Gergana Koleva blogs about public health for Forbes. She has written an excellent piece on the FDA’s lawsuit against Regenexx in their quest to regulate (read shunt down) a procedure that uses a patient’s own stem cells to treat ailing joints. In this lawsuit, the FDA justified their action by stating that cells are chemicals, just like drugs, and therefore, the have the right to regulate them. Ms. Koleva rightly notes that this lawsuit will change the face of medicine and medical innovation in this country. Read her blog article here.
Can stem cells transferred into the brains of newly-born babies with brain damage reverse brain damage? A study presented at the Society for Maternal-Fetal Medicine’s annual meeting in Dallas, Texas, researchers suggests that such a treatment might actually work. In this study, early transplantation of human placenta-derived mesenchymal stem cells into the lateral ventricles of neonatal rats with birth-related brain damage is feasible in this animal model. The transplanted donor cells survive and migrate within the recipient’s brain. Researchers designed this study so that the rat’s brain damage would mimic the type of brain injury observed in infants with very low birth weight.
Preterm delivery is one of the major causes of neonatal brain damage. Despite all efforts to prevent it, survivors of premature birth often suffer from some kind of injury to the brain. Survivors of preterm labor often display cognitive, behavioral, attention related and/or socialization deficits in twenty-five to fifty percent of cases; and major motor deficits in five to ten percent of cases.
Those infants with very low birth weights compose the majority of neonatal encephalopathy Such infants present with hypoxia-ischemia (low oxygen delivery to the tissues, which results in cell death and tissue damage) and inflammation. Approximately 63,000 infants are born in the United States with a very low birth weight (one to five percent of all live births). In order to understand the pathology of very premature infants, and if stem cells could ameliorate their conditions, this study, Early Intracranial Mesenchymal Stem Cell Therapy After a Perinatal Rat Brain Damage, was undertaken. This study investigated the neuroprotective effects of transplanted mesenchymal stem cells in recently born rats that had brain injuries that mimicked those found in infants with a very low birth weight.
One of the study’s authors, Martin Müller, MD, of the University of Bern, Obstetrics and Gynecology, Bern, Switzerland, said: “Stem cells are a promising source for transplant after a brain injury because they have the ability to divide throughout life and grow into any one of the body’s more than 200 cell types, which can contribute to the ability to renew and repair tissues. In our study, the donor cells survived, homed and migrated in the recipient brains and neurologic improvement was detected.”
Examination of the level of brain damaged after mesenchymal stem cell treatment indicated that stem cells exerted a neuroprotective effect on the brain. The transplanted cells survived in the brain, homed to damaged areas and migrated throughout the recipient brains. Furthermore, a combination of mesenchymal stem cells and erythropoietin (the signaling molecule made by the kidneys to signal to the bone marrow to make more red blood cells) might work even better.
While this work is still ongoing, it shows that such stem treatments are feasible and exert some positive effects.
The biotechnology company called Osiris Therapeutics, Inc. has developed an adult mesenchymal stem cell formulation it calls “Prochymal.” Osiris scientists have been busy subjecting Prochymal to a battery of clinical trials that include testing Prochymal as a treatment for chronic obstructive pulmonary disease, Crohn’s disease, myocardial infarction, and acute graft-versus-host disease. Now Osiris is in the process of testing Prochymal as a treatment for newly diagnosed diabetes mellitus.
This clinical trial transferred mesenchymal stem cells from unrelated adult donors into 63 pediatric and adult type diabetics to determine if such a transfer can slow the progression of this debilitating disease. Patients will randomly receive either the stem cells or a placebo. Thus far, no patients who have received the mesenchymal stem cell infusion have shown any adverse reactions, despite receiving the cells from unrelated donors and without any drugs to suppress the immune system. Additionally, no significant differences in insulin levels were observed between the placebo and the experimental group after one year of receiving the mesenchymal stem cell infusion. However, patients who had received Prochymal showed fewer severely low blood glucose concentrations hypoglycemic events) than those who had been given the placebo. The test is still ongoing, and all patients will be observed for another year.
