Stem Cells Injected into Nerve Guide Tubes Repair Injured Peripheral Nerve

Stem Cells Injected into Nerve Guide Tubes Repair Injured Peripheral Nerve

Friday, 10 January 2014

Using skin-derived stem cells (SDSCs) and a previously developed collagen tube designed to successfully bridge gaps in injured nerves in rat models, the research team in Milan, Italy that established and tested the procedure has successfully rescued peripheral nerves in the upper arms of a patient suffering peripheral nerve damage who would have otherwise had to undergo amputations.

The study will be published in a future issue of Cell Transplantation. 

"Peripheral nerve repair with satisfactory functional recovery remains a great surgical challenge, especially for severe nerve injuries resulting in extended nerve defects," said study corresponding author Dr. Yvan Torrente, of the Department of Pathophysiology and Transplantation at the University of Milan.

"However, we hypothesized that the combination of autologous (self-donated) SDSCs placed in collagen tubes to bridge gaps in the damaged nerves would restore the continuity of injured nerves and save from amputation the upper arms of a patient with poly-injury to motor and sensory nerves."

Although autologous nerve grafting has been the 'gold standard' for reconstructive surgeries, these researchers felt that there were several drawbacks to that approach, including graft availability, donor site morbidity, and neuropathic pain.

According to the researchers, autologous SDSCs have advantages over other stem cells as they are an accessible source of stem cells rapidly expandable in culture, and capable of survival and integration within host tissues.

While the technique of using the collagen tubes - NeuraGen, an FDA-approved device - to guide the transplanted cells over gaps in the injured nerve had been previously developed and tested by the same researchers with the original research successfully saving damaged sciatic nerves on rats, the present case, utilizing the procedure they developed employing SDSCs and a nerve guide, is the first to be carried out on a human.

Over three years, the researchers followed up on the patient, assessing functional recovery of injured median and ulnar nerves by pinch gauge test and static two-point discrimination and touch test with monofilaments along with electrophysiological and MRI examinations.

"Our three-year follow up has witnessed nerve regeneration with suitable functional recovery in the patient and the salvage of upper arms from amputation," said the researchers.

"This finding opens an alternative avenue for patients who are at-risk of amputation after the injury to important nerves."

"This single case study provides the first step towards a proof-of-principle for a new treatment for peripheral nerve injury" said Dr. Camillo Ricordi, coeditor-in-chief of Cell Transplantation, Stacy Joy Goodman Professor of Surgery and Director of the Cell Transplant Center at the University of Miami.

"Further studies will be necessary to determine whether the work in this report could be validated, introducing a novel therapeutic strategy for peripheral nerve injury".

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

Contact: Robert Miranda

Reference:

Stem Cell Salvage of injured peripheral nerve

Grimoldi, N.; Colleoni, F.; Tiberio, F.; Vetrano, I. G.; Cappellar, A.; Costa, A.; Belicchi, M.; Razini, P.; Giordano, R.; Spagnoli, D.; Pluderi, M.; Gatti, S.; Morbin, M.; Gaini, S. M.; Rebulla, P.; Bresolin, N.; Torrente, Y.

Cell Transplant. Appeared online: November 21, 2013

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Spine Function Improves Following Cell Replacement Therapy with Foetal Human Stem Cells

Spine Function Improves Following Cell Replacement Therapy with Foetal Human Stem Cells

Tuesday, 28 May 2013

Human foetal stem cell grafts improve both motor and sensory functions in rats suffering from a spinal cord injury, according to research published this week in BioMed Central's open access journal Stem Cell Research and Therapy. This cell replacement therapy also improves the structural integrity of the spine, providing a functional relay through the injury site. The research gives hope for the treatment of spinal cord injuries in humans.

Grafting human neural stem cells into the spine is a promising approach to promote the recovery of function after spinal injury. Sebastian van Gorp, from the University of California San Diego, and team's work looks specifically at the effect of intraspinal grafting of human foetal spinal cord-derived neural stem cells on the recovery of neurological function in a rats with acute lumbar compression injuries.

A total of 42 three month-old female Sprague-Dawley rats, with spinal compression injuries, were allocated to one of three groups. The rats in the first group received a spinal injection with the stem cells, those in the second group received a placebo injection, while those in the third group received no injection.

Treatment effectiveness was assessed by a combination of measures, including motor and sensory function tests, presence of muscle spasticity and rigidity which causes stiffness and limits residual movement. The team also evaluated of how well the grafted cells had integrated into the rodents' spines.

Gorp and colleagues found that, compared to rats who received either the placebo injection or no injection, those who received the stem cell grafts showed a progressive and significant improvement in gait/paw placement, reduced muscle spasticity as well as improved sensitivity to both mechanical and thermal stimuli. In addition to these behavioural benefits, the researchers observed long-term improvements in the structural integrity of previously injured spinal cord segments.

The authors say: "Importantly, spinal cavity formation and muscle spasticity are frequently observed in human patients with high-speed, high-impact induced spinal cord injuries. Our findings demonstrate that human foetal spinal cord-derived neural stem cells, with an already established favourable clinical safety profile, represent a potential cell candidate for cell replacement therapy in patients with traumatic spinal injuries."

Source: BioMed Central 

Contact: Hilary Glover

Reference:

Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation 

Sebastiaan van Gorp, Marjolein Leerink, Osamu Kakinohana, Oleksandr Platoshyn, Camila Santucci, Jan Galik, Elbert A Joosten, Marian Hruska-Plochan, Danielle Goldberg, Silvia Marsala, Karl Johe, Joseph D Ciacci and Martin Marsala 

Stem Cell Research & Therapy 2013 4:57

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Scientists Develops Implantable, Bioengineered Rat Kidney

Transplanted organ produces urine, but further refinement is needed

Sunday, 14 April 2013

Bioengineered rat kidneys developed by Massachusetts General Hospital (MGH) investigators successfully produced urine both in a laboratory apparatus and after being transplanted into living animals. In their report, receiving advance online publication in Nature Medicine, the research team describes building functional replacement kidneys on the structure of donor organs from which living cells had been stripped, an approach previously used to create bioartificial hearts, lungs and livers.

