At 5 years of age, Monty the golden retriever suffered with hip and elbow dysplasia as well as arthritis and immobilizing pain. When other types of treatments failed to help, Monty’s owners Steve and Beth Armogida decided to try stem cell therapy. Their veterinarian, Dr. Charisse Davidson of the CM Surgical Specialty Group in Pasadena, California, used adult stem cells harvested from Monty’s own body fat to treat the dog. As Dr. Davidson explains, “The stem cells aren’t a miracle, but they’re science and they’ve been shown to help in about 77% of cases.” Dr. Davidson removed some of the dog’s fat tissue in a simple procedure and shipped the tissue to Vet-Stem’s laboratories in San Diego where the stem cells were isolated, expanded and then returned to Dr. Davidson who administered the stem cells to the dog at the point of injury. According to Julie Ryan Johnson, DVM, of Vet-Stem, the stem cells “signal other cells to come in, which is an interesting concept called trophism. They’re basically signalling the body to send in other defense mechanisms to come in and clean things up.” Within six months after the treatment, Monty was free of the pain and arthritis and dysplasia that had previously plagued him.

Another successful example involved a 12-year-old golden retriever who couldn’t even stand up prior to receiving adult stem cell treatment, but who was restored to painfree mobility afterwards. According to the dog’s owner, Pat Glazier, “She was like a new dog. She can stand up by herself, she comes when she’s called she can go up and down stairs.”

Veterinary stem cell therapy has advanced most aggressively with race horses, since these are the “patients” who have been in most urgent need of such a therapy, and more than 3,000 horses have been treated with their own adult stem cells thus far. Since embryonic stem cells pose a number of serious risks, not the least of which is the formation of teratomas, which are a particular type of tumor, not only for humans but also for animals, the stem cells that have been used in veterinary medicine are adult stem cells, not embryonic stem cells, and are harvested from each animal’s own body. One of the most notable equine cases involved the treatment of the race horse known as Be a Bono, who suffered an injury which could have ended a highly successful career. Instead, after receiving the stem cell therapy, Be a Bona returned to racing and won more than a million dollars in prize money. As Dan Francisco, the horse’s trainer, explains, “You’re always skeptical. You want to see if it works, somebody has to try it. We did. It worked.” Indeed, adult stem cell therapy offers the first concrete evidence of improvement in the treatment of articular cartilage and tendon injuries to which horse joints are particularly vulnerable. Since such injuries in small animals are less of a life-threatening problem than they are in large animals, adult stem cell therapy has made the greatest and most noticeable difference in the lives of horses and dogs. Nevertheless, at least 19 cats have been treated with their own adult stem cells thus far, along with over 1,000 dogs of varying breeds, and more than three times that many horses. The price of the therapy varies according to the particular type and condition of the animal, but generally falls within the $2,500 to $4,000 range. A number of patents have been issued to biotech companies who are driving the development of innovative technology in this field, a recent example of which is a U.S. patent that was awarded to the South Korean company Medipost for its invention of a biodegradable polymer scaffolding on which mesenchymal stem cells derived from umbilical cord blood are stimulated to regenerate hyaline cartilage.

Like many other animals, Monty the golden retriever is now enjoying the benefits of his own adult stem cell therapy in this rapidly developing field. As Dr. Davidson points out, “Maybe this will set an example for the human world to say, look, we’re having success on dogs, maybe we can have success in people too.”

Cancer stem cells are thought to be the source of some types of primary and recurrent cancers and are characterized by their high degree of potency and self-renewing capacity. In embryonic stem cells and germ cells, properties of self-renewal and pluripotency are regulated by the Oct4A gene, a marker which has been suspected of playing a role in the origin of some cancers. Although a number of key questions still remain unanswered, scientists have now made important progress in understanding how the Oct4A gene might be involved in the development of prostate cancer.

Led by Dr. Paula Sotomayor, researchers in the Department of Urologic Oncology at the Roswell Park Cancer Institute in Buffalo, New York have identified Oct4A in a small subset of prostate cells which were negative for many other types of more conventional cancer stem cells markers, such as markers of luminal epithelial and basal epithelial cell differentiation, including the markers ABCG2, NANOG, CD133 and AMACR. A further subpopulation of the cells expressing Oct4A were also found to co-express the embryonic stem cell marker Sox2, which is a transcription factor necessary for the self-renewal of undifferentiated cells. Yet another subpopulation was found to co-express synaptophysin, while the majority of the Oct4A-expressing cells were found to co-express chromagranin A, both of which are neuroendocrine differentiation markers.

