January 12, 2014

Image Caption: Scanning electron microscopy of stem cells (yellow / green) in a scaffold structure (blue) serving as a basis for the artificial bone marrow. Credit: C. Lee-Thedieck/KIT

Rebekah Eliason for redOrbit.com Your Universe Online

An exciting breakthrough is offering hope for the treatment of blood diseases such as leukemia using artificial bone marrow.

Specialized cells, known as hematopoietic stem cells, located within bone marrow, continuously replace and supply new blood cells such as red blood cells and white blood cells. Traditionally a blood disease like leukemia is treated with bone marrow transplants that supply the patient with new hematopoietic stem cells. Researchers have now discovered a way to artificially reproduce hematopoietic stem cells.

Since not every leukemia patient can find a suitable transplant, there is a need for other forms of treatment. The lack of appropriate transplants could be solved by artificial reproduction of hematopoietic stem cells. Previously, reproduction of the cells has been impossible due to their inability to survive anywhere but in their natural environment. Hematopoietic stem cells are found in a special niche of the bone marrow. If the cells reside out of the bone marrow, the specialized properties are modified. Consequently, to effectively reproduce the cells, the stem cell niche environment must also be created.

In the microscopic environment of the stem cell niche, there are several specific properties of importance. Areas in the bone that house the stem cells are extremely porous like a sponge. Making things even more complex, the spongy tissue is also home to other cell types which exchange signal substances with the stem cells. Also, the space among the cells creates an environment ensuring stability along with a place for the cells to anchor. Furthermore, the stem cell niche supplies the cells with nutrients and oxygen.

Dr. Cornelia Lee-Thedieck is head of the Young Investigators Group Stem Cell-Material Interactions, which consists of scientitsts from the KIT Institute of Functional Interfaces (IFG), the Max Planck Institute for Intelligent Systems, Stuttgart and Tbingen University. The team was successful at artificially reproducing major properties of bone marrow at the laboratory.

Using synthetic polymers, the researchers were able to create a porous structure that simulated the spongy environment of the blood-forming bone marrow. Also, they were able to add protein building blocks which are similar to those found naturally in the environment of the bone marrow that enable cells to anchor. Finally, they added the other types of cells needed for exchanging signaling substances.

After the artificial bone marrow was created, the scientists placed hematopoietic stem cells that had been isolated from cord blood into it. For several days the cells were bred. Various analytical methods were then used to determine that cells were able to reproduce in the artificial bone marrow. When compared with standard cell cultivation methods, a larger number of stem cells in the artificial bone marrow retained their specific properties.

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New Treatment For Blood Diseases Using Artificial Bone Marrow

PATIENTS with potentially fatal superbug forms of tuberculosis (TB) could in future be treated using stem cells taken from their own bone marrow, according to the results of an early-stage trial of the technique. The finding, made by British and Swedish scientists, could pave the way for the development of a new treatment for the estimated 450,000 people worldwide who have multi drug-resistant (MDR) or extensively drug-resistant (XDR) TB. In a study in The Lancet Respiratory Medicine journal on Thursday, researchers said more than half of 30 drug-resistant TB patients treated with a transfusion of their own bone marrow stem cells were cured of the disease after six months. The results ... show that the current challenges and difficulties of treating MDR-TB are not insurmountable, and they bring a unique opportunity with a fresh solution to treat hundreds of thousands of people who die unnecessarily, said TB expert Alimuddin Zumla at University College London, who co-led the study. TB, which infects the lungs and can spread from one person to another through coughing and sneezing, is often falsely thought of as a disease of the past. In recent years, drug-resistant strains of the disease have spread around the world, batting off standard antibiotic drug treatments. The World Health Organization (WHO) estimates that in Eastern Europe, Asia and South Africa 450,000 people have MDR-TB, and around half of these will fail to respond to existing treatments. TB bacteria trigger an inflammatory response in immune cells and surrounding lung tissue that can cause immune dysfunction and tissue damage. Bone-marrow stem cells are known to migrate to areas of lung injury and inflammation and repair damaged tissue. Since they also modify the bodys immune response and could boost the clearance of TB bacteria, Zumla and his colleague, Markus Maeurer from Stockholms Karolinska University Hospital, wanted to test them in patients with the disease. In a phase 1 trial, 30 patients with either MDR or XDR TB aged between 21 and 65 who were receiving standard TB antibiotic treatment were also given an infusion of around 10 million of their own stem cells. The cells were obtained from the patients own bone marrow, then grown into large numbers in the laboratory before being re-transfused into the same patient, the researchers explained. During six months of follow-up, the researchers found that the infusion treatment was generally safe and well tolerated, with no serious side effects recorded. The most common non-serious side effects were high cholesterol levels, nausea, low white blood cell counts and diarrhea. Although a phase 1 trial is primarily designed only to test a treatments safety, the scientists said further analyzes of the results showed that 16 patients treated with stem cells were deemed cured at 18 months compared with only five of 30 TB patients not treated with stem cells. Maeurer stressed that further trials with more patients and longer follow-up were needed to better establish how safe and effective the stem cell treatment was. But if future tests were successful, he said, it could become a viable extra new treatment for patients with MDR-TB who do not respond to conventional drug treatment or those with severe lung damage.