Removal of all living cells from a rat kidney leaves
a collagen scaffolding, ready for repopulation with
new kidney and vascular cells. Credit: Massachusetts
General Hospital Center for Regenerative Medicine. 

"What is unique about this approach is that the native organ's architecture is preserved, so that the resulting graft can be transplanted just like a donor kidney and connected to the recipient's vascular and urinary systems," says Harald Ott, MD, PhD, of the MGH Center for Regenerative Medicine, senior author of the Nature Medicine article.

"If this technology can be scaled to human-sized grafts, patients suffering from renal failure who are currently waiting for donor kidneys or who are not transplant candidates could theoretically receive new organs derived from their own cells."

Around 18,000 kidney transplants are performed in the U.S. each year, but 100,000 Americans with end-stage kidney disease are still waiting for a donor organ. Even those fortunate enough to receive a transplant face a lifetime of immunosuppressive drugs, which pose many health risks and cannot totally eliminate the incidence of eventual organ rejection.

This is a previously decellularized rat kidney after
reseeding with endothelial cells, to repopulate the
organ's vascular system, and neonatal kidney cells.
Credit: Massachusetts General Hospital Center
for Regenerative Medicine.

The approach used in this study to engineer donor organs, based on a technology that Ott discovered as a research fellow at the University of Minnesota, involves stripping the living cells from a donor organ with a detergent solution and then repopulating the collagen scaffold that remains with the appropriate cell type – in this instance human endothelial cells to replace the lining of the vascular system and kidney cells from new-born rats. The research team first decellularized rat kidneys to confirm that the organ's complex structures would be preserved. They also showed the technique worked on a larger scale by stripping cells from pig and human kidneys.

Making sure the appropriate cells were seeded into the correct portions of the collagen scaffold required delivering vascular cells through the renal artery and kidney cells through the ureter. Precisely adjusting the pressures of the solutions enabled the cells to be dispersed throughout the whole organs, which were then cultured in a bioreactor for up to 12 days. The researchers first tested the repopulated organs in a device that passed blood through its vascular system and drained off any urine, which revealed evidence of limited filtering of blood, molecular activity and urine production.

Bioengineered kidneys transplanted into living rats from which one kidney had been removed began producing urine as soon as the blood supply was restored, with no evidence of bleeding or clot formation. The overall function of the regenerated organs was significantly reduced compared with that of normal, healthy kidneys, something the researchers believe may be attributed to the immaturity of the neonatal cells used to repopulate the scaffolding.

"Further refinement of the cell types used for seeding and additional maturation in culture may allow us to achieve a more functional organ," says Ott.

"Based on this initial proof of principle, we hope that bioengineered kidneys will someday be able to fully replace kidney function just as donor kidneys do. In an ideal world, such grafts could be produced 'on demand’ from a patient's own cells, helping us overcome both the organ shortage and the need for chronic immunosuppression. We're now investigating methods of deriving the necessary cell types from patient-derived cells and refining the cell-seeding and organ culture methods to handle human-sized organs."

Ott's team focuses on the regeneration of hearts, lungs, kidneys and grafts made of composite tissues, while other teams – including one from the MGH Center for Engineering in Medicine – are using the decellularization technique to develop replacement livers

Source: Massachusetts General Hospital 

Contact: Kory Dodd Zhao

Reference:

Regeneration and experimental orthotopic transplantation of a bioengineered kidney

Jeremy J Song, Jacques P Guyette, Sarah E Gilpin, Gabriel Gonzalez, Joseph P Vacanti & Harald C Ott

Nature Medicine, (2013), doi:10.1038/nm.3154

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Gene Therapy Reprograms Scar Tissue in Damaged Hearts into Healthy Heart Muscle

Gene Therapy Reprograms Scar Tissue in Damaged Hearts into Healthy Heart Muscle

Saturday, 05 January 2013

A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect, said researchers from Weill Cornell Medical College, Baylor College of Medicine and Stony Brook University Medical Center in a report that appears online in the Journal of the American Heart Association.

"The idea of reprogramming scar tissue in the heart into functioning heart muscle was exciting," said Dr. Todd K. Rosengart, chair of the Michael E. DeBakey Department of Surgery at BCM and the report's corresponding author.

"The theory is that if you have a big heart attack, your doctor can just inject these three genes into the scar tissue during surgery and change it back into heart muscle. However, in these animal studies, we found that even the effect is enhanced when combined with the VEGF gene."

"This experiment is a proof of principle," said Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College and a pioneer in gene therapy, who played an important role in the research.

"Now we need to go further to understand the activity of these genes and determine if they are effective in even larger hearts."

During a heart attack, blood supply is cut off to the heart, resulting in the death of heart muscle. The damage leaves behind a scar and a much weakened heart. Eventually, most people who have had serious heart attacks will develop heart failure.

Changing the scar into heart muscle would strengthen the heart. To accomplish this, during surgery, Rosengart and his colleagues transferred three forms of the vascular endothelial growth factor (VEGF) gene that enhances blood vessel growth or an inactive material (both attached to a gene vector) into the hearts of rats. Three weeks later, the rats received either Gata4, Mef 2c and Tbx5 (the cocktail of transcription factor genes called GMT) or an inactive material. (A transcription factor binds to specific DNA sequences and starts the process that translates the genetic information into a protein.)

