One of the great findings of regenerative medicine was that organs previously believed to be incapable of healing themselves actually contain stem cells that in response to injury cause some degree of healing. The problem being that these "endogenous healing mechanisms" are usually too small to mediate effects that are visible at the clinical level. For example, the brain was considered to have very limited ability to heal itself after damage. Recent studies that have allowed for observation of brain cells after experimental strokes have led to the discovery of brain stem cells in the dendate gyrus and subventricular zones of the brain, stem cells that start to multiple after a stroke. Interestingly, various hormones such as human chonrionic gonadotropin, are capable of stimulating brain stem cell multiplication. This is currently being used in clinical trials for stroke by the company Stem Cell Therapeutics.

In the area of heart failure, it was also believed that once cardiac tissue is damaged, the only repair process that the body performs is production of scar tissue, which is pathological to the patient. While this scar tissue is found in the majority of the injured area, molecular studies have revealed the existence of cardiac specific stem cells, which start to multiply after injury and serve to repair, albeit in small amounts, the infarct area.

One way to augment endogenous repair processes is to administer stem cells from the bone marrow, which are known to produce various growth factors that assist the tissue-specific stem cell in mediating its activity. Another way is to physically extract the tissue specific stem cells, expand them outside of the body and reimplant them into the damaged area.

In a recent publication in the journal Circulation, Piero Anversa, M.D., director, Center for Regenerative Medicine, Departments of Anesthesia and Medicine and Cardiovascular Division, Brigham and Women’s Hospital, Boston and Roberto Bolli, M.D., chief, cardiology, and director, Institute of Molecular Cardiology, University of Louisville, Kentucky, describe the use of cardiac specific stem cells in treatment of animals whose hearts of been damaged by the chemotherapeutic drug doxorubicin.
Doxorubicin is a chemotherapeutic drug that is mainly used in the treatment of breast, ovarian, lung, and thyroid cancers, as well as for neuroblastoma, lymphoma and leukemia. One of the main limiting factors to increasing the dose of doxorubicin to levels that can lead to tumor eradication is that it causes damage to the heart muscle, the myocardium.

In the published study, the investigators expanded the cardiac specific stem cells from rats, gave the rats high doses of doxorubicin and in some rats injected back cardiac specific stem cells, whereas other rats received control cells. The rats that received the cardiac specific stem cells had both preservation of cardiac function, and also regeneration of the damaged heart tissue. This is an important finding since the type of damage that doxorubicin does to the heart is different from other types of heart damage that have been studies, such as the damage that occurs after a heart attack. These data seem to suggest that stem cell therapy may be useful in a variety of injury situations.

"Theoretically, patients could be rescued using their own stem cells," said study author Dr. Piero Anversa, director of the Center for Regenerative Medicine at Brigham and Women’s Hospital in Boston. Dr. Aversa is one of the original discoverers of the cardiac specific stem cell when he published experiments in dogs demonstrating multiplication of cells in the myocardium that seem to have ability to generate new tissue after damage (Linke et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71).

"A Phase 1 clinical trial using a similar procedure in people is already under way", said Dr. Roberto Bolli, chief of cardiology and director of the Institute of Molecular Cardiology at the University of Louisville in Kentucky, who is heading the trial. The FDA has approved a Phase I clinical trial using cardiac specific stem cells in 30 patients who have congestive heart failure due to disseminated atherosclerosis. "In the trial, participants’ cardiac tissue will be harvested, the stem cells isolated and then expanded in vitro from about 500 cells to 1 million cells over several weeks", Bolli explained. "Several months after the patient has undergone bypass surgery, the stem cells will be re-injected." A similar clinical trial is being performed at Cedars Sinai in Los Angeles.

While the problems of tissue extraction (which is performed by an invasive procedure requiring biopsy of heart tissue) and cost of expansion are still formidable hurdles to widespread implementation, it is believed that the clinical evidence of a therapeutic response will open the door to other avenues of expanding tissue specific stem cells, such as administration of growth factors that can accomplish this without need for cell extraction outside of the body.

Lava Man is a race horse that has had quite a career: he has earned more than $5.2 million and was considered one of the top racehorses in North America. Unfortunately, the recent past has not been to kind to him. Last year he finished last in the 2008 Eddie Read Handicap at Del Mar, and previous to that he has lost a series of six races in a row. Lava Man had arthritis in the joints in his ankles and a small fracture in his left front leg, Being 7 years old at that time, his owners decided it was time for Lava Man to retire.

