Thomas Morgan removed one of a frog's two blastomeres and found that amphibians are able to form whole embryos from the remaining part. This meant that the cells can change their differentiation pathway. In 1924 Spemann and Mangold demonstrated the key importance of cellcell inductions during animal development.[20] The reversible transformation of cells of one differentiated cell type to another is called metaplasia.[21] This transition can be a part of the normal maturation process, or caused by an inducement.

One example is the transformation of iris cells to lens cells in the process of maturation and transformation of retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation.[22]

The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the embryo. They showed that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo.[23]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection. Moreover, they can make this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent "reserve" stem cells.[24] Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo.[25]

After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves and then differentiate into the cell types needing replacement in the damaged tissue[26] Macrophages can self-renew by local proliferation of mature differentiated cells.[27][28] In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been. This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand.[29]

A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency and can differentiate into endodermal, ectodermal and mesodermal cells both in vitro and in vivo.[30][31][32][33][34]

Other well-documented examples of transdifferentiation and their significance in development and regeneration were described in detail.[35][36]

Induced totipotent cells can be obtained by reprogramming somatic cells with somatic-cell nuclear transfer (SCNT). The process involves sucking out the nucleus of a somatic (body) cell and injecting it into an oocyte that has had its nucleus removed[3][5][37][38]

Using an approach based on the protocol outlined by Tachibana et al.,[3] hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells.[39] Such reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.

Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring.[40]

These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,[41] offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a SCNT method that includes a histone deacetylase inhibitor, trichostatin, added to the cell culture medium,[42] show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors[43] However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues.[44]

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[3][45] For example, the technology could prevent inherited mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, creating a cell that could be regarded as having two mothers. The eggs were then fertilised and the resulting embryonic stem cells carried the swapped mitochondrial DNA.[46] As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old and are the product of mitochondrial transplants across different genetic backgrounds.[47]

In late-generation telomerase-deficient (Terc/) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming.[48]

Other cloning and totipotent transformation achievements have been described.[49]

Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone.[50] Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (trophectodermal) markers.[51]

iPSc were first obtained in the form of transplantable teratocarcinoma induced by grafts taken from mouse embryos.[52] Teratocarcinoma formed from somatic cells.[53]Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency.[54][55][56] It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors.[57] In the 1980s, it became clear that transplanting pluripotent/embryonic stem cells into the body of adult mammals, usually leads to the formation of teratomas, which can then turn into a malignant tumor teratocarcinoma.[58] However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal.[59][60][61] This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").

In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.[7]

Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.[62] IPSC properties are very similar to ESCs.[63] iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo,[64] the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.[18]

An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.[9][65][66]

Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives.[67] Thus, reprogramming leads to the restoration of embryonic telomere length,[68] and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit.[69]

However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response,[70] which can be used for medical purposes,[71] or the formation of tumors such as teratoma.[72] The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms.[73] So, the immune system might detect and attack cells that are not cooperating properly.

A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via cytochrome c release across the mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation. This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines has the potential to reduce the risk of teratomas and other problems in regenerative medicine.[74]

In 2012 other small molecules (selective cytotoxic inhibitors of human pluripotent stem cellshPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture.[75][76] An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s) (i.e., survivin or Bcl10). A single treatment with chemical survivin inhibitors (e.g., quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation.[77] However, it is unlikely that any kind of preliminary clearance,[78] is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors.[79] This may be due to the disorder of let-7 regulation of its target Nr6a1 (also known as Germ cell nuclear factor - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following micro-RNA miRNA loss.[80]

Teratoma formation by pluripotent stem cells may be caused by low activity of PTEN enzyme, reported to promote the survival of a small population (0,1-5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of Nanog as well as a propensity for increased glucose and cholesterol metabolism.[81] These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.[82] In connection with the above safety problems, the use iPSC for cell therapy is still limited.[83] However, they can be used for a variety of other purposes - including the modeling of disease,[84] screening (selective selection) of drugs, toxicity testing of various drugs.[85]

It is interesting to note that the tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for autologous transplantation[86] At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs.[51] Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of Polycomb targets and altered DNA methylation) in cells that drive cancer development.[87]

Determining the unique set of cellular factors that is needed to be manipulated for each cell conversion is a long and costly process that involved much trial and error. As a result, this first step of identifying the key set of cellular factors for cell conversion is the major obstacle researchers face in the field of cell reprogramming. An international team of researchers have developed an algorithm, called Mogrify(1), that can predict the optimal set of cellular factors required to convert one human cell type to another. When tested, Mogrify was able to accurately predict the set of cellular factors required for previously published cell conversions correctly. To further validate Mogrify's predictive ability, the team conducted two novel cell conversions in the laboratory using human cells and these were successful in both attempts solely using the predictions of Mogrify.[89][90][91] Mogrify has been made available online for other researchers and scientists.