The GMT genes alone reduced the amount of scar tissue by half compared to animals that did not receive the genes, and there were more heart muscle cells in the animals that were treated with GMT. The hearts of animals that received GMT alone also worked better as defined by ejection fraction than those who had not received genes. (Ejection fraction refers to the percentage of blood that is pumped out of a filled ventricle or pumping chamber of the heart.)

The hearts of the animals that had received both the GMT and the VEGF gene transfers had an ejection fraction four times greater than that of the animals that had received only the GMT transfer.

Rosengart emphasizes that more work needs to be completed to show that the effect of the VEGF is real, but it has real promise as part of a new treatment for heart attack that would minimize heart damage.

"We have shown both that GMT can effect change that enhances the activity of the heart and that the VEGF gene is effective in improving heart function even more," said Dr. Crystal.

The idea started with the notion of induced pluripotent stem cells – reprograming mature specialized cells into stem cells that are immature and can differentiate into different specific cells needed in the body. Dr. Shinya Yamanaka and Sir John B. Gurdon received the Nobel Prize in Medicine and Physiology for their work toward this goal this year.

However, use of induced pluripotent stem cells has the potential to cause tumors. To get around that, researchers in Dallas and San Francisco used the GMT cocktail to reprogram the scar cells into cardiomyocytes (cells that become heart muscle) in the living animals.

Now Rosengart and his colleagues have gone a step farther – encouraging the production of new blood vessels to provide circulation to the new cells.

Source: Weill Cornell Medical College 

Contact: Lauren Woods

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Neural Stem Cells Regenerate Axons in Severe Spinal Cord Injury

New relay circuits, formed across sites of complete spinal transaction, result in functional recovery in rats

Friday, 14 September 2012

In a study at the University of California, San Diego and VA San Diego Healthcare, researchers were able to regenerate "an astonishing degree" of axonal growth at the site of severe spinal cord injury in rats. Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS).

The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances. Importantly, stem cells across species exhibit these properties. The work will be published in the journal Cell on September 14.

The scientists embedded neural stem cells in a matrix of fibrin (a protein key to blood clotting that is already used in human neuron procedures), mixed with growth factors to form a gel. The gel was then applied to the injury site in rats with completely severed spinal cords.

"Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before," said Mark Tuszynski, MD, PhD, professor in the UC San Diego Department of Neurosciences and director of the UCSD Center for Neural Repair, who headed the study.

"The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement."

In addition, adult cells above the injury site regenerated into the neural stem cells, establishing a new relay circuit that could be measured electrically.

"By stimulating the spinal cord four segments above the injury and recording these electrical stimulation three segments below, we detected new relays across the transaction site," said Tuszynski.

To confirm that the mechanism underlying recovery was due to formation of new relays, when rats recovered, their spinal cords were re-transected above the implant. The rats lost motor function – confirming formation of new relays across the injury.

The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 – a score reflecting the animals' ability to move all joints of affected legs.

Results were then replicated using two human stem cell lines, one already in human trials for ALS.

"We obtained the exact results using human cells as we had in the rat cells," said Tuszynski.

The study made use of green fluorescent proteins (GFP), a technique that had never before been used to track neural stem cell growth.

"By tagging the cells with GFP, we were able to observe the stem cells grow, become neurons and grow axons, showing us the full ability of these cells to grow and make connections with the host neurons," said first author Paul Lu, PhD, assistant research scientist at UCSD's Center for Neural Repair.

"This is very exciting, because the technology didn't exist before."

According to the researchers, the study makes clear that early-stage neurons can overcome inhibitors present in the adult nervous system that normally work to maintain the elaborate central nervous system and to keep cells in the adult CNS from growing aberrantly.

Source: University of California - San Diego 

Contact: Debra Kain

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Neural Stem Cell Transplants for Spinal Cord Injury

Maximized by combined, complimentary therapies in rat models   Wednesday, 18 April 2012

Combined, complimentary therapies have the ability to maximize the benefits of neural stem cell (NSC) transplantation for spinal cord repair in rat models, according to a study carried out by a team of Korean researchers who published in a recent issue of Cell Transplantation (20:9).

"When transplanted, neural stem cells have demonstrated their therapeutic potential to reverse complex pathological processes following spinal cord injury," said study corresponding author Dr. Byung G. Kim of the Ajou University School of Medicine's Brain Disease Research Center and Department of Neurology, Republic of Korea.

"However, many obstacles cannot be overcome by NSC transplant alone."

Their study demonstrated that a combination of treatment strategies - a polymer scaffold, neurotrophin-3 (NT3) and chondroitinase (an enzyme which helps digest the glial scar that formed after a spinal cord injury) - provided added therapeutic benefits to NSC transplantation. The implantation of a polymer scaffold designed to bridge lesion cavities, created a favourable tissue environment for nerve growth. Incorporating the NT3 gene into the transplanted cells improved cell survival and migration while the addition of chondroitinase positively affected neural activity between the scaffold and the spinal cord.

"The poly (ε-caprolactone) [PCL] scaffold in our study appeared to function like a reservoir supplying migratory NSCs to the spinal cord," said Dr. Kim.

"The NSCs grafted with the scaffolds survived the transplantation and migrated to the host spinal cord."

The study included four animal groups, only one of which received the full combination of therapies. Rats in the full combination therapy group were found to have some restored neuroplasticity and enhanced re-myelination of contralateral white matter. All four groups subsequently underwent functional testing for locomotor recovery.

"Rats in the full combination group attained well-coordinated plantar stepping accompanied by improved ankle positioning and toe clearance and reduced paw placement errors," explained Dr. Kim. "Furthermore, animals with the full complement of combination strategies responded to transcranial magnetic stimulation."

