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Biologists discover solution to problem limiting development of human stem cell therapies

By Stem Cell Medicine

PUBLIC RELEASE DATE:

2-Jan-2014

Contact: Kim McDonald kmcdonald@ucsd.edu 858-534-7572 University of California - San Diego

Biologists at UC San Diego have discovered an effective strategy that could prevent the human immune system from rejecting the grafts derived from human embryonic stem cells, a major problem now limiting the development of human stem cell therapies. Their discovery may also provide scientists with a better understanding of how tumors evade the human immune system when they spread throughout the body.

The achievement, published in a paper in this week's early online edition of the journal Cell Stem Cell by a collaboration that included scientists from China, was enabled by the development of "humanized" laboratory mice that contained a functional human immune system capable of mounting a vigorous immune rejection of foreign cells derived from human embryonic stem cells.

Because human embryonic stem cells are different from our own body's cells, or "allogenic," a normally functioning human immune system will attack these foreign cells. One way to reduce the body's "allogenic immune response" is to suppress the immune system with immunosuppressant drugs.

"For organ transplantation to save patients with terminal diseases that has been quite successful," says Yang Xu, a professor of biology who headed the team of researchers that included Ananda Goldrath, an associate biology professor at UC San Diego. "But for stem cell therapies, the long term use of toxic immunosuppressant drugs for patients who are being treated for chronic diseases like Parkinson's disease or diabetes pose serious health problems."

Researchers had long been searching for a human immunity relevant model that would allow them to develop strategies to implant allogenic cells derived from embryonic stem cells safely. "The problem is that we only had data from mouse immune system and those are not usually translatable in humans, because human and mouse immune systems are quite different," explains Xu. "So what we decided to do was to optimize the humanized mouse that carries a functional human immune system."

To do that, the biologists took immune deficient laboratory mice and grafted into their bodies human fetal thymus tissues and hematopoietic stem cells derived from fetal liver of the same human donor. "That reconstituted in these mice a normally functioning human immune system that effectively rejects cells derived human embryonic stem cells," says Xu. With these "humanized" mouse models, the biologists then tested a variety of immune suppressing molecules alone or in combination and discovered one combination that worked perfectly to protect cells derived from human embryonic stem cells from immune rejection.

That combination was CTLA4-lg, an FDA-approved drug for treating rheumatoid arthritis that suppresses T-cells responsible for immune rejection, and a protein called PD-L1 known to be important for inducing immune tolerance in tumors. The researchers discovered that the combination of these two molecules allowed the allogeneic cells to survive in humanized mice without triggering an immune rejection.

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Biologists discover solution to problem limiting development of human stem cell therapies

Solution to problem limiting stem cell therapies

By Stem Cell Medicine

Biologists at UC San Diego have discovered an effective strategy that could prevent the human immune system from rejecting the grafts derived from human embryonic stem cells, a major problem now limiting the development of human stem cell therapies. Their discovery may also provide scientists with a better understanding of how tumors evade the human immune system when they spread throughout the body.

The achievement, published in a paper in this week's early online edition of the journal Cell Stem Cell by a collaboration that included scientists from China, was enabled by the development of "humanized" laboratory mice that contained a functional human immune system capable of mounting a vigorous immune rejection of foreign cells derived from human embryonic stem cells.

Because human embryonic stem cells are different from our own body's cells, or "allogenic," a normally functioning human immune system will attack these foreign cells. One way to reduce the body's "allogenic immune response" is to suppress the immune system with immunosuppressant drugs.

"For organ transplantation to save patients with terminal diseases that has been quite successful," says Yang Xu, a professor of biology who headed the team of researchers that included Ananda Goldrath, an associate biology professor at UC San Diego. "But for stem cell therapies, the long term use of toxic immunosuppressant drugs for patients who are being treated for chronic diseases like Parkinson's disease or diabetes pose serious health problems."

Researchers had long been searching for a human immunity relevant model that would allow them to develop strategies to implant allogenic cells derived from embryonic stem cells safely. "The problem is that we only had data from mouse immune system and those are not usually translatable in humans, because human and mouse immune systems are quite different," explains Xu. "So what we decided to do was to optimize the humanized mouse that carries a functional human immune system."