Cells expressing Oct4A have been found in both benign and malignant prostate glands. As one would expect, the amount of Oct4A-expressing cells that are present in the gland is directly correlated with the Gleason score, which is a measure of glandular size and microscopic appearance of the prostate, with lower scores being associated with smaller, more tightly packed glands, whereas higher scores indicate a more loosely dispersed glandular structure.

Oct4A is one variant, along with Oct4B, of the Oct4 marker, and the precise molecular mechanisms governing these variants are yet to be determined. As the authors describe in their publication, “rare cells that express Oct4 were identified in several somatic cancers, however, the differential contributions of the Oct4A and Oct4B variants were not determined.”

Nevertheless, with the discovery that cells expressing Oct4A are present in cancerous prostates in numbers that correlate with the severity of the malignancy, scientists are one step closer to understanding this particular form of cancer. Further investigations will be focused especially on those various subpopulations of the cells that co-express the neuroendocrine differentiation markers chromagranin A and synaptophysin, both of which offer new and important pieces in the puzzle.

Scientists have finally determined the answer to a question that has been on the minds of most stem cell scientists for years: namely, where, exactly, in precise anatomical terms, are bone marrow stem cells produced? Thanks to the invention of new imaging technology, this mystery has now been solved.

In collaboration with several of the support facilities at the Stowers Institute in Kansas City, Missouri, the Linheng Li Lab led the development of the new “ex vivo imaging of stem cells” (EVISC) technology, which monitors in real time the dynamic behavior of stem cells. Using the EVISC, scientists were finally able to observe and track the homing of hematopoietic stem cells after transplantation in mice, which led to the discovery of the newly identified bone marrow niche. This is not the first time that the Linheng Li Lab has pioneered such breakthroughs, as the Lab was already renowned for its discovery in 2003 of the hematopoietic stem cell (HSC) niche, which was reported by Zhang et al. in Nature.

Now, according to Dr. Yucai Xie, predoctoral researcher and a coauthor of the most recent paper, “Using the EVISC technology, we were able to confirm our 2003 findings that HSCs tend to home to the inner bone surface. Additionally, we were able to resolve a debate in the field about whether the bone-forming niche or the blood-vessel-forming niche actually nurtures HSCs. Surprisingly, we revealed that the inner bone surface forms a special zone that includes both osteoblastic and endothelial components. This HSC zone maintains HSCs in their resting state and promotes HSC expansion in response to bone marrow stressors, such as irradiation.”

Scientists have long wondered about the precise location of the HSC niche, as well as details about the nature of the microenvironment of this niche, a better understanding of which would assist with the development of more effective bone marrow transplants by giving scientists and physicians greater control over the entire process by which stem cells from bone marrow are harvested and expanded. According to Dr. Winfried Wiegraebe, director of the Stowers Institute’s Advanced Instrumentation and Physics division, who assisted with the famed two-photon experiments, “The new technique developed in this study may have a variety of applications including monitoring other types of cells in low population numbers in vivo.” As Dr. Linheng Li adds, “EVISC technology will allow us to study HSC lineage commitment in vivo. Furthermore, we will be able to use this technology to study leukemia and other cancer stem cells to better understand whether they use the same or different niches that normal stem cells use, and even to evaluate drug resistance and treatment responses. This is an exciting new avenue for our work.”

Additional study and experimentation are now planned that will further examine the characteristics and processes that are unique to this niche. The mere fact that the inner bone surface actually forms a separate, distinct, unique zone with both osteoblastic and endothelial components, in which HSCs are maintained in their resting state and expanded in response to bone marrow stressors, is in and of itself a discovery with far-reaching applications to the field of regenerative medicine.

Scientists at the University of Minnesota have demonstrated that bone marrow-derived stem cells offer a novel treatment option for epidermolysis bullosa (EB), a rare disorder that is characterized by severely fragile skin that blisters on touch, to an extent similar to third degree burns. In infancy the disease is often fatal while in childhood and adulthood a recessive dytrophic form of EB (known as RDEB) usually results in years of painful blistering and mutilating scarring. The cause of the condition is a genetic inability of the body to produce an adequate amount of collagen type 7 (col7) protein, which is an essential component of the anchoring fibrils that connect mucosal tissue in the gastrointestinal tract and cutaneous membranes to the dermis of the skin. A lack of these fibrils results in a hypersensitive dermal-epidermal connection, to such a degree that any movement which causes even the slightest friction, such as eating, walking, or the rubbing of clothing, creates too much stress between the skin layers which results in blisters and sores.