The researchers concluded that, given their success, similar treatment for humans should be carried out in a chronic injury setting.

"We believe that our results have important clinical implications regarding the future design of NSC-based therapeutic strategies for human victims of traumatic spinal cord injury," concluded Dr. Kim and co-authors.

"The use of multiple strategies to treat spinal cord injury could prove to be more effective than any single treatment," said Cell Transplantation section editor Dr. John Sladek, professor of neurology and paediatrics at the University of Colorado School of Medicine.

"Changing the hostile environment post spinal cord injury by the use of scaffolds, neurotrophins and breakdown of the glial scar creates a favourable milieu for NSCs to be able to exert benefit".

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

Contact: David Eve

Reference:

Combination of multifaceted strategies to maximize the therapeutic benefits of neural stem cell transplantation for spinal cord repair
Hwang, D. H.; Kim, H. M.; Kang, Y. M.; Joo, I. S.; Cho, C. S.; Yoon, B. W.; Kim, S. U.; Kim, B. G.
Cell Transplant. 20(9):1361-1379; 2011
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Japanese Researchers Repairing Spinal Cord Injury with Human Dental Pulp Stem Cells

Japanese Researchers Repairing Spinal Cord Injury with Human Dental Pulp Stem Cells 
Saturday, 03 December 2011

One of the most common causes of disability in young adults is spinal cord injury. Currently, there is no proven reparative treatment. Hope that a stem cell population, specifically dental pulp stem cells, might be of benefit to individuals with severe spinal cord injury has now been provided by the work of Akihito Yamamoto and colleagues, at Nagoya University Graduate School of Medicine, Japan, in a rat model of this devastating condition.

In the study, when rats with severe spinal cord injury were transplanted with human dental pulp stem cells they showed marked recovery of hind limb function. Detailed analysis revealed that the human dental pulp stem cells mediated their effects in three ways: they inhibited the death of nerve cells and their support cells; they promoted the regeneration of severed nerves; and they replaced lost support cells by generating new ones. Yamamoto and colleagues therefore hope that this approach can be translated into an effective treatment for severe spinal cord injury.

Source: Journal of Clinical Investigation

Contact: Karen Honey

Reference:

Human dental pulp–derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms
Kiyoshi Sakai, Akihito Yamamoto, Kohki Matsubara, Shoko Nakamura, Mami Naruse, Mari Yamagata, Kazuma Sakamoto, Ryoji Tauchi, Norimitsu Wakao, Shiro Imagama, Hideharu Hibi, Kenji Kadomatsu, Naoki Ishiguro and Minoru Ueda
J Clin Invest. 2011, doi:10.1172/JCI59251
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Bone Marrow Stromal Stem Cells May Aid in Stroke Recovery

Bone Marrow Stromal Stem Cells May Aid in Stroke Recovery
Thursday, 02 December 2010

A research study from the Farber Institute for Neurosciences and the Department of Neuroscience at Thomas Jefferson University determines bone marrow stromal stem cells may aid in stroke recovery. The results is published in Cell Transplantation – The Regenerative Medicine Journal, issue 19(9).

The study examining the effects of a systematic administration of either rat (allogenic) or human (xenogenic) bone marrow stem cells (MSC) administered to laboratory rats one day after their simulated strokes found "significant recovery" of motor behaviour on the first day. Early administration was found to be more effective than administration seven days after the simulated strokes.

"The timing of stem cell treatment was critical to the magnitude of the positive effects," said the study's lead author, Lorraine Iacovitti, Ph.D., professor, Department of Neuroscience at Jefferson Medical College of Thomas Jefferson University.

"In the host animals we found profound changes and preserved brain structure along with long-lasting motor function improvement."

According to Dr. Iacovitti, there has been little research into just how stem cell transplantation modifies inflammatory and immune effects as well as promotes regenerative effects, such as blood vessel growth. They observed increased activation of microglia as well as modification of the circulating levels of cytokines and growth factors, including elevated VEGF and new blood vessel formation (angiogenesis) following transplantation.

"The mechanism through which MSCs achieve these remarkable effects remains elusive," said Dr. Iacovitti.

"It is possible that activated glia cells (non-neuronal cells that perform a number of tasks in the brain) may play some role in the response, perhaps by partitioning off the infarcted region and limiting the spread of ischemic brain damage without inducing scar formation."

The research team concluded that there was "little doubt" that the administration of stem cells can modify the cellular and molecular landscape of the brain and blood, limiting damage and protecting the stroke-injured brain.

Source: Thomas Jefferson University
Contact: Ed Federico

Reference:
Changes in Host Blood Factors and Brain Glia Accompanying the Functional Recovery after Systemic Administration of Bone Marrow Stem Cells in Ischemic Stroke Rats
Yang, M., Wei, X., Li, J.. Heinel, L. A., Rosenwasser, R., Iacovitti, L.
Cell Transplant. 19(9):1073-1084; 2010
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Natural Lung Material is Promising Scaffold for Engineering Lung Tissue Using Embryonic Stem Cells

Natural Lung Material is Promising Scaffold for Engineering Lung Tissue Using Embryonic Stem Cells
Friday, 20 August 2010

The first successful report of using cell-depleted lung as a natural growth matrix for generating new rat lung from embryonic stem cells is presented in a breakthrough article in Tissue Engineering, Part A, a peer-reviewed journal published by Mary Ann Liebert, Inc..

Embryonic stem cells (ESCs) have the potential to mature into virtually any type of cell and tissue type, but they require an appropriate environment and chemical signals to drive their differentiation into specific cell types and to form 3-dimensional tissue structures. Alternatives to available synthetic tissue matrices are needed to drive this technology forward and develop clinical applications for engineered lung tissue.