To do that, the biologists took immune deficient laboratory mice and grafted into their bodies human fetal thymus tissues and hematopoietic stem cells derived from fetal liver of the same human donor. "That reconstituted in these mice a normally functioning human immune system that effectively rejects cells derived human embryonic stem cells," says Xu. With these "humanized" mouse models, the biologists then tested a variety of immune suppressing molecules alone or in combination and discovered one combination that worked perfectly to protect cells derived from human embryonic stem cells from immune rejection.

That combination was CTLA4-lg, an FDA-approved drug for treating rheumatoid arthritis that suppresses T-cells responsible for immune rejection, and a protein called PD-L1 known to be important for inducing immune tolerance in tumors. The researchers discovered that the combination of these two molecules allowed the allogeneic cells to survive in humanized mice without triggering an immune rejection.

"If we express both molecules in cells derived from human embryonic cells, we can protect these cells from the allogenic immune rejection," says Xu. "If you have only one such molecule expressed, there is absolutely no impact. We still don't know exactly how these pathways work together to suppress immune rejection, but now we've got an ideal system to study this."

He and his team of researchers also believe their discovery and the development of their humanized mouse models may offer the much needed tools to develop ways to activate immune response to tumors, because these molecules are known to be important in allowing tumors to evade the human immune system.

"You're dealing with the same exact pathways that protect tumors from our immune system," says Xu. "If we can develop strategies to disrupt or silence these pathways in tumors, we might be able to activate immunity to tumors. The humanized mouse system is really a powerful model with which to study human tumor immunity."

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Solution to problem limiting stem cell therapies

Cell Therapy – Cancer

By Uncategorized

Other common name(s): cellular therapy, fresh cell therapy, live cell therapy, glandular therapy, xenotransplant therapy

Scientific/medical name(s): none

In cell therapy, processed tissue from the organs, embryos, or fetuses of animals such as sheep or cows is injected into patients. Cell therapy is promoted as an alternative form of cancer treatment.

Available scientific evidence does not support claims that cell therapy is effective in treating cancer or any other disease. Serious side effects can result from cell therapy. It may in fact be lethalseveral deaths have been reported. It is important to distinguish between this alternative method involving animal cells and mainstream cancer treatments that use human cells, such as bone marrow transplantation.

In cell therapy, live or freeze-dried cells or pieces of cells from the healthy organs, fetuses, or embryos of animals such as sheep or cows are injected into patients. This is supposed to repair cellular damage and heal sick or failing organs. Cell therapy is promoted as an alternative therapy for cancer, arthritis, heart disease, Down syndrome, and Parkinson disease.

Cell therapy is also marketed to counter the effects of aging, reverse degenerative diseases, improve general health, increase vitality and stamina, and enhance sexual function. Some practitioners have proposed using cell therapy to treat AIDS patients.

The theory behind cell therapy is that the healthy animal cells injected into the body can find their way to weak or damaged organs of the same type and stimulate the body's own healing process. The choice of the type of cells to use depends on which organ is having the problem. For instance, a patient with a diseased liver may receive injections of animal liver cells. Most cell therapists today use cells taken from taken from the tissue of animal embryos.

Supporters assert that after the cells are injected into the body, they are transported directly to where they are most needed. They claim that embryonic and fetal animal tissue contains therapeutic agents that can repair damage and stimulate the immune system, thereby helping cells in the body heal.

The alternative treatment cell therapy is very different from some forms of proven therapy that use live human cells. Bone marrow transplants infuse blood stem cellsfrom the patient or a carefully matched donorafter the patients own bone marrow cells have been destroyed. Studies have shown that bone marrow transplants are effective in helping to treat several types of cancer. In another accepted procedure, damaged knee cartilage can be repaired by taking cartilage cells from the patient's knee, carefully growing them in the laboratory, and then injecting them back into the joint. Approaches involving transplants of other types of human stem cells are being studied as a possible way to replace damaged nerve or heart muscle cells, but these approaches are still experimental.

First, healthy live cells are harvested from the organs of juvenile or adult live animals, animal embryos, or animal fetuses. These cells may be taken from the brain, pituitary gland, thyroid gland, thymus gland, liver, kidney, pancreas, spleen, heart, ovaries, testicles, or even from whole embryos. Patients might receive one or several types of animal cells. Some cell therapists inject fresh cells into their patients. Others freeze them first, which kills the cells, and they may filter out some of the cell components. Frozen cell extracts have a longer "shelf life" and can be screened for disease. Fresh cells cannot be screened. A course of cell therapy to address a specific disease might require several injections over a short period of time, whereas cell therapy designed to treat the effects of aging and "increase vitality" may involve injections received over many months.