By using solely small molecules, Deng Hongkui and colleagues demonstrated that endogenous "master genes" are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds.[17] The effectiveness of the method is quite high: it was able to convert 0.02% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months". So, this chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.[92][93]

In 2015th year a robust chemical reprogramming system was established with a yield up to 1,000-fold greater than that of the previously reported protocol. So, chemical reprogramming became a promising approach to manipulate cell fates.[94]

The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to genetically modified pig or mouse that has suppressed immune system activation on human cells. The formed teratoma is cut out and used for the isolation of the necessary differentiated human cells[95] by means of monoclonal antibody to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid and lymphoid human cells suitable for transplantation (yet only to mice).[96] Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation and drug screening applications. Using MitoBloCK-6[74] and/or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al.[97] They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases.[98]

For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human SIRP.[99] To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig, which disrupts T cell costimulatory pathways and PD-L1, which activates T cell inhibitory pathway.[100]

See also: US 20130058900 patent.

In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs[101][102] and how to use them for cell therapy.[103][104] Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation.[105] However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restoredincluding a woman who had only 17 percent of her vision left.[106]

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. So there is an urgent need for effective cell therapy and lung tissue engineering.[107][108] Several protocols have been developed for generation of the most cell types of the respiratory system, which may be useful for deriving patient-specific therapeutic cells.[109][110][111][112][113]

Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro.[114]

The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use. An alternative approach is so-called "direct reprogramming" - transdifferentiation of cells without passing through the pluripotent state.[115][116][117][118][119][120] The basis for this approach was that 5-azacytidine - a DNA demethylation reagent - can cause the formation of myogenic, chondrogenic and adipogeni clones in the immortal cell line of mouse embryonic fibroblasts[121] and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.[122] Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division.[123] The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.[120] For example, Chandrakanthan et al., & Pimanda describe the generation of tissue-regenerative multipotent stem cells (iMS cells) by treating mature bone and fat cells transiently with a growth factor (platelet-derived growth factorAB (PDGF-AB)) and 5-Azacytidine. These authors claim that: "Unlike primary mesenchymal stem cells, which are used with little objective evidence in clinical practice to promote tissue repair, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner without forming tumors" and so "has significant scope for application in tissue regeneration."[124][125][126]

Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm Caenorhabditis elegans with no requirement for a dedifferentiated intermediate.[127]

The cell fate can be effectively manipulated by epigenome editing. In particular, by directly activating of specific endogenous gene expression with CRISPR-mediated activator. When dCas9 (that has been modified so that it no longer cuts DNA, but still can be guided to specific sequences and to bind to them) is combined with transcription activators, it can precisely manipulate endogenous gene expression. Using this method, Wei et al., enhanced the expression of endogenous Cdx2 and Gata6 genes by CRISPR-mediated activators, thus directly converted mouse embryonic stem cells into two extraembryonic lineages, i.e., typical trophoblast stem cells and extraembryonic endoderm cells.[128] An analogous approach was used to induce activation of the endogenous Brn2, Ascl1, and Myt1l genes to convert mouse embryonic fibroblasts to induced neuronal cells.[129] Thus, transcriptional activation and epigenetic remodeling of endogenous master transcription factors are sufficient for conversion between cell types. The rapid and sustained activation of endogenous genes in their native chromatin context by this approach may facilitate reprogramming with transient methods that avoid genomic integration and provides a new strategy for overcoming epigenetic barriers to cell fate specification.