However it seems like Lava Man’s fortunes may have changed. 17 months after his last race, he is scheduled to make a come-back this Saturday at Hollywood Park in the Native Diver Handicap. The horse was treated with his own fat derived stem cells by Dr. Doug Herthel, who stated:

"The trainer is the only one who can tell you how he’s going to run Saturday, but as far as the way he looks and based on our experience with other horses, theoretically, he should be much better than he was," said Dr. Doug Herthel, who treated Lava Man at the Alamo Pintado Equine Medical Center in Los Olivos, Calif.

"We think of those stem cells as little paramedics," Herthel said. "They go in and they help; they enhance the health of the cartilage." Dr. Herthel stated that significant improvements have occurred in Lava Man following stem cell therapy. He also stated that if Lava Man makes a triumphant return due to stem cells, this would not be the first case of this occurring. He cited the example of Ever A Friend , a 6-year-old horse, who was injured in May 2008, received the same type of fat derived stem cells as Lava Man and returned to win an allowance race and finish second in the Grade I Citation Handicap.

The fat derived stem cells that are being used in the treated of horses appear to work through several mechanisms. On the one hand they can become new cartilage and bone tissue directly, while on the other hand the stem cells producing various growth factors that accelerate the process of healing. Another method, that is more debated amongst scientists, is that the stem cells can actually produce enzymes that degrade scar tissue and allow replacement with functional tissue.

Human use of fat stem cells has been performed for multiple sclerosis (Riordan et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009 Apr 24;7:29) and is currently being investigated for other conditions such as heart failure and rheumatoid arthritis.

The use of stem cells for multiple sclerosis can be categorized into two main approaches. The first involves transplantation of blood making stem cells, called hematopoietic stem cells, after the immune response of the patient is destroyed. This is performed because multiple sclerosis is an immunological disease in which the T cells are attacking the "insulator" of the nerves, a protein called myelin basic protein. By destroying the immune system and subsequently adding stem cells that will make a new immune system, this approach "resets the clock" and has yielded success in early clinical studies. Unfortunately, the problem with destroying the patient immune system is that they undergo a period of immune compromise during which they are susceptible to bacterial, fungal, and viral infections. The second method of using stem cells in multiple sclerosis is to administer a type of stem cell called mesenchymal stem cells, which actually reprogram the pathogenic T cells so that they slow down their immune attack. Mesenchymal stem cells also possess two other important properties: a) they induce the generation of T regulatory cells, which block pathologic T cells from attacking myeling&; and b) they help to regenerate the injured neurons through producing growth factors, as well as becoming new neurons.

For the study of this second approach, the Cleveland Clinic has received a $2.75 million federal grant from the Department of Defense. This is a 4-year grant that will fund a 24-patient study which will be conducted by the Center for Stem Cell and Regenerative Medicine. The study will investigate patients with relapse-remitting MS that are still able to walk but have moderate to severe disability. Collaborators in the study will include the stem cell company Athersys Inc., Case Western Reserve University, the Clinic, Ohio State University and University Hospitals Case Medical Center.

"Mesenchymal stem cells are primitive cells in the bone marrow that have a wide range of effects that decrease the activity of immune cells which are over-active in MS," said Dr. Jeffrey Cohen of the Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. "In addition, in numerous laboratory studies, MSC’s were able to migrate from the blood in to areas of inflammation or injury in the nervous system and reduce damage by developing into cells resembling neurons (nerve cells) and glia (support cells) and, probably more importantly, by creating a tissue environment that encourages intrinsic repair mechanisms," he said.

The proposed study is similar to work performed by the Cellmedicine (www.cellmedicine.com ) stem cell treatment clinic which has published on 3 patients with MS undergoing a recovery after treatment with their own fat derived stem cells, without immune suppression. This was published with collaborators at the company Medistem Inc, the University of California San Diego, Indiana University, the company Vet-Stem and the University of Utah. The publication is freely available at this link www.translational-medicine.com/content/7/1/29.