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Bone marrow stem cells could defeat drug-resistant TB

A team of biochemists has engineered artificial bone marrow capable of hosting hematopoietic stem cells -- the potentially life-saving cells used in the treatment of leukemia -- for regeneration.

The work was carried out at the KIT Institute of Functional Interfaces (IFG), the Max Planck Institute for Intelligent Systems, Stuttgart and Tbingen University in Germany, where Cornelia Lee-Thedieck led a team in building a scaffold for stem cell regeneration.

Hematopoietic stem cells, which are derived from both blood and bone marrow, are known for their extraordinary regenerative properties -- they can differentiate into a whole series of specialised cells in the body and travel into the blood from the bone marrow. This makes it an excellent treatment for cancers of the blood, including leukemia and lymphoma where underdeveloped white blood cells multiply out of control. In these cases the patient's own supply of hematopoietic cells is destroyed and they are replenished via a bone marrow transplant from a matched donor. These are not in plentiful supply, so for years artificial bone marrow has been in development to help fill the need -- existing hematopoietic stem cells only replenish and thrive within the complex, porous structure of bone marrow and do not survive without it. If researchers could develop a suitable host, they could continually transplant cells onto that host to regenerate cells and meet demand.

"Multiplication of hematopoietic stem cells in vitro with current standard methods is limited and mostly insufficient for clinical applications of these cells," write the team in the journal Biomaterials. "They quickly lose their multipotency in culture because of the fast onset of differentiation. In contrast, HSCs efficiently self-renew in their natural microenvironment (their niche) in the bone marrow."

The team believes it has now created a potentially game-changing host that mimics that niche. They used synthetic polymers to build macroporous hydrogel scaffolds that mimic the spongy texture of bone marrow. Protein building blocks were then introduced, which would encourage introduced stem cells to stick to the scaffold. They had to introduce a number of other cells which importantly also thrive within bone marrow to exchange nutrients and oxygen.

To test the scaffold, stem cells from bone marrow and umbilical cord blood were introduced. It took a few days, but those from the cord blood began to multiply.

The authors concluded: "Co-culture in the pores of the three-dimensional hydrogel scaffold showed that the positive effect of MSCs on preservation of HSPC stemness was more pronounced in 3D than in standard 2D cell culture systems."

This is not the first time that artificial bone marrow has been attempted, however. Back in 2008 a team from the University of Michigan maintained that it had created a replica that could make red and white blood cells, and within which blood stem cells could replicate and produce B cells (important immune cells). In this instance, scaffolds were made from a transparent polymer using tiny spheres that were then dissolved to create pores the nutrients could pass through. It's unclear for how long the stem cells thrived, and Wired.co.uk has contacted the team to try and find out how the research has progressed and if the engineered bone marrow has continued to be effective.

If the research is successful going forward, it could mean the beginning of "blood farming", where artificial bone marrow is used to produce red and white blood cells and platelets to be banked for transfusions.

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Study: potentially life-saving blood stem cells regenerate in artificial bone marrow

Jan. 10, 2014 Age-related macular degeneration (AMD) is the most frequent cause of blindness. Scientists at the Department of Ophthalmology at the Bonn University Hospital and from the Neural Stem Cell Institute in New York (USA) have developed a method for using stem cells to replace cells in the eye destroyed by AMD. The implants survived in rabbit eyes for several weeks. Additional research is needed for clinical application. The results are now presented in the journal "Stem Cell Reports."

About four and a half million people in Germany suffer from age-related macular degeneration (AMD). It is associated with a gradual loss of visual acuity and the ability to read or drive a car can be lost. The center of the field of vision is blurry, as if covered by a veil. This is caused by damage to a cell layer under the retina, known as the retinal pigment epithelium (RPE). It coordinates the metabolism and function of the sensory cells in the eye. Inflammatory processes in this layer are associated with AMD and "metabolic waste" is less efficiently recycled. To date, there is no cure for AMD; treatments can only relieve the symptoms.