Another way of reprogramming is the simulation of the processes that occur during amphibian limb regeneration. In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates into limb tissue. However, sequential small molecule treatment of the muscle fiber with myoseverin, reversine (the aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), SB203580 (p38 MAP kinase inhibitor), or SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone and nervous system cells.[130]

The researchers discovered that GCSF-mimicking antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells. The technique[131] enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.[132]

Schlegel and Liu[133] demonstrated that the combination of feeder cells[134][135][136] and a Rho kinase inhibitor (Y-27632) [137][138] induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally.[133][139][140] CRC technology can generate 2106 cells in 5 to 6 days from needle biopsies and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors.[133][141][142]

The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking.[133][141][142] Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor.[143] Engleman's group[144] describes a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance using CRC system. In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs and more importantly that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.[145]

Riegel et al.[146] demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neuinduced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs). Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells. However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+ and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation. Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies.

A different approach to CRC is to inhibit CD47a membrane protein that is the thrombospondin-1 receptor. Loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. Thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.[147] In vivo blockade of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow-derived cells and radioprotection of radiosensitive gastrointestinal tissues.[148]

Differentiated macrophages can self-renew in tissues and expand long-term in culture.[27] Under certain conditions macrophages can divide without losing features they have acquired while specializing into immune cells - which is usually not possible with differentiated cells. The macrophages achieve this by activating a gene network similar to one found in embryonic stem cells. Single-cell analysis revealed that, in vivo, proliferating macrophages can derepress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. This happened when concentrations of two transcription factors named MafB and c-Maf were naturally low or were inhibited for a short time. Genetic manipulations that turned off MafB and c-Maf in the macrophages caused the cells to start a self-renewal program. The similar network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers.[28]

Hence macrophages isolated from MafB- and c-Maf-double deficient mice divide indefinitely; the self-renewal depends on c-Myc and Klf4.[149]

Indirect lineage conversion is a reprogramming methodology in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation in a specially developed chemical environment (artificial niche).[150]

This method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes and results in much greater yield than other methods. However, the safety of these cells remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo.[151]

A common feature of pluripotent stem cells is the specific nature of protein glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not white blood cells.[152] The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60 and Tra 1-81.[153] Suila Heli et al.[154] speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, leftright asymmetry, apoptosis, somitogenesis, angiogenesis and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin[155] and Jafar-Nejad et al.[156])

Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation.[157] The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state.[158]

For example, activation of glycoprotein ACA,[159] linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes Wnt, Notch-1, BMI1 and HOXB4 through a signaling cascade PI3K/Akt/mTor/PTEN and promotes the formation of a self-renewing population of hematopoietic stem cells.[160]

Furthermore, dedifferentiation of progenitor cells induced by ACA-dependent signaling pathway leads to ACA-induced pluripotent stem cells, capable of differentiating in vitro into cells of all three germ layers.[161] The study of lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.[162]

Cell adhesion protein E-cadherin is indispensable for a robust pluripotent phenotype.[163] During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin.[164] These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells.[165] Moreover, sphere formation, due to forced growth of cells on a low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors.

Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells' epigenetic state. Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)a subunit of H3 methyltranferaseby microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state.[166]

Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting neural crest differentiation of hESCs in a BMP4-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility.[167]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cellsubstratum adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biosubstrates, or by manipulating the cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA does not promote differentiation.[168] Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described.[169][170]

A new method has been developed that turns cells into stem cells faster and more efficiently by 'squeezing' them using 3D microenvironment stiffness and density of the surrounding gel. The technique can be applied to a large number of cells to produce stem cells for medical purposes on an industrial scale.[171][172]

Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in microfluidic devices,[173] which is:

Stem cells possess mechanical memory (they remember past physical signals)with the Hippo signaling pathway factors:[174] Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostatthat stores information from past physical environments and influences the cells' fate.[175][176]

Stroke and many neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases.[177] Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation.[178] Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications.[118][119][120][179][180]

For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains.[181] INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models.[180]

Neural chemically induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of TGF beta signaling pathways), under a physiological hypoxic condition.[182] Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase and TGF- pathways (where: sodium butyrate (NaB) or Trichostatin A (TSA) could replace VPA, Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with SB-431542 or Tranilast) show similar efficacies for ciNPC induction.[182] Zhang, et al.,[183] also report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components.

Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.[184]

Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and Myt1l) are activated after transplantation using a drug.[185]

Astrocytesthe most common neuroglial brain cells, which contribute to scar formation in response to injurycan be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation.[186] The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord.[187]

Without myelin to insulate neurons, nerve signals quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings and as a consequence lead to cognitive, motor and sensory problems. Transplantation of oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight[188] or of the three[189] transcription factors Sox10, Olig2 and Zfp536, may provide such cells.

Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors[115] or microRNAs[14] to the heart.[190] Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation.[115][191] These results implicated therapies that can directly remuscularize the heart without cell transplantation. However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes.[192]

Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.[193][194] Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts and reduced remodeling of the heart after ischemic damage.[195]

The team of scientists, who were led by Sheng Ding, used a cocktail of nine chemicals (9C) for transdifferentiation of human skin cells into beating heart cells. With this method, more than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs and developed into healthy-looking heart muscle cells within the organ.[196] This chemical reprogramming approach, after further optimization, may offer an easy way to provide the cues that induce heart muscle to regenerate locally.[197]

In another study, ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.[198] One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds.[199]

Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug ITD-1, which effectively clears the cell surface from TGF- receptor type II and selectively inhibits intracellular TGF- signaling. It thus selectively enhances the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.[200]

One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts. In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs.[201]

Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) in situ represents a promising strategy for cardiac regeneration. Mice exposed in vivo, to three cardiac transcription factors GMT (Gata4, Mef2c, Tbx5) and the small-molecules: SB-431542 (the transforming growth factor (TGF)- inhibitor), and XAV939 (the WNT inhibitor) for 2 weeks after myocardial infarction showed significantly improved reprogramming (reprogramming efficiency increased eight-fold) and cardiac function compared to those exposed to only GMT.[202]

See also: review[203]

The elderly often suffer from progressive muscle weakness and regenerative failure owing in part to elevated activity of the p38 and p38 mitogen-activated kinase pathway in senescent skeletal muscle stem cells. Subjecting such stem cells to transient inhibition of p38 and p38 in conjunction with culture on soft hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength.[204]

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions.[205]

Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100ng/ml) of fibroblast growth factor-2 (FGF-2) and epidermal growth factor.[206]

Unlike current protocols for deriving hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014)[207] did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state.

These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Cocktail of small molecules, Y-27632, A-83-01 (a TGF kinase/activin receptor like kinase (ALK5) inhibitor), and CHIR99021 (potent inhibitor of GSK-3), can convert rat and mouse mature hepatocytes in vitro into proliferative bipotent cells - CLiPs (chemically induced liver progenitors). CLiPs can differentiate into both mature hepatocytes and biliary epithelial cells that can form functional ductal structures. In long-term culture CLiPs did not lose their proliferative capacity and their hepatic differentiation ability, and can repopulate chronically injured liver tissue.[208]

Complications of Diabetes mellitus such as cardiovascular diseases, retinopathy, neuropathy, nephropathy and peripheral circulatory diseases depend on sugar dysregulation due to lack of insulin from pancreatic beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).[209] Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal cells rather than adult cells. In contrast to adult cells, fetal cells seem functionally immature, as indicated by increased basal glucose secretion and lack of glucose stimulation and confirmed by RNA-seq of whose transcripts.[210]

An alternative strategy is the conversion of fibroblasts towards distinct endodermal progenitor cell populations and, using cocktails of signalling factors, successful differentiation of these endodermal progenitor cells into functional beta-like cells both in vitro and in vivo.[211]

Overexpression of the three transcription factors, PDX1 (required for pancreatic bud outgrowth and beta-cell maturation), NGN3 (required for endocrine precursor cell formation) and MAFA (for beta-cell maturation) combination (called PNM) can lead to the transformation of some cell types into a beta cell-like state.[212] An accessible and abundant source of functional insulin-producing cells is intestine. PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into -like cells possibly acceptable for transplantation.[213]

Adult proximal tubule cells were directly transcriptionally reprogrammed to nephron progenitors of the embryonic kidney, using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line.[214] The generation of such cells may lead to cellular therapies for adult renal disease. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development.[215]

As blood vessels age, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain and lower extremities. So, an important goal is to stimulate vascular growth for the collateral circulation to prevent the exacerbation of these diseases. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells.[150] The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels. That is why, when iVPCs were implanted into myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells.[216]

Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrowderived cells[217] or human cardiac progenitor cells, isolated from failing myocardium[218] results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.