Children with RDEB develop a number of complications which often include squamous cell carcinoma. Currently there is no cure for the disease, and even the best palliative care is grossly inadequate in alleviating the suffering of the patients.

According to Dr. Jakub Tolar of the University of Minnesota, who led the study, “We have been looking into stem cells as viable treatment options for the correction of conditions such as epidermolysis bullosa, because stem cells can produce extracellular matrix proteints. In this condition, the skin, the largest organ in the body, can significantly benefit from a renewable source of healthy cells that can help improve the connection between the dermis and epidermis and strengthen the skin against everyday stresses.”

Dr. Tolar’s team used a mouse model from which bone marrow cells infused with RDEB were found to increase production of the col7 protein and hence the formation of anchoring fibrils, which slowed the progression of the disease and improved survival in the mice. In addition to the RDEB-infused cells, bone marrow cells were enriched with hematopoietic and progenitor cells and were also found to target the diseased areas of the skin where they increased col7 protein and the production of anchoring fibrils, thereby preventing the formation of blisters. Survival time was increased to ten days in mice who received both the cells that were treated with RDEB and the cells that had been enriched with hematopoietic and progenitor cells, as opposed to 6 days in mice that received only the RDEB-treated but not the enriched marrow cells, and 5.6 days in mice that received untreated cells. Of the 20 mice that received both the treated and the enriched cells, 3 mice improved so significantly that they outlived the treatment period, wheras untreated RDEB mice usually die within two weeks. Each surviving mouse also exhibited dramatic improvement and healing of old blisters.

As Dr. Tolar explains, “Our data provide the first evidence that a selected population of marrow cells can connect the epidermis and dermis in a mouse model of the disease and offer a potentially valuable approach for the treatment of human RDEB and other extracellular matrix disorders. These results provide proof-of-principle of bone marrow transfer to repair the basement membrane defect in RDEB, and they warrant a clinical trial to assess the safety and efficacy of treatment of human RDEB by means of hematopoietic cell transplantation.”

Bone marrow stem cells are already widely known for their therapeutic properties, and this study demonstrates the systemic benefits of these cells in treating disorders that specifically involve defects of the extracellular matrix. New studies are currently in progress to further test the capacity of bone marrow-derived stem cells to produce the various proteins that constitute the highly specialized microenvironment of the extracellular matrix.

Approximately 50 births in one million are diagnosed with EB, which has been documented in all major ethnic groups throughout the world.

The findings were published in the online edition of Blood, the official journal of the American Society of Hematology.

A previously held theory that many types of cancerous tumors are formed by a very small subset of cancer stem cells has now been contradicted.

Using a different strain of “knock-out” mice than those which are usually used in such studies, scientists at the University of Michigan have discovered that a much larger percentage of stem cells are capable of causing cancer, at least for some types of cancer.

Led by Dr. Sean Morrison, a highly respected stem cell oncologist and a cofounder of the cancer stem cell biotech company Oncomed, the scientists discovered in a melanoma mouse model that as much as 25% of the cancerous cells are capable of reproducing, which is a significantly higher percentage than formerly expected. According to the previously held theory, only approximately one in a million cancerous stem cells should be capable of reproducing.

According to Dr. Morrison, who is also director of the Center for Stem Cell Biology at the University of Michigan Life Sciences Institute, “We’re not trying to claim there is no merit to the field, but we think that the frequency of cancer stem cells will be much higher. And there will be some cancers like melanoma where lots of cells will be tumorigenic and it won’t be possible to treat those cancers by treating a small subset of cells.”

In recent years the field of oncology has been strongly influenced by the cancer stem cell theory of tumorigenesis, which spawned an entire biotech industry that mobilized itself around the development of a new class of cancer drugs that were specifically bioengineered to attack cancer stem cells. Many of these drugs are just now entering clinical trials. Oncomed itself has been a leader in this industry, having recently signed a $1.4 billion commercialization deal with GlaxoSmithKline, which is the largest ever biotech deal for a product that was still in the preclinical stage. A number of other major pharmaceutical companies are still developing their own pipelines of anti-cancer drugs based on the now-outdated theory.

