Long-Term Survival of Transplanted Human Neural Stem Cells in Primate Brains

A Korean research consortium has transplanted human neural stem cells (hNSCs) into the brains of nonhuman primates and ascertained the fate of these cells after being inside the brains of these animals for 22 and 24 months. They discovered that the implanted hNSCs had not only survived, but differentiated into neurons and never caused any tumors.

This important study is slated to be published in the journal Cell Transplantation.

To properly label the hNSCs so that they were detectable inside the brains of the animals, Lee and others loaded them with magnetic nanoparticles to enable them to be followed by magnetic resonance imaging (MRI). Also, they did not use immunosuppressants when they transplanted their hNSCs into the animals. This study is the first to examine the long-term survival and differentiation of hNSCs without the need for immunosuppression.

“Stroke is the fourth major cause of death in the US behind heart failure, cancer, and lower respiratory disease,” said study co-author Dr. Seung U. Kim of University of British Columbia Hospital’s department of neurology in Canada. “While tissue plasminogen activator (tPA) treatment within three hours after a stroke has shown good outcomes, stem cell therapy has the potential to address the treatment needs of those stroke patients for whom tPA treatment was unavailable or did not help.”

Based on the ability of hNSCs to differentiate into a variety of types of nerves cells, Lee and his colleagues thought that these cells have remarkable potential to treat damaged brain tissue and replace what was lost after a stroke, head injury or other type of brain trauma. Cell regeneration therapy can potentially treat brain-specific diseases like Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), spinal cord injury and stroke.

Dr. Kim and colleagues in Korea grafted magnetic particle-labeled hNSCs into the brains of laboratory primates and evaluated their performance to assess their survival and differentiation over 24 months. Of particular interest was determining their ability to differentiate into neurons and to determine whether the cells caused tumors.

“We injected hNSCs into the frontal lobe and the putamen of the monkey brain because they are included in the middle cerebral artery (MCA) territory, which is the main target in the development of the ischemic lesion in animal stroke models,” commented Dr. Kim. “Thus, research on survival and differentiation of hNSCs in the MCA territory should provide more meaningful information to cell transplantation in the MCA occlusion stroke model.”

Lee’s team said that they chose NSCs for transplantation because the existence of multipotent NSCs “has been known in developing rodents and in the human brain with the properties of indefinite growth and multipotent potential to differentiate” into the three major CNS cell types – neurons, astrocytes and oligodendrocytes.

“The results of this study serve as a proof-of-principle and provide evidence that hNSCs transplanted into the non-human primate brain in the absence of immunosuppressants can survive and differentiate into neurons,” wrote the researchers. “The study also serves as a preliminary study in our planned preclinical studies of hNSC transplantation in non-human primate stroke models.”

“The absence of tumors and differentiation of the transplanted cells into neurons in the absence of immunosuppression after transplantation into non-human primates provides hope that such a therapy could be applicable for use in humans.” said Dr. Cesar V. Borlongan, Prof. of Neurosurgery and Director of the Center of Excellence for Aging & Brain Repair at the University of South Florida. “This is an encouraging study towards the use of NSCs to treat neurodegenerative disorders”.

Transplanted Human Umbilical Cord Blood Cells Improved Long-Term Heart Muscle Structure and Function in Rats After a Heart Attack

Jianyi Zhang, from the University of Minnesota Health Science Center, in Minneapolis, Minnesota and his co-workers have shown that the transplantation of human umbilical cord blood cells into the rat hearts after a heart attack experience long-term effects that are not observed in the control animals that did not receive the stem cells. Furthermore, none of these laboratory animals required immunosuppressive therapy. The study is scheduled to be published in the journal Cell Transplantation.

“Myocardial infarction induced by coronary artery disease is one of the major causes of heart attack,” said Dr. Zhang. “Because of the loss of viable myocardium after an MI, the heart works under elevated wall stress, which results in progressive myocardial hypertrophy and left ventricular dilation that leads to heart failure. We investigated the long-term effects of stem cell therapy using human non-hematopoietic umbilical cord blood stem cells (nh-UCBCs). These cells have previously exhibited neuro-restorative effects in a rodent model of ischemic brain injury in terms of improved LV function and myocardial fiber structure, the three-dimensional architecture of which make the heart an efficient pump.”

According to Zhang and his co-authors, stem cell researchers have intently examined the ability of stem cells to regenerate and heal damaged heart tissue. Many laboratories all over the world have employed different types of stem cells, different animal models, and distinct modes of stem cell delivery into the heart tissue, and different stem cell doses. All of these studies have produced varying levels of improvement of left ventricular function. Zhang and others also note that, for the most part, the underlying mechanisms by which implanted stem cells improve heart function are “poorly understood and that the overall regeneration of heart muscle cells is modest at best.