Stem cells extracted from fat tissue after liposuction may be coaxed into becoming progenitor smooth muscle cells (iPVSMCs) found in arteries and veins.[219]

The 2D culture system of human iPS cells[220] in conjunction with triple marker selection (CD34 (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblasts), NP1 (receptor - neuropilin 1) and KDR (kinase insert domain-containing receptor)) for the isolation of vasculogenic precursor cells from human iPSC, generated endothelial cells that, after transplantation, formed stable, functional mouse blood vessels in vivo, lasting for 280 days.[221]

To treat infarction, it is important to prevent the formation of fibrotic scar tissue. This can be achieved in vivo by transient application of paracrine factors that redirect native heart progenitor stem cell contributions from scar tissue to cardiovascular tissue. For example, in a mouse myocardial infarction model, a single intramyocardial injection of human vascular endothelial growth factor A mRNA (VEGF-A modRNA), modified to escape the body's normal defense system, results in long-term improvement of heart function due to mobilization and redirection of epicardial progenitor cells toward cardiovascular cell types.[222]

RBC transfusion is necessary for many patients. However, to date the supply of RBCs remains labile. In addition, transfusion risks infectious disease transmission. A large supply of safe RBCs generated in vitro would help to address this issue. Ex vivo erythroid cell generation may provide alternative transfusion products to meet present and future clinical requirements.[223][224] Red blood cells (RBC)s generated in vitro from mobilized CD34 positive cells have normal survival when transfused into an autologous recipient.[225] RBC produced in vitro contained exclusively fetal hemoglobin (HbF), which rescues the functionality of these RBCs. In vivo the switch of fetal to adult hemoglobin was observed after infusion of nucleated erythroid precursors derived from iPSCs.[226] Although RBCs do not have nuclei and therefore can not form a tumor, their immediate erythroblasts precursors have nuclei. The terminal maturation of erythroblasts into functional RBCs requires a complex remodeling process that ends with extrusion of the nucleus and the formation of an enucleated RBC.[227] Cell reprogramming often disrupts enucleation. Transfusion of in vitro-generated RBCs or erythroblasts does not sufficiently protect against tumor formation.

The aryl hydrocarbon receptor (AhR) pathway (which has been shown to be involved in the promotion of cancer cell development) plays an important role in normal blood cell development. AhR activation in human hematopoietic progenitor cells (HPs) drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells.[228] See also Concise Review:[229][230] The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation.[231] (See also overview.[230][232])

Platelets help prevent hemorrhage in thrombocytopenic patients and patients with thrombocythemia. A significant problem for multitransfused patients is refractoriness to platelet transfusions. Thus, the ability to generate platelet products ex vivo and platelet products lacking HLA antigens in serum-free media would have clinical value. An RNA interference-based mechanism used a lentiviral vector to express short-hairpin RNAi targeting 2-microglobulin transcripts in CD34-positive cells. Generated platelets demonstrated an 85% reduction in class I HLA antigens. These platelets appeared to have normal function in vitro[233]

One clinically-applicable strategy for the derivation of functional platelets from human iPSC involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) through doxycycline-dependent overexpression of BMI1 and BCL-XL. The resulting imMKCLs can be expanded in culture over extended periods (45 months), even after cryopreservation. Halting the overexpression (by the removal of doxycycline from the medium) of c-MYC, BMI1 and BCL-XL in growing imMKCLs led to the production of CD42b+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo.[234] Thomas et al., describe a forward programming strategy relying on the concurrent exogenous expression of 3 transcription factors: GATA1, FLI1 and TAL1. The forward programmed megakaryocytes proliferate and differentiate in culture for several months with megakaryocyte purity over 90% reaching up to 2x105 mature megakaryocytes per input hPSC. Functional platelets are generated throughout the culture allowing the prospective collection of several transfusion units from as few as one million starting hPSCs.[235] See also overview[236]

A specialised type of white blood cell, known as cytotoxic T lymphocytes (CTLs), are produced by the immune system and are able to recognise specific markers on the surface of various infectious or tumour cells, causing them to launch an attack to kill the harmful cells. Thence, immunotherapy with functional antigen-specific T cells has potential as a therapeutic strategy for combating many cancers and viral infections.[237] However, cell sources are limited, because they are produced in small numbers naturally and have a short lifespan.