Originally posted here:
Cell Therapy – Cancer

Stem cell transplant problem solved, UCSD-led study says

By Uncategorized

(This is my blog post about the embryonic stem cell study. For my news article about the study, go here.)

Genetically modified human embryonic stem cells can solve one of the toughest problems facing embryonic stem cell therapy, immune rejection of transplanted cells, may have been solved, according to a UC San Diego-led research team.

The cells can be made invisible to the immune system by genetically modifying them to make two immune-suppressing chemicals, according to a study performed in mice given a human immune system. Immune functioning in the rest of the animal remains active. The immune protection also applies to differentiated cells derived from the stem cells.

If the approach works in people, patients receiving transplanted tissue or organs made from embryonic stem cells wouldn't have to take harsh immune-suppressing drugs, said Yang Xu, a UCSD professor of biology. The method also may prevent immune rejection of tissues grown from other types of stem cells.

These arehumanized laboratory mice that contain a functional human immune system. Such mice have been used for years; a UCSD research team developed a model with a stronger immune response to test their immune-suppressing tissues. / Zhili Rong, UCSD

Researchers placed genes in the stem cells to produce the two chemicals, CTLA4-lg and PD-L1, naturally made in the body. The humanized immune systems of the mice accepted transplants of cells engineered to make the chemicals. The researchers transplanted cardiomyocytes and fibroblasts derived from the engineered stem cells. Transplants derived from regular embryonic stem cells were rejected.

The study was published online Thursday in the journal Cell Stem Cell. Its findings will have to be confirmed for safety and effectiveness in more animal studies before human trials can be considered, which will take years. The mouse model itself was "optimized" for the study to more faithfully reflect the human immune system than other immune models, the study said.

Xu said a further study is being considered in monkeys, a large animal model considered to better reflect human biology than mice.

Embryonic stem cells are being tested along with many other kinds of stem cells to replace diseased or destroyed body parts, such as spinal cord segments and insulin-producing beta cells in the pancreas. All of these cells have advantages and drawbacks. Immune rejection, along with a tendency to form tumors, are two big drawbacks to embryonic stem cells.

San Diego-based ViaCyte is preparing to test a therapy with beta cells within a year. The company encapsulates them in a permeable barrier that allows insulin to diffuse out but prevents the immune system from entering. However, that approach won't worth with transplants that must integrate into the body, such as spinal cord tissue. So a way of turning off the immune system just in those cells is an attractive idea.

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Stem cell transplant problem solved, UCSD-led study says

Embryonic stem cell rejection problem fixed, study says

By Uncategorized

One of the toughest problems facing embryonic stem cell therapy, immune rejection of transplanted cells, may have been solved, according to a UC San Diego-led research team.

The cells can be made invisible to the immune system by genetically engineering them to make two immune-suppressing molecules, according to the study. Researchers tested the approach in mice given a human immune system. Immune functioning in the rest of the animal remained active.

If the approach works in people, patients receiving transplanted tissue or organs made from embryonic stem cells wouldnt have to take harsh immune-suppressing drugs, said study leader Yang Xu, a UC San Diego professor of biology.

Human embryonic stem cells. The green markers indicate the presence of a protein expressed only in these cells. / Samantha Zeitlin, 2006 CIRM fellow

Researchers placed genes in the stem cells to produce the two molecules, called CTLA4-lg and PD-L1, naturally made in the body. The mice accepted transplants of heart and skin cells derived from the engineered stem cells. They rejected transplants derived from regular embryonic stem cells.

The study was published online Thursday in the journal Cell Stem Cell. Its findings will have to be confirmed for safety and effectiveness before human trials can be considered, which will take years.

Three scientists given the paper for comment had mixed reactions. While they praised the works scientific prowess, two said genetically engineering the transplanted cells could cause serious side effects that might preclude their use.

The researchers employed a clever strategy to use the immune systems natural regulatory systems, said Mitchell Kronenberg, president of the La Jolla Institute for Allergy & Immunology.

This is an especially promising approach, because it avoids the toxic side effects of the drugs now used to suppress the rejection response, and therefore this is an important step forward in showing the feasibility of using human embryonic stem cells from unrelated donors, Kronenberg said.

More skeptical were Jeanne Loring, a stem cell researcher at The Scripps Research Institute, and Craig M. Walsh, associate director of the Institute for Immunology at UC Irvine.