Scientists from the Bonn University Department of Ophthalmology, together with researchers in New York (USA), have now tested a new method in rabbits by which the damaged RPE cells in AMD may be replaced. The researchers implanted different RPEs which were obtained, among others, from stem cells from adult human donors. "These cells have now been used for the first time in research for transplantation purposes," says lead author Dr. Boris V. Stanzel from the Department of Ophthalmology at the University of Bonn. The discovery and characterization of the adult RPE stem cells was performed in the group of Prof. Sally Temple and Dr. Jeffrey Stern from the Neural Stem Cell Institute (NSCI) in New York, USA. Dr. Timothy Blenkinsop at NSCI pioneered methods to grow them to closely resemble true RPE.

Researchers in Bonn developed the implantation techniques

The implantation techniques for the new method were developed by researchers working with Dr. Stanzel from the Department of Ophthalmology at the University of Bonn. They allowed the stem cell derived RPE to grow on small polyester discs, thus yielding a thin cell layer. The researchers implanted this human RPE monolayer in rabbits under the retina. "Our research group developed special instruments to implant the replacement cells can under the retina," reports Dr. Stanzel. After four days, the researchers used tomographic methods to check whether the replacement cells had integrated into the surrounding cell layers. "The implanted cells were alive," reports the researcher at the Department of Ophthalmology at the University of Bonn. "That is a clear indication that they have joined with the surrounding cells." After one week, the implanted cell layer was still stable. Even after four weeks, tissue examinations showed that the transplant was intact.

A new approach for possible treatment of AMD

"The results from the experiments prove that retinal pigment epithelial cells obtained from adult stem cells have the potential to replace cells destroyed by age-related macular degeneration," summarizes Dr. Stanzel. Moreover, using the newly developed basic method, it will be possible in the future to test which stem cell lines are suitable for transplantation in the eye. "However, clinical application is still far away," says Dr. Stanzel. More research is needed.

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Stem cell replacement for frequent age-related blindness

In a ground-breaking discovery, German researchers have successfully developed artificial bone marrow - capable of hosting life-saving hematopoietic stem cells that can facilitate the treatment of leukemia in a few years.

Till date, the affected cells of a leukemic patient are replaced by healthy hematopoietic stem cells - blood cells that give rise to all the other blood cells - from an eligible donor.

Now, the scientists at Karlsruhe Institute of Technology's (KIT) Institute of Functional Interfaces in Germany have artificially reproduced major properties of natural bone marrow in the laboratory.

With the help of synthetic polymers, the scientists created a porous structure that possesses essential properties of natural bone marrow.

This can be used for the reproduction of stem cells at the laboratory, said a study published in the journal Biomaterials.

"We introduced hematopoietic stem cells isolated from cord blood into this artificial bone marrow. Analyses with various methods revealed that the cells really reproduce in the newly-developed artificial bone marrow," said Cornelia Lee-Thedieck from the KIT Institute of Functional Interfaces.

In a normal human being, blood cells are continuously replaced by new ones supplied by hematopoietic stem cells located in the bone marrow.

"This knowledge might contribute to producing an artificial stem cell niche for the specific reproduction of stem cells and the treatment of leukemia in 10-15 years from now," said the study.

A prototype has already been developed by scientists at KIT, the Max Planck Institute for Intelligent Systems, Stuttgart and Tbingen University in Germany.

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Artificial bone marrow boon for leukemia patients

Jan. 10, 2014 Harvard stem cells scientists at Brigham and Women's Hospital and MIT can now engineer cells that are more easily controlled following transplantation, potentially making cell therapies, hundreds of which are currently in clinical trials across the United States, more functional and efficient.

Associate Professor Jeffrey Karp, PhD, and James Ankrum, PhD, demonstrate in this month's issue of Nature Protocols how to load cells with microparticles that provide the cells cues for how they should behave over the course of days or weeks as the particles degrade.

"Regardless of where the cell is in the body, it's going to be receiving its cues from the inside," said Karp, a Harvard Stem Cell Institute Principal Faculty member at Brigham and Women's Hospital. "This is a completely different strategy than the current method of placing cells onto drug-doped microcarriers or scaffolds, which is limiting because the cells need to remain in close proximity to those materials in order to function. Also these types of materials are too large to be infused into the bloodstream."