Joaquin Cortiella, MD, MPH, and colleagues from University of Texas Medical Branch (Galveston), Stanford University (Palo Alto, CA), Brown Medical School (Providence, RI), and Duke University (Durham, NC), describe the first attempt to make acellular rat lung and use it as a biological matrix for differentiating ESCs into lung tissue. The authors present evidence of improved cell retention, repopulation of the matrix, and differentiation into the cell types present in healthy lung. They also report signs that the cells are organizing into the 3-D structures characteristic of complex tissues and are producing the chemical signals and growth factors that guide lung tissue function and development.

Cortiella and co-authors describe the process used to remove the cellular component of natural lung tissue and create a growth matrix for ESCs in the article: "Influence of Acellular Natural Lung Matrix on Murine Embryonic Stem Cell Differentiation and Tissue Formation".

"Organ-specific extracellular matrices, properly prepared, are serving more and more as the appropriate structural scaffold for the recapitulation of a specific organ's tissues. This turns out to be especially true in an organ such as the lung, whose parenchyma must have a structure that accommodates atmospheric gas transmission as well as vascular, lymphatic, and neural systems," says Peter C. Johnson, MD, Co-Editor-in-Chief of Tissue Engineering and Vice President, Research and Development, Avery Dennison Medical Products.

Source: Mary Ann Liebert, Inc./Genetic Engineering News
Contact: Vicki Cohn

Reference:
Influence of Acellular Natural Lung Matrix on Murine Embryonic Stem Cell Differentiation and Tissue Formation
Joaquin Cortiella, Jean Niles, Andrea Cantu, Andrea Brettler, Anthony Pham, Gracie Vargas, Sean Winston, Jennifer Wang, Shannon Walls, and Joan E. Nichols
TISSUE ENGINEERING: Part A, Volume 16, Number 8, 2010, DOI: 10.1089/ten.tea.2009.0730
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Human iPS Cells to Treat Parkinson's in Rats

Technologies developed at the Buck Institute can speed the manufacturing of authentic neurons from stem cells for future clinical applications Monday, 16 August 2010

Researchers at the Buck Institute for Age Research have successfully used human induced pluripotent stem cells (iPSCs) to treat rodents afflicted with Parkinson's Disease (PD). The research, which validates a scalable protocol that the same group had previously developed, can be used to manufacture the type of neurons needed to treat the disease and paves the way for the use of iPSC's in various biomedical applications. Results of the research, from the laboratory of Buck faculty Xianmin Zeng, Ph.D., are published August 16, 2010 in the on-line edition of the journal Stem Cells.

Human iPSC's are a "hot" topic among scientists focused on regenerative medicine.

"These cells are reprogrammed from existing cells and represent a promising unlimited source for generating patient-specific cells for biomedical research and personalized medicine," said Zeng, who is lead author of the study.

"Human iPSCs may provide an end-run around immune-rejection issues surrounding the use of human embryonic stem cells (hESCs) to treat disease," said Zeng.

"They may also solve bioethical issues surrounding hESCs."

Researchers in the Zeng lab used human iPSCs that were derived from skin and blood cells and coaxed them to become dopamine-producing neurons. Dopamine is a neurotransmitter produced in the mid-brain, which facilitates many critical functions, including motor skills. Patients with PD lack sufficient dopamine; the disease is a progressive, incurable neurodegenerative disorder that affects 1.5 million Americans and results in tremor, slowness of movement and rigidity.

Researchers transplanted the iPSC-derived neurons into rats that had mid-brain injury similar to that found in human PD. The cells became functional and the rats showed improvement in their motor skills. Zeng said this is the first time iPSC-derived cells have been shown to engraft and ameliorate behavioural deficits in animals with PD. Dopamine-producing neurons derived from hESCs have been demonstrated to survive and correct behavioural deficits in PD in the past.

"Both our functional studies and genomic analyses suggest that overall iPSCs are largely similar to hESCs," said Zeng.

The research also addresses the current lack of a robust system for the efficient production of functional dopamine-producing neurons from human iPSCs, Zeng said. The protocol used to differentiate the iPSCs was similar to one developed by Zeng and colleagues for hESCs.

"Our approach will facilitate the adoption of protocols to good manufacturing practice standards, which is a pre-requisite if we are to move iPSC's into clinical trials in humans," said Zeng.

"The studies are very encouraging for potential cell therapies for Parkinson's disease," said Alan Trounson, Ph.D., the President of the California Institute for Regenerative Medicine.

"The researchers showed they could produce quantities of dopaminergic neurons necessary to improve the behaviour of a rodent model of PD. We look forward to further work that could bring closer a new treatment for such a debilitating disease," Trounson said.

Source: Buck Institute for Age Research
Contact: Kris Rebillot
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Engineered Stem Cells May Limit Heart Attack Damage, Improve Function

Engineered Stem Cells May Limit Heart Attack Damage, Improve Function
Wednesday, 21 July 2010

Implanting tiny plastic scaffolds seeded with genetically engineered stem cells reduced organ damage and led to better cardiac function after a heart attack, according to an animal study presented at the American Heart Association's Basic Cardiovascular Sciences 2010 Scientific Sessions – Technological and Conceptual Advances in Cardiovascular Disease.

The study was designed to help determine what role cytokines – substances secreted by cells that have an effect on other cells – might play following a heart attack, said lead Matthias Siepe, M.D., lead author, assistant professor and staff surgeon at the Department of Cardiovascular Surgery, Medical University Center in Freiburg, Germany.