A potentially efficient approach for generating antigen-specific CTLs is to revert mature immune T cells into iPSCs, which possess indefinite proliferative capacity in vitro and after their multiplication to coax them to redifferentiate back into T cells.[238][239][240]

Another method combines iPSC and chimeric antigen receptor (CAR)[241] technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture.[242] This approach of generating therapeutic human T cells may be useful for cancer immunotherapy and other medical applications.

Invariant natural killer T (iNKT) cells have great clinical potential as adjuvants for cancer immunotherapy. iNKT cells act as innate T lymphocytes and serve as a bridge between the innate and acquired immune systems. They augment anti-tumor responses by producing interferon-gamma (IFN-).[243] The approach of collection, reprogramming/dedifferentiation, re-differentiation and injection has been proposed for related tumor treatment.[244]

Dendritic cells (DC) are specialized to control T-cell responses. DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and after that be completely eliminated. DC-like antigen-presenting cells obtained from human induced pluripotent stem cells can serve as a source for vaccination therapy.[245]

CCAAT/enhancer binding protein- (C/EBP) induces transdifferentiation of B cells into macrophages at high efficiencies[246] and enhances reprogramming into iPS cells when co-expressed with transcription factors Oct4, Sox2, Klf4 and Myc.[247] with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population.[248] Furthermore, C/EBPa can convert selected human B cell lymphoma and leukemia cell lines into macrophage-like cells at high efficiencies, impairing the cells' tumor-forming capacity.[249]

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Induced stem cells - Wikipedia

When it comes to gene expression -- the process by which our DNA provides the recipe used to direct the synthesis of proteins and other molecules that we need for development and survival -- scientists have so far studied one single gene at a time. A new approach developed by Harvard geneticist George Church, Ph.D., can help uncover how tandem gene circuits dictate life processes, such as the healthy development of tissue or the triggering of a particular disease, and can also be used for directing precision stem cell differentiation for regenerative medicine and growing organ transplants.

The findings, reported by Church and his team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School in Nature Methods, show promise that precision gene therapies could be developed to prevent and treat disease on a highly customizable, personalized level, which is crucial given the fact that diseases develop among diverse pathways among genetically-varied individuals. Wyss Core Faculty member Jim Collins, Ph.D., was also a co-author on the paper. Collins is also the Henri Termeer Professor of Medical Engineering & Science and Professor in the Department of Biological Engineering at the Massachusetts Institute of Technology.

The approach leverages the Cas9 protein, which has already been employed as a Swiss Army knife for genome engineering, in a novel way. The Cas9 protein can be programmed to bind and cleave any desired section of DNA -- but now Church's new approach activates the genes Cas9 binds to rather than cleaving them, triggering them to activate transcription to express or repress desired genetic traits. And by engineering the Cas9 to be fused to a triple-pronged transcription factor, Church and his team can robustly manipulate single or multiple genes to control gene expression.

"In terms of genetic engineering, the more knobs you can twist to exert control over the expression of genetic traits, the better," said Church, a Wyss Core Faculty member who is also Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT. "This new work represents a major, entirely new class of knobs that we could use to control multiple genes and therefore influence whether or not specific genetics traits are expressed and to what extent -- we could essentially dial gene expression up or down with great precision."

Such a capability could lead to gene therapies that would mitigate age-related degeneration and the onset of disease; in the study, Church and his team demonstrated the ability to manipulate gene expression in yeast, flies, mouse and human cell cultures.

"We envision using this approach to investigate and create comprehensive libraries that document which gene circuits control a wide range of gene expression," said one of the study's lead authors Alejandro Chavez, Ph.D., Postdoctoral Fellow at the Wyss Institute. Jonathan Schieman, Ph.D, of the Wyss Institute and Harvard Medical School, and Suhani Vora, of the Wyss Institute, Massachusetts Institute of Technology, and Harvard Medical School, are also lead co-authors on the study.

The new Cas9 approach could also potentially target and activate sections of the genome made up of genes that are not directly responsible for transcription, and which previously were poorly understood. These sections, which comprise up to 90% of the genome in humans, have previously been considered to be useless DNA "dark matter" by geneticists. In contrast to translated DNA, which contains recipes of genetic information used to express traits, this DNA dark matter contains transcribed genes which act in mysterious ways, with several of these genes often having influence in tandem.

But now, that DNA dark matter could be accessed using Cas9, allowing scientists to document which non-translated genes can be activated in tandem to influence gene expression. Furthermore, these non-translated genes could also be turned into a docking station of sorts. By using Cas9 to target and bind gene circuits to these sections, scientists could introduce synthetic loops of genes to a genome, therefore triggering entirely new or altered gene expressions.