Cells are relatively simple to control in a Petri dish. The right molecules or drugs, if internalized by a cell, can change its behavior; such as inducing a stem cell to differentiate or correcting a defect in a cancer cell. This level of control is lost after transplantation as cells typically behave according to environmental cues in the recipient's body. Karp's strategy, dubbed particle engineering, corrects this problem by turning cells into pre-programmable units. The internalized particles stably remain inside the transplanted cell and tell it exactly how to act, whether the cell is needed to release anti-inflammatory factors or regenerate lost tissue.

"Once those particles are internalized into the cells, which can take on the order of 6-24 hours, we can deliver the transplant immediately or even cryopreserve the cells," Karp said. "When the cells are thawed at the patient's bedside, they can be administered and the agents will start to be released inside the cells to control differentiation, immune modulation or matrix production, for example."

It could take more than a decade for this type of cell therapy to be a common medical practice, but to speed up the pace of research, Karp published the Nature Protocols study to encourage others in the scientific community to apply the technique to their fields. The paper shows the range of different cell types that can be particle engineered, including stem cells, immune cells, and pancreatic cells.

"With this versatile platform, which leveraged Harvard and MIT experts in drug delivery, cell engineering, and biology, we've demonstrated the ability to track cells in the body, control stem cell differentiation, and even change the way cells interact with immune cells," said Ankrum, a former graduate student in Karp's laboratory. "We're excited to see what applications other researchers will imagine using this platform."

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Scientists control cells following transplantation, from inside out

Jan. 10, 2014 Artificial bone marrow may be used to reproduce hematopoietic stem cells. A prototype has now been developed by scientists of KIT, the Max Planck Institute for Intelligent Systems, Stuttgart, and Tbingen University. The porous structure possesses essential properties of natural bone marrow and can be used for the reproduction of stem cells at the laboratory. This might facilitate the treatment of leukemia in a few years.

The researchers are now presenting their work in the journal Biomaterials.

Blood cells, such as erythrocytes or immune cells, are continuously replaced by new ones supplied by hematopoietic stem cells located in a specialized niche of the bone marrow. Hematopoietic stem cells can be used for the treatment of blood diseases, such as leukemia. The affected cells of the patient are replaced by healthy hematopoietic stem cells of an eligible donor.

However, not every leukemia patient can be treated in this way, as the number of appropriate transplants is not sufficient. This problem might be solved by the reproduction of hematopoietic stem cells. So far, this has been impossible, as these cells retain their stem cell properties in their natural environment only, i.e. in their niche of the bone marrow. Outside of this niche, the properties are modified. Stem cell reproduction therefore requires an environment similar to the stem cell niche in the bone marrow.

The stem cell niche is a complex microscopic environment having specific properties. The relevant areas in the bone are highly porous and similar to a sponge. This three-dimensional environment does not only accommodate bone cells and hematopoietic stem cells but also various other cell types with which signal substances are exchanged. Moreover, the space among the cells has a matrix that ensures a certain stability and provides the cells with points to anchor. In the stem cell niche, the cells are also supplied with nutrients and oxygen.

The Young Investigators Group "Stem Cell-Material Interactions" headed by Dr. Cornelia Lee-Thedieck consists of scientists of the KIT Institute of Functional Interfaces (IFG), the Max Planck Institute for Intelligent Systems, Stuttgart, and Tbingen University. It artificially reproduced major properties of natural bone marrow at the laboratory. With the help of synthetic polymers, the scientists created a porous structure simulating the sponge-like structure of the bone in the area of the blood-forming bone marrow. In addition, they added protein building blocks similar to those existing in the matrix of the bone marrow for the cells to anchor. The scientists also inserted other cell types from the stem cell niche into the structure in order to ensure substance exchange.

Then, the researchers introduced hematopoietic stem cells isolated from cord blood into this artificial bone marrow. Subsequent breeding of the cells took several days. Analyses with various methods revealed that the cells really reproduce in the newly developed artificial bone marrow. Compared to standard cell cultivation methods, more stem cells retain their specific properties in the artificial bone marrow.

The newly developed artificial bone marrow that possesses major properties of natural bone marrow can now be used by the scientists to study the interactions between materials and stem cells in detail at the laboratory. This will help to find out how the behavior of stem cells can be influenced and controlled by synthetic materials. This knowledge might contribute to producing an artificial stem cell niche for the specific reproduction of stem cells and the treatment of leukemia in ten to fifteen years from now.

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Researchers develop artificial bone marrow; May be used to reproduce hematopoietic stem cells