The rationale behind this trial resides in the unique ability of mesenchymal stem cells to down-regulate the immune response. Because type 1 diabetes typically results from the patient’s immune system attacking and destroying the insulin-secreting beta cells found in the pancreatic islets, an influx of mesenchymal stem cells might be able to decelerate the destruction of the beta cells. This suppression of beta cell destruction might lead to the regeneration of the beta cells, since several stem cell populations in the pancreas and pancreatic ducts can differentiate into beta cells. Since, Prochymal is specifically designed to control inflammation, promote tissue regeneration and prevent the formation of scar tissue; it is a prime candidate agent to reduce the loss of beta cells at the onset of type 1 diabetes.
Jay Skyler, professor and medicine and deputy researcher of the Diabetes Research Institute at the University Of Miami Miller School Of Medicine commented, “This groundbreaking study in an important first step in the use of stem cells to potentially alter the course of type 1 diabetes. The ability to safely use stem cells from unrelated donors is an important finding of this study and provides new possibilities for further development and stem cell therapies for type 1 diabetes.”
New findings from researchers from the University of Illinois showed that adult stem cells in muscle are responsive to exercise. This discovery might provide a link between exercise and muscle health, and could provide the impetus for therapeutic techniques that use muscle-specific stem cells to heal injured muscles and prevent or restore muscle loss with age.
Mesenchymal stem cells (MSCs) in skeletal muscles have been known to be important for muscle repair in response to injury. Experiments that demonstrate the roles of mesenchymal stem cells in muscle repair have use chemical-induced injuries that initiate damage muscle tissue and inflammation. However, exercise also stresses muscle, and a research group led by kinesiology and community health professor Marni Boppart investigated whether MSCs also responded to exercise-induced stress.
According to Boppart, “Since exercise can induce some injury as part of the remodeling process following mechanical strain, we wondered if MSC accumulation was a natural response to exercise and whether these cells contributed to the beneficial regeneration and growth process that occurs post-exercise.”
Boppart’s group found that muscle-based MSCs respond to mechanical strain. In fact, mice subjected to vigorous exercise showed robust accumulation after exercise. They also found that MSCs do not directly contribute to new muscle fibers, but, instead, they release growth factors that spur other cells in muscle to fuse and generate new muscle.
Boppart’s research group isolated muscle-based MSCs after the mice exercised, and then they stained the MSCs with a fluorescent marker and injected them into other mice to see how they coordinated with other muscle-building cells. In addition to examining MSCs in vivo, Boppart’s laboratory examined the response of MSCs to strain on different substrates. They discovered that MSC response is very sensitive to the mechanical environment, indicating that conditions under which muscles are strained affects the activity of the cells.
Boppart added, “We’ve identified an adult stem cell in muscle that may provide the basis for muscle health with exercise and enhanced muscle healing with rehabilitation/movement therapy. The fact that MSCs in muscle have the potential to release high concentrations of growth factor into the circulatory system during exercise also makes us wonder if they provide a critical link between enhanced whole-body health and participation in routine physical activity.”
Since, preliminary data suggest MSCs become deficient in muscle with age; the group hopes to determine if these cells contribute to the decline in muscle mass over a person’s lifetime. The team hopes to develop a combinatorial therapy that utilizes molecular and stem-cell-based strategies to prevent age-related muscle loss.
Osteoporosis is a disease that affects bone and results from aging or a lack of estrogen. Osteoporotic bone is less dense than normal bone, and the loss of bone density leads a tendency for bones to fracture easily. In particular, the bones of the wrist, hip, or back can fracture and fortunately, bone scans can help diagnose osteoporosis earlier and earlier.
Typically, osteoporosis is treated by prescribing a group of drugs collectively known as the “bisphosphonates.” These drugs have a common mode of action that includes one of the two cells involved in bone remodeling and healing. Cells called “osteoblasts” act as bone-building cells. Osteoblasts come from bone marrow (the squishy stuff inside your long bones), and they make new bone called “osteoid” that consists of a protein called “collagen” and a few other proteins. Then they deposit calcium and other minerals onto the protein matrix. After filling a cavity with bone, the osteoblasts flatten and line the cavity where they regulate the movement of calcium into and from the bone. Some of the osteoblasts become trapped in the bone while it is being deposited and they extend long extensions and become known as “osteocytes.” Osteocytes monitor the bone health and signal when there are breaks in the bone.