The ability to manipulate multiple genes in tandem so precisely also has big implications for advancing stem cell engineering for development of transplant organs and regenerative therapies.

"In order to grow organs from stem cells, our understanding of developmental biology needs to increase rapidly," said Church. "This multivariate approach allows us to quickly churn through and analyze large numbers of gene combinations to identify developmental pathways much faster than has been previously capable."

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Activating genes on demand: Possible?

A team of European researchers has devised a strategy to ensure that adult epidermal stem cells are safe before they are used as treatments for patients. The approach involves a clonal strategy where stem cells are collected and cultivated, genetically modified and single cells isolated before being rigorously tested to make sure they meet the highest possible safety criteria. The strategy, which is published online in EMBO Molecular Medicine, is inspired by the approaches the biotechnology industry and regulatory affairs authorities have adopted for medicinal proteins produced from genetically engineered mammalian cells.

"Until now there has not been a systematic way to ensure that adult epidermal stem cells meet all the necessary requirements for safety before use as treatments for disease," says EMBO Member Yann Barrandon, Professor at Lausanne University Hospital, the Swiss Federal Institute of Technology in Lausanne and the lead author of the study. "We have devised a single cell strategy that is sufficiently scalable to assess the viability and safety of adult epidermal stem cells using an array of cell and molecular assays before the cells are used directly for the treatment of patients. We have used this strategy in a proof-of-concept study that involves treatment of a patient suffering from recessive dystrophic epidermolysis bullosa, a hereditary condition defined by the absence of type VII collagen which leads to severe blistering of the skin."

The researchers cultivated epidermal cells from the patient that can be used to regenerate skin. The scientists used their array of tests to determine which of the transduced cells met the necessary requirements for stemness -- the characteristics of a stem cell that distinguish it from a regular cells -- and safety. Clonal analysis revealed that the transduced stem cells varied in their ability to produce functional type VII collagen. When the most viable, modified stem cells were selected, transplantation onto immunodeficient mice regenerated skin that did not blister in the mouse model system for recessive dystrophic epidermolysis bullosa and produced functional type VII collagen. Safety was assessed by determining the sites of integration of the viral vector, looking for rearrangements and hit genes, as well as whole genome sequencing.

"Our work shows that at least for adult epidermal stem cells it is possible to use a clonal strategy to deliver a level of safety that cannot be obtained by other gene therapy approaches. A clonal strategy should make it possible to integrate some of the more recent technologies for targeted genome editing that offer more precise ways to change genes in ways that may further benefit the treatment of disease. Further work is in progress in this direction."

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The above story is based on materials provided by EMBO - excellence in life sciences. Note: Materials may be edited for content and length.

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Quality control for adult stem cell treatment

Irvine, California (PRWEB) December 08, 2014

The Ageless Derma skin care company has added a moisturizing product to their line that provides continuous hydration to skin throughout the day. The Swiss Apple Stem Cell Oil-Free Continuous Moisturizer uses rare Swiss apple stem cells in combination with other natural substances to aid in skins retention of moisture for a lessening of fine lines and a silky, more comfortable feeling.

The Swiss Apple Stem Cell Oil-Free Continuous Moisturizer contains stem cells from the exotic Malus Domestica, a rare apple from Switzerland known for its long shelf life and its ability to stay fresh without shriveling. This apple species had a flavor that consumers found too acidic, making farmers reluctant to grow it. The Malus Domestica, however, was discovered to have interesting scientific advantages due to its ability to live a long, healthy life without the usual shriveling that accompanies fruit as it ages. The same idea has been transferred to Ageless Dermas latest moisturizer with its incorporation of these stem cell extracts for a renewed and rejuvenated facial complexion. The stem cells help with not only apple longevity, but also with repairing human skin cells. This results in the ultimate reduction of fine lines and wrinkles with regular use.

Other ingredients are added to the Swiss Apple Stem Cell Oil-Free Continuous Moisturizer to make this moisturizer a workhorse of anti-aging and hydrating skin renewal. Ceramides and essential fatty acids account for maximum skin hydration and strengthening of the skin barrier function. Capric Triglycerides silken skin, glycerin keeps moisturization and hydration in balance, and Ceramides 3, 611, and 1 (all lipids) stop moisture from escaping and hold the skin barrier intact. Swiss Apple Stem Cell Oil-Free Continuous Moisturizer also has sodium hyaluronate to attract and keep moisture in. The hyaluronate also aids in blood microcirculation and the smoothing of wrinkles.