The researchers implanted five groups of 10 rats each with tiny polyurethane scaffolds seeded with different genetically engineered stem cells. Three groups received cells that overproduced one of three cytokines: hepatocyte growth-factor (HGF), stromal cell-derived factor 1 (SDF-1) or vascular endothelial growth factor (VEGF); one group received a gene called Akt1 associated with several cytokine pathways, and the fifth group received scaffolds seeded with unmodified stem cells, Siepe said. Five more groups were injected with the same types of modified and unmodified stem cells without the plastic scaffolding. An 11th group, the control group, received a sham operation, he said. A sham procedure is similar but omits a key therapeutic element of the treatment or procedure under investigation.

During six weeks of follow-up, the researchers observed significant improvements in blood pressure function in the rats implanted with scaffolds seeded with stem cells modified to overproduce Akt1, SDF-1 and HGF. There was no functional change in the group that received scaffolds containing VEGF-modified stem cells, he said.

In comparison, there was a decrease in blood pressure function in the control group that got the sham procedures. In addition, blood dynamics were stable in rats that received scaffolds with unmodified stem cells. In addition, two therapies – SDF-1 and Akt1 overproduction – seemed to limit cardiac damage from the heart attack, Siepe said.

Source: American Heart Association
Contact: Karen Astle
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Magnetic Attraction of Stem Cells

More potent treatment for heart attack created
Friday, 09 April 2010

Researchers at the Cedars-Sinai Heart Institute have found in animals that infusing cardiac-derived stem cells with micro-size particles of iron and then using a magnet to guide those stem cells to the area of the heart damaged in a heart attack boosts the heart's retention of those cells and could increase the therapeutic benefit of stem cell therapy for heart disease.

Circulation Research, a scientific journal of the American Heart Association, publishes the study today online. The study also will appear in the journal's May 28th printed edition.

"Stem cell therapies show great promise as a treatment for heart injuries, but 24 hours after infusion, we found that less than 10 percent of the stem cells remain in the injured area," said Eduardo Marbán, M.D., director of the Cedars-Sinai Heart Institute.

"Once injected into a patient's artery, many stem cells are lost due to the combination of tissue blood flow, which can wash out stem cells, and cardiac contraction, which can squeeze out stem cells. We needed to find a way to guide more of the cells directly to the area of the heart that we want to heal."

Marbán's team, including Ke Cheng, Ph.D. and other researchers, then began a new animal investigation, loading cardiac stem cells with micro-size iron particles. The iron-loaded cells were then injected into rats with a heart attack. When a toy magnet was placed externally above the heart and close to the damaged heart muscle, the stem cells clustered at the site of injury, retention of cells in the heart tripled, and the injected cells went on to heal the heart more effectively.

"Tissue viability is enhanced and heart function is greater with magnetic targeting," said Marbán, who holds the Mark Siegel Family Foundation Chair at the Cedars-Sinai Heart Institute and directs Cedars-Sinai's Board of Governors Heart Stem Cell Center.

"This remarkably simple method could easily be coupled with current stem cell treatments to enhance their effectiveness."

In the future, this finding in the animal model may build on the ongoing, groundbreaking clinical trial led by Raj Makkar, M.D., director of interventional cardiology for the Cedars-Sinai Heart Institute. In the clinical trial, which is based on Marbán's research, heart attack patients undergo two minimally-invasive procedures in an effort to repair and re-grow healthy muscle in a heart injured by a heart attack. First, a biopsy of each patient's own heart tissue is used to grow specialized heart stem cells. About a month later, the multiplied stem cells are then injected back into the patient's heart via a coronary artery.

The two-step procedure was completed on the first patient in June 2009. Complete results are expected in early-2011.

Recently, Marbán received a $5.5 million grant from the California Institute for Regenerative Medicine to continue developing cardiac stem cell therapies.

The Cedars-Sinai Heart Institute is internationally recognized for outstanding heart care built on decades of innovation and leading-edge research. From cardiac imaging and advanced diagnostics to surgical repair of complex heart problems to the training of the heart specialists of tomorrow and research that is deepening medical knowledge and practice, the Cedars-Sinai Heart Institute is known around the world for excellence and innovations.

Marbán invented the methods used to grow and expand stem cells from heart biopsies. Marbán filed patents regarding those innovations which are licensed by Capricor, Inc. Marbán and his wife, Linda Marban, Ph.D. are both founders of Capricor, Inc. Dr. Eduardo Marban serves on its Board of Directors, and owns equity in the company. Dr. Linda Marban serves as a consultant to Capricor.
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ZenMaster

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Novel Parkinson's Treatment Strategy Involves Cell Transplantation

Novel Parkinson's Treatment Strategy Involves Cell Transplantation

Thursday, 25 March 2010

UCSF scientists have used a novel cell-based strategy to treat motor symptoms in rats with a disease designed to mimic Parkinson's disease.

The strategy suggests a promising approach, the scientists say, for treating symptoms of Parkinson's disease and other neurodegenerative diseases and disorders, including epilepsy.

The scientists transplanted embryonic neurons from foetal rats into an area of the adult rat brain known as the striatum, which integrates excitatory and inhibitory neurotransmitter signals to control movement. In Parkinson's disease, cells that produce the neurotransmitter dopamine are damaged, and thus unable to project their communication wires, or axons, to the region. As a result, the balance of excitation and inhibition in the striatum is lost, causing the motor deficits that are a primary symptom of the disease.

In the study, the transplanted embryonic neurons migrated and integrated into the correct neural circuitry of the striatum, matured into so-called GABA-ergic inhibitory interneuron’s, and dampened the over-excitation in the region. The rats had improved motor function, as seen in their balance, speed, and length of stride during walking. Moreover, the healthy "control" rats in which the cells had been transplanted took longer strides and ran faster on a runway test.