Originally posted here:
Embryonic stem cell rejection problem fixed, study says

Study finds patients give ‘broad endorsement’ to stem cell research

By Stem Cell Treatment

11 hours ago

In an early indication of lay opinions on research with induced pluripotent stem cells (iPSCs), which are stem cells made from skin or other tissues, a new study by bioethicists at Johns Hopkins University indicates that despite some ethical concerns, patients give the research "broad endorsement".

During focus group discussions patients were largely in favor of participating in iPSC research even if personal benefit was unlikely, though they raised concerns about consent, privacy and transparency when considering donating tissue for this research. The bioethicists report their findings in the journal Cell Stem Cell.

"Bioethicists, as well as stem cell researchers and policy-makers, have discussed the ethical issues of induced pluripotent stem cells at length, but we didn't have any systematic information about what patients think about these issues, and that is a huge part of the equation if the potential of this research is to be fully realized," says Jeremy Sugarman, the senior author of the report and the Harvey M. Meyerhoff Professor of Bioethics and Medicine at the Johns Hopkins Berman Institute of Bioethics.

Unlike human embryonic stem cells, iPSCs are derived without destroying a human embryo. Research with human iPSCs is valuable for developing new drugs, studying disease, and perhaps developing medical treatments. Sugarman explains that, while far off, scientists are hopeful that iPSCs could someday be used to develop organs for transplantation that the body's immune system will not attack, because they can be created from the person's own cells.

The study reveals the importance of prior informed consent for those asked to participate in it. According to the report, consent was highly important for patients in all five of the focus groups that were convened. Some patients even suggested that proper informed consent could compensate for other concerns they had about privacy, the "immortalization" of cells, and the commercialization of stem cells.

There was a "strong desire among participants to have full disclosure of the anticipated uses," the report notes, with some participants wanting to be able to veto certain uses of their cells. The authors acknowledge the "practical difficulties" of this request but hope that their findings will "prompt investigation into creative approaches to meeting these desires."

The study also revealed another side to some patients' selfless motivations to participate in research as they might relate to eventual commercialization. The report quotes one participant as saying, "It won't be just taken to become a money maker and the very people who need it the most will no longer be able to benefit from it" and another, "it was a donation. It's a humanitarian effort."

The authors also note that the unique characteristics of their small study could have influenced the results; for instance, the fact that it was conducted in Baltimore, Maryland, among patients who have received care at Johns Hopkins, where the first immortal cell line was created from tumor cells taken from Henrietta Lacks, put related issues at the forefront of many focus groups. "The idea that donated cells would potentially live forever was unnerving to some participants. In particular, the story about the creation of the HeLa cell line from Henrietta Lacks' cervical cancer tissue, taken without consent, was raised in four out of the five focus groups," the report states.

Additionally, the report indicates that the opinions that were expressed by patients may be influenced by their health, and whether or not they have personal experience with a debilitating illness, as some of the participants did.

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Study finds patients give 'broad endorsement' to stem cell research

Lund Stem Cell Center | Medicinska fakulteten, Lunds universitet

By Stem Cell Clinic

Lund center for Stem Cell Biology and Cell Therapy is one of six Swedish strategic centers of excellence in life sciences, supported by the Swedish Foundation for Strategic Research. Established in January 2003, the center focuses on stem cell and developmental biology of the central nervous and blood systems, and development of stem cell and cell replacement therapies in these organ systems as well as research in non-mammalian model systems.

Associate Professor Ewa Sitnicka from Lund Stem Cell Center, member of the StemTherapy program, received 3 million SEK, for her project in the field of stem cell-based research, Cancer therapy using NK cells.

Wednesday18thDecember at 13:00 in Segerfalk lecture hall, BMC A10, Wan Man Wong defends her thesis Integrin 2 and Akt in early hematopoiesis Main Supervisor: ProfessorMarja Ekblom Opponent:Professor Bo Porse, University of Copenhagen, Denmark Chairman: Associate Professor Ewa Sitnicka

Congratulations StemTherapy and Stem Cell Center researcher Joan Yuan, nominated by the Knut and Alice Wallenberg Foundation to participate in the career program Wallenberg Academy Fellows! The program aims to provide long term financing for promising young Swedish and international researchers in all disciplines.