According to Dr. Scott Kern, an oncologist at Johns Hopkins and a noted critic of the previous theory, “The paper seems in line with what one should expect. Solid tumors will not be found to follow the stem cell theory.”

The theory, based heavily upon mathematical extrapolation which many critics found to be weak, may still apply to some types of cancers such as leukemia, but not to carcinomas such as brain tumors and sarcomas. And when examined closely, the results of Dr. Morrison’s study make intuitive as well as scientific sense. As Dr. Morrison explains, “When you look back at science, it’s the theories that make the most intuitive sense that people run with before the data exists.” Now the corroborating data have been provided.

Dr. Max Wicha, however, who is also a cofounder of Oncomed and an oncologist at the University of Michigan, believes that further clarification and studies are still needed, and offers yet another alternative perspective by adding that, “Morrison’s work is very interesting and important but we need to look at the different mouse models and see which provides the best representation of what’s in patients. He’s saying that we may have underestimated the number of tumorigenic cells. I say his new model may have overestimated that number. These are cells which have stem cell properties.”

Further clarification may take some time, however, since a number of anti-cancer stem cell drugs are currently in clinical trials but the complete results of such trials will not be forthcoming for another few years. Drugs specifically designed to target cancer stem cells are now in phase I clinical trials, which test for safety, and will not begin phase II clinical trials, which test for efficacy, for another year or two. As Dr. Wichia explains, “Those will really tell us whether the clinical endpoints will improve. If we start seeing any improvement in survival and the patients doing better, it’ll all take off.”

One of the drugs currently in clinical trials is Oncomed’s own drug candidate, OMP-21M18. According to Dr. Morrison, “If the therapeutic shows a benefit to patients, then all of these scientific concerns go by the wayside. And even if the model is flawed in fundamental ways, if it led them to a good therapeutic, that’s still worth a lot.”

Anyone who is awaiting one single silver bullet that can be used categorically against all types of cancers, however, will probably be disappointed, since each successive discovery merely illuminates the inherent complexity of all types of cancer, and therefore the importance of developing specific treatments that are as unique as is each individual type of cancer. As Dr. Morrison explains, “The reality is that cancer is an extraordinarily resourceful disease and every time there has been a new idea, people have seized on it to make it the big answer. Cancer is resourceful enough that there isn’t going to be a big answer.”

Scientists at the University of California at Los Angeles have definitively identified both the place and the time at which the human body manufactures blood stem cells: the place is within endothelial cells, and the time is specifically during the period of mid-gestational embryonic development.

Although the basic, general anatomic location within the embryo from which blood stem cells originate had already been identified, no one knew with certainty which specific cell type it is within the embryo that gives rise to the blood stem cells. Two of the leading, competing theories argued that blood stem cells might be created within the endothelium, or perhaps outside of the endothelium in a neighboring location. Now it has finally been proven that the place of origin of blood stem cells is within the endothelium itself.

Scientists at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research made the discovery using genetically marked endothelial cells, which line the inside of blood vessels, and a “cell fate tracing technique” by which any new cells generated by the endothelial cells could be identified and their paths of migration followed.

According to Dr. Luisa Iruela-Arispe, professor of molecular, cell and developmental biology and director of the Cancer Cell Biology Program at UCLA’s Jonsson Comprehensive Cancer Center, “We genetically traced the endothelial cells to find out what they became over time. In that way, we were able to understand that, within the embryo, endothelial cells were responsible for the generation of blood stem cells. They make blood, they aren’t just the pipes that carry it.”

The finding has broad potential application to the development of new stem cell therapies for blood disorders and for certain types of cancer such as leukemia. Until now, no one has been able to grow blood stem cells outside of the human body without the cells losing their potency, but as a result of this discovery, however, it may now be possible to grow blood stem cells in the laboratory, directly from endothelial cells.

According to Dr. Ann Zovein, a Broad Stem Cell Research Center Training Grant postdoctoral fellow at the California Institute for Regenerative Medicine, “We found that endothelial cells are capable of making blood stem cells within embryonic areas that prevent differentiation into other lineages. In trying to understand how blood stem cells arise from the endothelium, we may learn enough to be able to grow pure, designer blood stem cells outside the human body.”