The second cell involved in bone remodeling is the osteoclast. Osteoclasts are large cells with many nuclei that dissolve existing bone. When a bone is broken, the osteocytes signal to each other and recruit osteoclasts to the site of the bone break. Osteoclasts dissolve the broken bone, and this gives room to the osteoblasts so that they can deposit new bone. The activities of both cell types are essential for bone healing and remodeling. The activities of these two cell types are also very carefully regulated.
When osteoblast activity is too high, a disease called “osteopetrosis” ensues, and this disease squeezes out the bone marrow and prevents the synthesis of enough blood cells. When osteoclast activity is too high, osteoporosis ensues, and bone density decreases so that fractures are a genuine possibility. Bisphosphonates bind to the surface of osteoclasts and prevent them from destroying bone. However, since both osteoclasts and osteoblasts are required for proper bone health, bisphosphonates essentially cause bone deposition to come to a stand-still. For this reason, some people experience increased fractures on bisphosphonates. What is needed is a treatment that can reverse the thinning of the bones and increase bone density.
A very interesting study led by scientists at the UC Davis Heath System examined a mouse model of osteoporosis to test the efficacy of a new treatment that can potentially increase bone density. If the results of this study are confirmed by further work, it could revolutionize osteoporosis treatments. The UC Davis team developed a novel technique to enhance bone growth by injecting a specific molecule into the bloodstream that guides mesenchymal stem cells to bone surfaces. Once there, these stem cells differentiate into osteoblasts, which promote bone growth.
Wei Yao, the principal investigator and lead author of the study said: “There are many stem cells, even in elderly people, but they do not readily migrate to bone. Finding a molecule that attaches to stem cells and guides them to the targets we need is a real breakthrough.”
Even though there is a great deal of research to develop stem cell-based treatments for many conditions and injuries that range from peripheral artery disease and macular degeneration to blood disorders, skin wounds and diseased organs, directing stem cells to travel and adhere to the surface of bone for bone formation has been among the elusive goals in regenerative medicine. To accomplish this, Yao and others used a unique hybrid molecule, LLP2A-alendronate that consists of two parts: the LLP2A part that attaches to mesenchymal stem cells in the bone marrow, and a second part that consists of the bone-homing bisphosphonate-class drug, alendronate (trade name – Fosamax). LLP2A-alendronate was injected into the bloodstream, and it bound to the cell surfaces of mesenchymal stem cells in the bone marrow and directed those cells to the surfaces of bone, where the stem cells carried out their natural bone-formation and repair functions.
The study shows that stem-cell-binding molecules can be exploited to direct stem cells to therapeutic sites inside an animal. One author even said. It represents a very important step in making this type of stem cell therapy a reality.
Twelve weeks after the LLP2A-alendronate was injected into mice, bone mass in the femur (thigh bone) and vertebrae (in the spine) increased and bone strength improved compared to control mice who did not receive LLP2A-alendronate. The treated mice were older mice that normally showed a particular degree of bone loss, but with this treatment, they had improved bone formation, as did those that were models for menopause.
Even though alendronate is commonly prescribed to women with osteoporosis to reduce the risk of fracture, it was used in this study because it goes directly to the bone surface, where it slows the rate of bone breakdown. The alendronate dose in this experiment was very low and was, therefore, unlikely to have inhibited LLP2A’s therapeutic effect.
Co-investigator on the study and director of the UC Davis Musculoskeletal Diseases of Aging Research Group, Nancy Lane, noted: “For the first time, we may have potentially found a way to direct a person’s own stem cells to the bone surface where they can regenerate bone. This technique could become a revolutionary new therapy for osteoporosis as well as for other conditions that require new bone formation.”
Mesenchymal stem cells from bone marrow induce new bone remodeling, which thicken and strengthen bone. The potential use of this stem cell therapy is not limited to treating osteoporosis, since it may prove invaluable for other disorders and conditions that could benefit from enhanced bone rebuilding, which includes bone fractures, bone infections or cancer treatments.