The use of fat as a source of mesenchymal stem cells for treatment of MS is appealing for several reasons. Firstly, the high content of these stem cells in the fat makes expansion of the cells unnecessary for certain uses. The process of cell expansion is technically complex and can only be performed at specialized institutions with experience in cell processing. Secondly, fat contains high concentrations of T regulatory cells, therefore in addition to administering mesenchymal stem cells, the presence of these T cells is theoretically beneficial since they are known to inhibit pathological immune responses. An explanation of the importance/relevance of T regulatory cells in fat is provided in this video:

Other cells found in fat include endothelial progenitor cells (EPC), these are useful for healing injured tissue by creating new blood vessels, a critical part of the healing process.

Fat tissue is becoming increasingly recognized as a major contributor to the biochemical balance in the body. For example, during times of obesity, fat tissue produces compounds such as leptin that suppress, or attempt to suppress appetite. Fat tissue contains numerous cell types that control inflammation such as T regulatory cells, and alternatively activated macrophages (Riordan et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009 Apr 24;7:29). Additionally, fat tissue contains several populations of stem cells, including mesenchymal stem cells, and hematopoietic stem cells.

In the study published today, fat mesenchymal stem cells were isolated from rats and tested for ability to promote healing of the endothelium, which is the lining of the blood vessels. The endothelium is very important because damaged endothelium is believed to be the cause of atherosclerosis.

The first set of experiments that the scientists performed was to try to “differentiate” or transform the fat mesenchymal stem cells into endothelial cells in the test tube. Treatment of the stem cells with an optimized mix of chemicals, called “endothelial growth media” resulted in cells that resembled endothelium based on expression of proteins on the cell surface. Specifically, the “home grown” endothelial cells expressed the markers Flt-1 and responded to SDF-1, a protein known to attract endothelial cells.

In order to mimic the condition of atherosclerosis development, a wire was inserted into the femoral artery and used to “scratch” the endothelial surface so as to produce an injury. In animals that did not receive stem cells, the injury resulted in a lesion that resembled the atherosclerotic plaque. When stem cells that were differentiated into endothelial cells were administered in the injured area, the lesion size was reduced, or in some animals completely absent.

Most interesting in the study was that the differentiated endothelial cells did not incorporate themselves into the existing blood vessel endothelium. Specifically, the injected cells could have been injected even outside of the endothelium and prevention of injury would be seen. These data suggest that the endothelial cells generated in vitro seem to work by producing therapeutic factors that accelerate healing, but not necessarily by replacing the function of the old endothelium. One interesting next step of this research may be to purify the growth factors made, and administer them instead of stem cells as a therapeutic approach to prevention of atherosclerosis.

Stem Cell Therapeutics is a biotechnology company from Calgary Canada that is developing a novel type of stem cell therapy: instead of administering stem cells, they give drugs that activate the patient’s own stem cells. The company licensed intellectual property from Dr. Samuel Wise, which covered the use of agents such as erythropoietin, human chorionic gonadotropin (hCG), parathyroid hormone, and prolactin, for stimulation of the body’s own stem cells.

The company published a paper describing their Phase I clinical trial of hCG entitled "Open labeled, uncontrolled pharmacokinetic study of single intramuscular hCG dose in healthy male volunteers" the August 2009 issue of the International Journal of Clinical Pharmacology and Therapeutics. Which assessed feasibility of administration of hCG and demonstrated it can cross the blood brain barrier by assessment of cerebral spinal fluid levels of the hormone. These data were important because it allowed the company to enter Phase II clinical trials for treatment of stroke using a combination of the red blood cell stimulating hormone erythropoietin, together with hCG.
If successful, this will be one of the very few companies that uses injectable drugs as a substitute for stem cells. This is an important paradigm shift in cell therapy since many of the current therapies require manipulation of cells outside of the body, which is expensive and currently limited to a small number of clinical trials.

The company is also working on other neurological conditions including multiple sclerosis and traumatic brain injury, both of which are in preclinical stages of development, however animal data to date has been promising. For multiple sclerosis the hormone prolactin is being used as a stem cell stimulatory drug, whereas for brain injury hCG and erythropoietin are used, in a similar model as in the current stroke trials.

Today Stem Cell Therapeutics announced that it has closed on two separate financing deals that together yielded $2,186,941 in gross proceeds. The first deal was a brokered private placement through J.F. Mackie & Company Ltd for $1,138,741, whereas the second was a non-brokered offering of $1,048,200. The company reported that proceeds will be used for general working capital purposes.