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Lund Stem Cell Center | Medicinska fakulteten, Lunds universitet

FEMA Search and Rescue Canine Receives Stem Cell Therapy So He Can Continue to Save Lives

By Uncategorized

Poway, CA (PRWEB) January 02, 2014

Phizer is a seven year old black lab belonging to Ohio Task Force 1 that recently had stem cell therapy by Vet-Stem, Inc. Phizer was brought to Cleveland Road Animal Hospital for a limp in his right hind. Dr. Chad Bailey recommended stem cell therapy. Both Vet-Stem and Cleveland Road Animal Hospital value the working dog and offered their services pro-bono in hopes that Phizers stem cell therapy would permit him to continue to provide search and rescue service.

Phizer is one of only five search and rescue canines owned by Ohio Task Force 1, one of 28 Task Forces across the US that make up the FEMA Urban Search and Rescue System. Phizer is trained to find living victims who may be trapped under collapsed buildings. He is unique because he is certified to work with more than one handler meaning that he can be used on more missions. If one of his handlers is not available the other may be. Phizer is trained to cover obstacles and treacherous terrain, climb metal ladders and investigate acres of terrain quickly and efficiently. These skills came in handy when Phizer was assigned to a mission recovering victims from hurricane Sandy.

Handlers Maureen May and Deana Hudgins noticed an intermittent limp in Phizers right rear leg when he first started moving, but got better with exercise. Although the limp was not preventing Phizer from his job, he was started on pain medicine, joint supplements and taken for exams to the local veterinarian. His radiology report showed signs consistent with mild degenerative joint disease in addition to another injury. Deana and Dr. Bailey started Phizer on injectable treatments, laser therapy, and discussed stem cells.

Since Phizers stem cell therapy used his own stem cells, a small portion of fat was collected and sent to Vet-Stems lab in California. Within 48 hrs the doses of stem cells were ready for injection by Dr. Bailey. Stem cells are regenerative cells that can differentiate into many tissue types and reduce pain and inflammation thus helping to restore range of motion and regenerate tendon, ligament and joint tissues (http://www.vet-stem.com/science). For Phizer this means that all of the issues identified in his exams may be helped with one therapy.

About Vet-Stem, Inc. Vet-Stem, Inc. was formed in 2002 to bring regenerative medicine to the veterinary profession. The privately held company is working to develop therapies in veterinary medicine that apply regenerative technologies while utilizing the natural healing properties inherent in all animals. As the first company in the United States to provide an adipose-derived stem cell service to veterinarians for their patients, Vet-Stem, Inc. pioneered the use of regenerative stem cells in veterinary medicine. The company holds exclusive licenses to over 50 patents including world-wide veterinary rights for use of adipose derived stem cells. In the last decade over 10,000 animals have been treated using Vet-Stem, Inc.s services, and Vet-Stem is actively investigating stem cell therapy for immune-mediated and inflammatory disease, as well as organ disease and failure. For more on Vet-Stem, Inc. and Veterinary Regenerative Medicine visit http://www.vet-stem.com or call 858-748-2004.

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FEMA Search and Rescue Canine Receives Stem Cell Therapy So He Can Continue to Save Lives

Search is on for donor to save Hannah Day

By Stem Cell Doctors

Hannah Day's family are searching for a matching donor to provide the four-year-old cancer patient with a stem cell transplant.

image credit: Submitted photo

Langfords Hannah Day, 4, and her family are desperately searching for a stem cell transplant match as Hannah faces the second cancer diagnosis of her young life.

Hannah, 4, is back in Langford after spending Christmas in B.C. Childrens Hospital for treatment after she suffered a seizure at home. As a result of the seizure Hannah had gone pale and her lips were purple, prompting her mother to call 911, rushing her to the hospital.

Hannah was mostly not alert as doctors ran tests on her. When she started to develop jaundice Hannah was flown to Childrens Hospital in Vancouver.

I have been holding her hand for so long, just to see if shell squeeze back, Hannahs mother wrote to family friend and fundraising organizer Kim Roost.

Hannah eventually began to come around, talking and remaining awake for periods of time, though in pain. Roost said they never really determined what caused the seizure.

Meanwhile Hannahs cancer, a form of leukemia, is getting worse, though she is back in Langford and celebrated Christmas with her family at home on Dec. 28.

Hannahs only hope of curing her cancer is finding a match for a stem cell transplant, Roost said. Her best hope lay in her little sister, Hailey, but she proved to not be a 100 per cent match, which is necessary. The family received that news Christmas Eve.

Its kind of like one step forward, two steps back, Roost said. Its not how anyone wants to spend their Christmas.

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Search is on for donor to save Hannah Day

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