The developers at Ageless Derma Skin Care know they are making something extraordinary happen. Their line of physician-grade skin care products incorporates an important philosophy: supporting overall skin health by delivering the most cutting-edge biotechnology and pure, natural ingredients to all of the skin's layers. This attitude continues to resonate to this day with the companys founder, Dr. Farid Mostamand, who nearly ten years ago began his journey to deliver the best skin care alternatives for people who want to have healthy and beautiful looking skin at any age. About this latest Ageless Derma product, Dr. Mostamand says, The Swiss Apple Stem Cell Oil-Free Continuous Moisturizer is a multi-beneficial product that protects skin and works to smooth lines and wrinkles as it keeps moisture in, working throughout the entire day. Without the correct distribution of moisture, skin becomes dry and susceptible to wrinkling. This product is oil-free and can be used for any skin type.

Ageless Derma products are formulated in FDA-approved Labs. All ingredients are inspired by nature and enhanced by science. Ageless Derma products do not contain parabens or any other harsh additives, and they are never tested on animals. The company has developed five unique lines of products to address any skin type or condition.

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Ageless Derma Launches Its Latest Moisturizing Product Featuring Exotic Apple Stem Cells

Irvine, California (PRWEB) November 27, 2014

The Ageless Derma skin care company has just released their latest development in the form of a facial mask that exfoliates skin with ingredients such as apple stem cells to renew the complexion and correct texture and tone. The companys Swiss Apple Stem Cell Mask incorporates the cells of a long-living rare apple with other revitalizing ingredients from nature to result in a gentle mask that is effective and calming.

The Swiss apple, Malus Domestica, has its beginnings that go as far back as 18th century Switzerland. Ageless Derma recognized the importance of this plants stem cell extract for its ability to keep the fruit fresh for extended periods of time without wrinkling or shriveling. The Swiss Apple Stem Cell Mask contains the scientific advances that come from the cultivation of these stem cells, having incorporated it into a powerful and effective facial mask to rejuvenate skin and keep wrinkles at bay.

The Swiss Apple Stem Cell Mask contains other natural ingredients that work together to keep skin at its purest and return youthful life to the complexion. Kaolin Clay from the earth absorbs toxins that can enter the skins surface due to environmental pollutants in the air. The clay helps draw out grime and purify skin. Sweet Almond Oil nourishes skin, and adds much needed moisture and smoothness. Safflower Oil improves the texture of skin; especially skin that has become roughened with time and sun exposure. The Safflower Oil in Swiss Apple Stem Cell Mask also locks in moisture and tones skin for a flawless and radiant complexion.

Ageless Derma added fruit extracts to the Swiss Apple Stem Cell Mask for added health and radiance. Pumpkin Fruit Ferment, Pineapple Enzyme, and Papaya Enzyme make this mask luscious and plush. Age-defying antioxidants are also included, with Green Tea Extract and Aloe Leaf Extract added for soothing and fighting free radicals.

The developers at Ageless Derma Skin Care know they are making something extraordinary happen. Their line of physician-grade skin care items incorporates an important philosophy: promoting overall skin health by delivering the most cutting-edge biotechnology and pure, natural ingredients to all of the skin's layers. This attitude continues to resonate to this day with the companys founder, Dr. Farid Mostamand, who nearly a decade ago began his journey to deliver the best skin care alternatives for people who want to have healthy and beautiful looking skin at any age. About this latest Ageless Derma product, Dr. Mostamand says, This natural enzymatic Swiss Apple Stem Cell Mask gently exfoliates dead skin cells that are blocking new cell turnover for a renewed and radiant complexion. This is accomplished without the use of unnatural chemicals that can harm your skins delicate balance.

Ageless Derma products are formulated in FDA-approved Labs. All ingredients are inspired by nature and enhanced by science. Ageless Derma products do not contain parabens or any other harsh additives, and they are never tested on animals. The company has developed five unique lines of products to address any skin type or condition.

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Ageless Derma Introduces Their Latest Innovation: Swiss Apple Stem Cell Mask