The results, the scientists say, demonstrate that the transplanted cells, known as embryonic medial ganglionic eminence (MGE) cells, can very precisely modify the balance of excitation and inhibition in neural circuits to influence behaviour. As overactive neural circuits are associated with other neurodegenerative diseases – a result of non-functioning or missing cells or abnormal synaptic transmission -- the finding may have broad implications.

"This strategy represents a whole new approach to treating nervous system disorders," says neurologist Arnold Kriegstein, MD, PhD, the senior author of the study and director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

The study, featured on the cover of the journal Cell Stem Cell (vol. 6, issue 3, 2010), was led by Verónica Martínez-Cerdeño, PhD, at the time a postdoctoral fellow in the Kriegstein lab, and was a collaboration involving Arturo Alvarez-Buylla, PhD, UCSF Heather and Melanie Muss Professor of Neurological Surgery and Krys Bankiewicz, MD, PhD, UCSF professor of neurological surgery.

The approach used by the team differs from another cell-based strategy for Parkinson's disease currently being explored by other research teams. This traditional transplantation strategy involves attempting to replace the dopamine-producing cells that are lost in the disease, by grafting precursors for these cells directly in the striatum. The loss of these cells is thought to account for most of the disease's symptoms – motor deficits, cognitive and autonomic dysfunction and disturbances in mood.

This traditional strategy has shown severe drawbacks, including that the grafted dopaminergic cells show little, if any, dispersion when grafted into the striatum, and that patients have developed disabling spontaneous movements in preliminary trials, prompting early suspension of the trials.

The ability to modify the neural circuitry of the striatum, part of a larger region known as the basal ganglia, is a function only cells can perform, says Kriegstein. The nervous system is a complex system of neural networks composed of highly individualized cells that relay electrochemical signals between regions of the brain and spinal cord at millisecond speeds, accounting for every behaviour, emotion, and thought.

"Each cell has its own role to play based on the circuits in which it is embedded," he says.

"It has to carry out its role at exactly the right time, with exactly the right partners, and the activity pattern changes moment by moment.”

"Once MGE cells were integrated into striatal neural circuitry, they would be able to modify circuit activity, in a way no other therapies can."

Current treatment approaches – drugs, surgery and electrical stimulation – are relatively blunt instruments, he says. Drugs, for instance, generally act indiscriminately, affecting whole areas of the nervous system, so there often are multiple side effects.

The new study findings complement two other recent UCSF studies using MGE cells to modify neural circuits. In a collaborative study among the laboratories of Scott Baraban, PhD, professor of neurological surgery; John Rubenstein, MD, PhD, professor of psychiatry, and Alvarez-Buylla, the cells were grafted into the neocortex of juvenile rodents, where they reduced the intensity and frequency of epileptic seizures. (Proceedings of the National Academy of Sciences, vol. 106, no. 36, 2009). Other teams are exploring this tactic, as well.

In the other study (Science, Vol. 327. no. 5969, 2010), UCSF scientists reported the first use of MGEs to broaden the period of plasticity, or capacity to change, in the mouse visual cortex. The finding, reported by the labs of Alvarez-Buylla and Michael Stryker, PhD, professor of physiology, might some day be used, they say, to create a new period of plasticity of limited duration for repairing damaged brains.

Looking ahead, the team studying MGE cells in the rat model of Parkinson's disease plans to target a more specific sub region of the striatum, with the goal of getting a more precise effect. They also want to see if the cells could be genetically modified to produce dopamine, thus more directly addressing the biochemical changes of Parkinson's disease, and they plan to attempt to prompt human embryonic stem cells to differentiate, or specialize, into MGE cells in the lab, with the goal of establishing a mechanism for creating a sufficient supply of the cells for clinical use.
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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at
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Stem Cells Improves Repair of Major Bone Injuries in Rats