In order to investigate the heart’s remodeling processes and to characterize the alterations in cardiac fiber architecture, Zhang’s team used diffusion tensor MRI (DTMRI), which has been previously used to study heart muscle fiber structure in both humans and animals. Most previous studies have concentrated on the short-term effects of umbilical cord blood cells (UCBCs) on damaged heart muscles. Fortunately, this study, which examined the long-term effects of UCBCs, not only demonstrated evidence of significantly improved heart function in treated rats, but also showed evidence of delay and prevention of myocardial fiber structural remodeling. Keep in mind that such alterations in heart muscle fiber structure could have resulted in heart failure.

When compared to the age-matched but untreated rat hearts that had suffered a heart attack, the regional heart muscle function of non-hematopoietic UCBC-treated hearts was significantly improved and the preserved myocardial fiber structure seems to have served as an “underlying mechanism for the observed function improvements.”

“Our data demonstrate that nh-UCBC treatment preserves myocardial fiber structure that supports the improved LV regional and chamber function,” concluded the researchers.

“This study provides evidence that UCBCs could be a potential therapy with long-term benefits for MI” said Dr. Amit N. Patel, director of cardiovascular regenerative medicine at the University of Utah and section editor for Cell Transplantation. “Preservation of the myocardial fiber structure is an important step towards finding an effective therapy for MIs”

See: Chen, Y.; Ye, L.; Zhong, J.; Li, X.; Yan, C.; Chandler, M. P.; Calvin, S.; Xiao, F.; Negia, M.; Low, W. C.; Zhang, J.; Yu, X. The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation . Cell Transplant. Appeared or available online: December 10, 2013.

Skeletal Muscle Engineering for Degenerative Muscle Disorders

A collaborative effort between researchers in Italy, Israel and the United Kingdom has resulted in the development of a new therapeutic technique to repair and rebuild muscle in those who suffer from degenerative muscle disorders. This therapeutic strategy brings together two existing techniques for muscle repair: 1) cell transplantation; and 2) tissue engineering.

Several different conditions can lead to muscle degeneration or loss of skeletal muscle. Skeletal muscle only has a limited capacity to repair itself. Therefore, strategies for muscle reconstitution and regeneration are often necessary.

There are presently two different ways to rebuild muscle. The first utilizes stem cells that are injected directly into the muscle or injected into the arteries that feed blood into large muscles. Stem cell transplantation often shows limited success because the transplanted cells show poor survival rates. The second method is tissue engineering in which cells are embedded into the muscle on a biodegradable biomaterial scaffold that reconstructs the muscle. In this present study, the authors hoped to increase the rates of stem cell survival by implanting them in hydrogel material.

For this experiment, the research team went with a tried and true method for tissue engineering: polyethylene glycol and fibrinogen (PF) hydrogel scaffolds. PF scaffolds have been successfully employed in several experiments and when stem cells are embedded into these scaffolds, the stem cells survive at very high rates.

The stem cell chosen for this experiment is a “mesoangioblast” (Mab). Mabs are stem cells found in the walls of large blood vessels that have the ability to differentiate into blood vessel cells and, under some conditions, muscle.  Why use Mabs for muscle regeneration rather than stem cells that give rise to muscle (myoblasts)? Several experiments have shown that Mabs overcome some of the problems associated with injecting myoblasts into muscle. When injected into muscle, myoblasts tend to not migrate very well, then many of them die and few of them get incorporated into muscle. Mabs, on the other hand, survive better and get incorporated into muscle at a much higher rate. Mabs have the ability to cross the endothelium and to migrate extensively in the space between blood vessels and muscles, where they are recruited by regenerating muscle to reconstitute new functional muscle fibers (See M. Sampaolesi, et al., Science 2003, 301(5632):487–492; M. Guttinger Exp Cell Res 2006, 312:3872–3879; & M. Sampaolesi, et al., Nature 2006, 444(7119):574–579).  These experiments show that mesoangioblasts can also form skeletal muscle.  A phase I/II clinical trial based on intraarterial delivery of donor-derived mesoangioblasts is currently ongoing in children affected by Duchene Muscular Dystrophy at the San Raffaele Hospital in Milan (EudraCT no. 2011-



When this team implanted PF scaffolds with embedded Mabs directly into the inflamed and sclerotic regions typical of the advanced states of muscular dystrophy, they observed high levels of Mab survival and engraftment. Five weeks after treatments, the mice treated with Mabs embedded into PF scaffolds showed much higher rates of integration into the muscle fibers than Mabs that were injected directly into the muscle. Also, Mabs that had been delivered into the muscle on PF scaffolds resulted in muscle that showed much better organization that muscle treated with direct injections of Mabs.

This study demonstrated that a novel tissue engineering approach can produce enriched donor cell engraftment into skeletal muscle after an acute injury or in those more difficult to treat cases of advanced muscular dystrophy.