A further delineation of the time-line during which blood stem cells develop is also an important discovery with far-reaching applications of its own. The fact that endothelial cells manufacture blood stem cells only during a specific period of time during embryonic development, namely, at mid-gestation, has vast implications for any researcher who hopes to mimic the embryonic microenvironment in the lab. Among other variables, for example, cell signaling pathways that exist only during that particular phase of embryonic development play a major role in the self-renewing, non-differentiating nature of the blood stem cells at that stage, which scientists will need to understand in order to recreate such an environment in vitro, which thus far no one has been able to do. As Dr. Iruela-Arispe explains, “Next we need to understand what signaling mechanisms are at work that allow endothelial cells to make blood stem cells. We need to find out how we can program the endothelial cells to make blood stem cells, what’s important in the embryonic blood vessel wall that allows for this phenomenon and whether we can reprogram adult blood vessels to do the same thing.”

Although the discovery was made with mouse endothelial cells, Dr. Iruela-Arispe and her colleagues are now planning experiments with human endothelial cells in order to examine further the cellular and molecular signaling mechanisms behind the formation of blood stem cells.

An eleven-year-old golden retriever named KC is now running and jumping around actively and painlessly, as any dog half his age might do. Merely 3 months ago, however, KC could not even walk without difficulty.

According to the dog’s owner, Krista Moyes, “He likes to swim and run and he’s very active. I just wanted to do whatever I could. He was having a hard time getting up in the morning and really wasn’t walking at all on his back leg. “KC was suffering from a combination of injuries and age-related arthritic joint degeneration, and because of the dog’s advanced age, surgery was not a viable option. Ms. Moyes therefore took KC to a veterinary specialist in Sonora to explore alternative options.

According to veterinarian Dr. Lillian Rizzo, “We had some chronic old injuries, some chronic arthritis, decreased range of motion and pain in that right leg.” Consequently, Dr. Rizzo suggested an adult stem cell therapy which has shown great success in treating a variety of tendon, ligament and joint injuries in small animals such as cats and dogs and also in large animals such as horses. Developed by the company Vet-Stem, the procedure is fast, simple and minimally invasive, requiring only that the vet extract some fat tissue from the animal which is then sent to Vet-Stem where technicians isolate and expand the stem cells from the fat, and return the cells to the vet who injects them directly into the site of injury. As Dr. Rizzo explains, “I send the fat to [Vet-Stem] and they turn it around back to me in the form of an injection syringe within 48 hours. I concentrate the stem cells at the site of injury and then the stem cells mediate inflammation and repair. The injury is to the joint cartilage and that’s really the only thing that can do that. The medications can help with pain and support but the stem cells actually rebuild the damaged joint cartilage.” Another advantage to the therapy is that results are usually seen so quickly that pain medication is no longer needed once the adult stem cell therapy is actually administered.

As any modern, well-informed, scientifically savvy, 21st century patient would do, KC underwent the adult stem cell therapy with eagerness and enthusiasm. According to the dog’s owner, Ms. Moyes, “Two weeks after the surgery I looked at him one day and he was standing on his foot instead of just his toe. I really noticed an attitude change as far as his energy level. He felt better so he was wrestling, carrying on and playing.”

Since Vet-Stem’s therapy uses stem cells that are derived from the animal’s own fat, such stem cells are strictly and exclusively classified as adult stem cells, not embryonic stem cells. Even in animals, as with humans, embryonic stem cells are not available as clinical therapies since embryonic stem cells are inherently very problematic and pose a number of life-threatening risks, including the formation of teratomas which are a type of tumor with very specific, and grotesque, characteristics. Adult stem cells, by sharp contrast, are not scientifically problematic and, most notably, adult stem cells do not carry the risk of teratoma formation nor any of the other dangers which thus far are inextricably tied to embryonic stem cells. It should come as no surprise, therefore, that adult stem cells are already available as viable clinical therapies in the treatment of a wide range of diseases and injuries, for humans as well as for animals, whereas any hope of any clinical therapy ever being developed from embryonic stem cells is at least another decade away, if not further.

As any dog owner can testify, the question has often been posed as to who, exactly, is training whom, in the symbiotic evolution of humans and their canine friends. At least in the case of adult stem cell therapy, perhaps the two-legged species can learn and benefit from the noble example of its four-legged faithful companion.