Jan Nolta, professor of internal medicine, an author of the study and director of the UC Davis Institute for Regenerative Cures opined, “These results are very promising for translating into human therapy. We have shown this potential therapy is effective in rodents, and our goal now is to move it into clinical trials.”
Paper citation: “Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass;” Min Guan, Wei Yao, Nancy E Lane et al.; Nature Medicine, 2012; DOI: 10.1038/nm.2665.
Cells use gene expression programs to respond to external stimuli and maintain their present form and identity. Genes are stretches of DNA that encode a protein or RNA. Gene expression requires DNA sequences directly attached to the gene, and these sequences are called the “promoter” of the gene. The promoter is the binding site for the enzyme that executes the first step of gene expression. That enzyme is called “RNA polymerase.” RNA polymerase binds to the promoter and initiates the synthesis of an RNA copy of the gene, and process by which an RNA copy of the gene is synthesized rom the DNA template is called “Transcription.”
If the gene encodes a protein, the RNA is processed and sent from the nucleus of the cell to the cytoplasm, where protein/RNA complexes called “ribosomes” use the sequence in the RNA to make proteins that have amino acid sequences. Some genes, however, encode RNA molecules that are not used to direct the synthesis of protein, but are used for some other purpose.
Whatever the case, cells have a great deal of DNA in their nuclei. Almost every human cell, for example, contains so much DNA that if the DNA in one human cell was laid out end-to-end, it would stretch to a length of at least 1 meter. To pack all that DNA into the nucleus of a cell, the DNA is wound into a tight complex of DNA and proteins that is collectively called “chromatin.” Chromatin consists of DNA wound around proteins called histones, in ways that resemble the way thread is wound around a spool. These little histone spools are then wound into spirals that are then wound into a rosette of fibers. It is exceedingly for RNA polymerase to transcribe genes when they are wound into chromatin. How then are genes expressed? It turns out that particular proteins modify chromatin and cause it to loosen up so that RNA polymerase can access it.
Histone modifying proteins include those that encourage the formation of chromatin and tend to shut gene expression off (histone deacetylase, Polycomb-group proteins), and those that loosen chromatin and encourage gene expression (histone acetyl-transferases, histone methyltransferases). Therefore, we might expect to see such enzymes playing an important role in stem cell differentiation.
Therefore, we should not be surprised that stem cells researchers at the Whitehead Institute have discovered that a specific chromatin enzyme called lysine-specific demethylase 1 (LSD1) plays as embryonic stem cells differentiate into other cell types. Cell differentiation requires two key steps: 1) the genes active in the initial cell type must be deactivated; and 2) those genes important for the establishment of the new cell type must be activated. If the switch is not flawless, a transitioning cell may die or be driven to divide uncontrollably. Interestingly, LSD1 was known to be critical to development, but little was known about the key role it plays during differentiation, when cell-specific gene expression systems are switched on or off.
Paper author, Steve Bilodeau, who is also a postdoctoral research fellow in the laboratory of Whitehead Member, Richard Young, said; “We knew that cells express a new set of genes when the operating switch occurs. But this study shows it is also essential to shut off genes that were active in the prior cell state. If you don’t, the new cell is corrupted.”
Bilodeau and Warren Whyte, a Young lab graduate student and co-author, redefined LSD1’s role and described a previously unknown mechanism for silencing genes. They examined embryonic stem cell gene expression during differentiation and concentrated their efforts on those genes that must be shut off during differentiation. Whyte and Bilodeau found LSD1 was located on the promoters of those genes that had to be repressed in order for differentiation to occur. LSD1 was also found near DNA sequences called “enhancers,” which are associated with promoters and increase the ability of the promoters to activate gene expression.
What is LDS doing at the promoter and enhancer? When LSD1 receives the signal that the stem cell is going to differentiate, it transitions into an active conformation and silences those genes. Specifically, LSD1 hamstrings the ability of the enhancers of those genes to activate gene expression. With their enhancers rendered nonfunctional, transcription of these genes is silenced. While this occurs, other mechanisms switch on those genes necessary for the adoption of the new cell type.
Whyte added: “This reveals the critical function of LSD1 in cell differentiation. The enzyme decommissions the stem cell enhancers, thus allowing the new cell to function entirely within the parameters of the new operating system.”