Stem Cells Improves Repair of Major Bone Injuries in Rats Monday, 11 January 2010 A study published this week reinforces the potential value of stem cells in repairing major injuries involving the loss of bone structure. The study shows that delivering stem cells on a polymer scaffold to treat large areas of missing bone leads to improved bone formation and better mechanical properties compared to treatment with the scaffold alone. This type of therapeutic treatment could be a potential alternative to bone grafting operations. "Massive bone injuries are among the most challenging problems that orthopaedic surgeons face, and they are commonly seen as a result of accidents as well as in soldiers returning from war," said the study's lead author Robert Guldberg, a professor in Georgia Institute of Technology’s Woodruff School of Mechanical Engineering. "This study shows that there is promise in treating these injuries by delivering stem cells to the injury site. These are injuries that would not heal without significant medical intervention." Details of the research were published in the early edition of the journal Proceedings of the National Academy of Sciences on January 11, 2010. The National Institutes of Health and the National Science Foundation funded this work. The study was conducted in rats in which two bone gaps eight millimetres in length were created to simulate massive injuries. One gap was treated with a polymer scaffold seeded with stem cells and the other with scaffold only. The results showed that injuries treated with the stem cell scaffolds showed significantly more bone growth than injuries treated with scaffolds only. Guldberg and mechanical engineering graduate student Kenneth Dupont experimented with scaffolds containing two different types of human stem cells – bone marrow-derived mesenchymal adult stem cells and amniotic fluid foetal stem cells. "We were able to directly evaluate the therapeutic potential of human stem cells to repair large bone defects by implanting them into rats with a reduced immune system," explained Guldberg, who is also the director of the Petit Institute for Bioengineering and Bioscience at Georgia Tech. Micro-CT measurements showed no significant differences in bone regeneration between the two stem cell groups. However, combining the two types of stem cells produced significantly higher bone volume and strength compared to scaffolds without cellular augmentation. Although stem cell delivery significantly enhanced bone growth and biomechanical properties, it was not able to consistently repair the injury. Eight weeks after the treatment, new bone bridged the gaps in four of nine defects treated with scaffolds seeded with adult stem cells, one of nine defects treated with scaffolds seeded with foetal stem cells, and none of the defects treated with the scaffold alone. "We thought that the functional regeneration of the bone defects may have been limited by stem cells migrating away from the injury site, so we decided to investigate the fate and distribution of the delivered cells," said Guldberg. To do this, Guldberg labelled stem cells with fluorescent quantum dots – nanometre-scale particles that emit light when excited by near-infrared radiation – to track the distribution of stem cells after delivery on the scaffolds and completed the same experiments as previously described. Throughout the entire study, the researchers observed significant fluorescence at the stem cell scaffold sites. However, beginning seven to 10 days after treatment, signals appeared at the scaffold-only sites. Additional analysis with immunostaining revealed that the quantum dots present at the scaffold-only sites were contained in inflammatory cells called macrophages that had taken up quantum dots released from dead stem cells. "While our overall study shows that stem cell therapy has a lot of promise for treating massive bone defects, this experiment shows that we still need to develop an improved way of delivering the stem cells so that they stay alive longer and thus remain at the injury site longer," explained Guldberg. The researchers also found that the quantum dots diminished the function of the transplanted stem cells and thus their therapeutic effect. When the stem cells were labelled with quantum dots, the results showed a failure to enhance bone formation or bridge defects. However, the same low concentration of quantum dots did not affect cell viability or the ability of the stem cells to become bone cells in laboratory studies. "Although in vitro laboratory studies remain important, this work provides further evidence that well-characterized in vivo models are necessary to test the ability of regenerative tissue strategies to effectively integrate and restore function in complex living organisms," added Guldberg. "Improved methods of non-invasive cell tracking that do not alter cell function in vivo are needed to optimize stem cell delivery strategies and compare the effectiveness of different stem cell sources for tissue regeneration." Guldberg is currently exploring alternative cell tracking methods, such as genetically modifying the stem cells to express green fluorescent protein and/or other luminescent enzymes such as luciferase. He is also investigating the addition of programming cues to the scaffold that will direct the stem cells to differentiate into bone cells. These signals may be particularly effective for foetal stem cells, which are believed to be more primitive than adult stem cells, according to Guldberg. Lessons learned from the current work are also being applied to develop effective stem cell therapies for severe composite injuries to multiple tissues including bone, nerve, vasculature and muscle. This follow-on work is being conducted in the Georgia Tech Center for Advanced Bioengineering for Soldier Survivability in collaboration with Ravi Bellamkonda and Barbara Boyan, professors in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ......... ZenMaster

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A 'Fountain of Youth' For Stem Cells?

A 'Fountain of Youth' For Stem Cells? Monday, 04 January 2010 Researchers from the University of Hong Kong and the Massachusetts Institute of Technology have published a study in the current issue of Cell Transplantation (18:9), that explores ways to successfully keep stem cells "forever young" during implantation by slowing their growth, differentiation and proliferation. "The successful storage and implantation of stem cells poses significant challenges for tissue engineering in the nervous system, challenges in addition to those inherent to neural regeneration," said Dr. Rutlege Ellis-Behnke, corresponding author. "There is a need for creating an environment that can regulate cell activity by delaying cell proliferation, proliferation and maturation. Nanoscaffolds can play a central role in organ regeneration as they act as templates and guides for cell proliferation, differentiation and tissue growth. It is also important to protect these fragile cells from the harsh environment in which they are transplanted." According to Dr. Ellis-Behnke, advancements in nanotechnology offer a "new era" in tissue and organ reconstruction. Thus, finding the right nano-sized scaffold could be beneficial, so the research team developed a "self-assembling nanofibre scaffold" (SAPNS), a nanotechnology application to use for implanting young cells. "Fine control of the nano-domain will allow for increased targeting of cell placement and therapeutic delivery amplified by cell encapsulation and implantation," explained Dr. Ellis-Behnke. The research team created the scaffold to provide a substrate for cell adhesion and migration and to influence the survival of transplanted cells or the invasion of cells from surrounding tissue. The SAPNS they developed appear to slow the growth rate and differentiation of the cells, allowing the cells time to acclimate to their new environment. "That delay is very important when the immune system tries attacking cells when they are placed in vivo," he further explained. By manipulating both cell density and SAPNS concentration, the researchers were able to control the nano-environment surrounding PC 12 cells (a cell line developed from transplantable rat cells that respond to nerve growth factor), Schwann cells (glial cells that keep peripheral nerve fibres alive) and neural precursor cells (NPCs) and also control their proliferation, elongation, differentiation and maturation in vitro. They extended the method to living animals with implants in the brain and spinal cord. The researchers concluded that the use of a combination of SAPNS and young cells eliminated the need for immuno-suppressants when cells were implanted in the central nervous system. "Implanted stem cells are adversely susceptible to their new environment and quickly get old, but this study suggests a solution to conquer this problem," said Prof. Shinn-Zong Lin, professor of Neurosurgery at China University Medical Hospital, Taiwan and Chairman of the Pan Pacific Symposium on Stem Cell Research where part of this work was first presented. "The self-assembling nanofibre scaffold (SAPNS) provides a niche for the encapsulated stem cells by slowing down their growth, differentiation and proliferation, as well as potentially minimizing the immune response, thus enhancing the survival rate of the implanted stem cells. This allows the implanted stem cells to "stay forever young" and extend their neurites to reach distant targets, thereby re-establishing the neural circuits.” “This combination of stem cells and SAPNS technologies gives a new hope for building up younger neural circuit in the central neural system." ......... ZenMaster

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