Although this work focuses on one enzyme’s job in normal cells, Young sees broader implications, since LSD1 is a member of a class of molecules that regulate both gene activity and chromosome structure. Therefore, these findings about LSD1 could provide insights into how related regulators function. Similarly, understanding how a mechanism operates in normal cells provides a solid foundation for teasing apart what is going wrong in abnormal cells.
Young summed it up this way: This new knowledge brings us one important step closer to understanding defective operating systems in diseases such as cancer. And this may give us a new angle on drug development for these diseases.”
This work was published in “Enhancer decommissioning by LSD1 during embryonic stem cell differentiation;” Warren A. Whyte, Steve Bilodeau et al.; Nature, 2012; DOI: 10.1038/nature10805.
The injection of stem cells into the carotid artery of brain-injured rats allows the stem cells to move directly to the brain where they greatly enhance brain repair and healing, speeding functional neurological recovery.
This stem cell injection technique was combined with imaging to track the injected stem cells after their introduction into the animal. This study is part of a larger project to study the feasibility of stem cell treatments for traumatic brain injury (TBI) in humans. This research group is being led by Dr. Toshiya Osanai of Hokkaido University Graduate School of Medicine, Sapporo, Japan.
In this experiment, traumatic brain injuries were induced in laboratory rats, and seven days later, bone marrow stem cells were isolated and injected into the carotid arteries. Since injections directly into the brain are dangerous and can cause further brain damage, a technique that places stem cells into the peripheral circulation is preferable. However, many animal and clinical studies have shown that stem cells placed into the peripheral circulation tend to get stuck in the lungs, spleen, liver, and other places. For example, Wang W, et al Cell Transplant 2010;19(12):1599-1607 injected bone marrow mesenchymal stem cells into the heart of rats that had recently experienced a heart attack, and found the many of the injected stem cells stayed in the heart, but many others spread to the lungs, spleen, and lungs. This finding has been confirmed by several other studies as well (Zhang H, et al J Thorac Cardiovasc Surg. 2007;134(5):1234-40 & Wang W, et al, Regen Med. 2011;6(2):179-90). Therefore, Osanai’s research group decided to inject stem cells into the blood vessels that directly feed the brain. This way, the stem cells should find their way to the brain without getting lost in general circulation.
Before injection, the bone marrow stem cells were labeled with “quantum dots,” which are a biocompatible, fluorescent semiconductor created using nanotechnology. The quantum dots emit near-infrared light. Near-infrared light has very long wavelengths that penetrate bone and skin, which allowed the researchers to noninvasively monitor the stem cells for four weeks after transplantation.
Using this in vivo combination of optical imaging and carotid injection, Osanai and colleagues observed the bone marrow-derived stem cells enter the brain on the “first pass,” without entering general circulation. Within three hours, the stem cells began to migrate from the smallest brain blood vessels (capillaries) into the area of brain injury.
After four weeks, rats treated with stem cells showed significant recovery of motor function (movement), while untreated rats showed no such recovery. Examination of the treated brains confirmed that the stem cells had transformed into different types of brain cells and participated in healing of the injured brain area.
Stem cells from bone marrow are likely to become an important new treatment for patients with traumatic brain injuries and stroke. Bone marrow stem cells, like the ones used in this study, are a promising source of donor cells. However, despite the many questions that remain regarding the optimal timing, dose, and route of stem cell delivery.
In the new animal experiments, stem cell transplantation was performed one week after a traumatic brain injury, which is a “clinically relevant” time, since it takes at least that long to develop stem cells from bone marrow. Injecting such stem cells into the carotid artery is a relatively simple procedure that delivers the cells directly to the brain.
These experiments also add to the evidence that stem cell treatment can promote healing after traumatic brain injury, with significant recovery of function. Osanai and colleagues wrote that, with the use of in vivo optical imaging, “The present study was the first to successfully track donor cells that were intra-arterially transplanted into the brain of living animals over four weeks.”
Some similar form of imaging technology might be useful in monitoring the effects of stem cell transplantation in humans. However, tracking stem cells in human patients will pose challenges, as the skull and scalp are much thicker in humans than in rats. Clearly further studies are warranted to apply in vivo optical imaging clinically.