Successful Stem Cell Treatment Of Autoimmune Diseases

Recent findings published in the Journal of Translational Medicine report the first ever treatment of autoimmune diseases with fat-derived stem cells. The article is entitled “Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells,” and contained contributions from researchers in five different countries: South Korea, United States, Japan, China, and Germany.

The senior author, Jeong Chan Ra, president of RNL Stem Cell Technology Institute, and his collaborators were successful in treating patients with autoimmune diseases who had experienced severe tissue damage as a result of their diseases and had limited treatment options.

Autoimmune diseases are caused by mis-regulation of the immune system that allows the body’s immune system to attack the very tissues and organs that house it. There are different kinds of autoimmune diseases which include systemic lupus erythematosis, rheumatoid arthritis, multiple sclerosis, autoimmune hearing loss, spastic myelitis, Bechet’s syndrome and so on.  Symptoms of autoimmune diseases are long-term, and these diseases often caused permanent damage.

In previous work, Ra’s team demonstrated the safety of intravenously infused adipose (fat)-derived stem cells in humans. Patients who received multiple stem cell infusions showed no adverse effects and no severe side effects. In this present study, the team showed that infusions of these stem cells were effective in treating diseases that ranged from autoimmune hearing loss, multiple sclerosis, polymyositis, atopic dermatitis, and rheumatoid arthritis, in this study.

In the case of autoimmune hearing loss, the patient was administered with her own stem cells. Her hearing returned to normal (scaled out to 15 decibels) even though she had previously not responded to steroid treatments.

A multiple sclerosis patient suffered severe side effects from high dose steroid treatments and had difficulty walking. However after infusions of her own stem cells, her condition improved tremendously, and she was able to move her legs using her own muscular strength.

Other autoimmune diseases treated in this paper were patients with multiple sclerosis, atopic dermatitis, and rheumatoid arthritis, all of whom were not able to be treated with existing medication. However, after multiple infusions of their own fat-derived stem cells, their illnesses became manageable.

Researchers are continuing to develop sophisticated stem cell technology using five grams of fat as a standard, which can be expanded to 1 billion stem cells. This technology became more efficient and convenient for patients because repetitive stem cell injections are possible from one time fat extraction. These studies also showed that the fat-derived stem cells were capable of homing to the site of damage where they were able to suppress the inflammation that was the cause of the pathology and symptoms of these diseases. These patients required less surgeries, transplants and fewer drugs.

Dr. Ra said: “The fact that we showed the way patients can be treated from their own stem cells is very rewarding to me. We are working towards becoming our country’s medical hub for treating autoimmune diseases.”

Engineering Blood Cells to Fight Melanoma

University of California, Los Angeles (UCLA) scientists have successfully completed a proof-of-principle experiment in mice that shows that blood cells can be re-engineered to become melanoma fighting immune cells.

Senior author on this study, Jerome Zack, who is also a scientist with UCLA’s Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, noted that genetic engineering techniques can remodel the blood cells of the mouse so that they form cancer-killing T-cells that seek out the tumor and destroy it. Zack stated: “We knew from previous studies that we could generate engineered T-cells, but would they work to fight cancer in a relevant model of human disease, such as melanoma. We found with this study that they do work in a human model to fight cancer, and it’s a pretty exciting finding.”

White blood cells come in several different varieties, but one group of white blood cells is the “lymphocytes,” which play an exceedingly central role in adaptive immunity. There are two main types of lymphocytes; B-lymphocytes, also known as B-cells and T lymphocytes or T-cells. T-cells receive their name from an organ that sits over the top part of the heart called the thymus. Once T-cells are born, they migrate to the thymus where they undergo a complex maturation process. Once they are released from the thymus into the peripheral circulation, they are ready to serve the immune system. T-cells differ from B-cells in that they possess a surface protein called the “T-cell receptor.” The T-cell receptor recognized foreign substances or “antigens” that are bound to the surfaces of cells. When the T-cell binds to this antigen, it becomes activated and begins to divide and initiates the formation of an immune response against this antigen.

In this experiment, Zack and his co-workers used a T-cell receptor that they had isolated from a cancer patient. This particular T-cell receptor recognized an antigen that is specific to melanomas. The UCLA group then used genetic engineering techniques to place the T-cell receptor gene into the blood-making stem cells in the bone marrow of laboratory mice. After re-introducing these engineered blood-making stem cells into the experimental mice. Next, Zack and his colleagues transplanted a small piece of human thymus into the experimental mice. This gave the mice a place to allow the newly made T-cells to mature.

After approximately six weeks, engineered blood stem cells had formed a large population of mature, melanoma-specific T-cells that were able to target the particular cancer cells. To demonstrate this, the experimental mice were then implanted with two types of melanoma, one that expressed the antigen complex recognized by the T-cell receptor introduced into the bone marrow stem cells, and another tumor that did not. The engineered cells specifically went after the melanoma that expressed the particular antigen, but they left the other tumor alone. Of the nine nude mice used in this study, four animals showed complete elimination of the antigen-expressing melanomas, and the other five showed a marked decrease in the size of the tumors. The immune response against the tumors was determined not only by measuring physical tumor size, but by monitoring the cancer’s metabolic activity using Positron Emission Tomography (PET), which measures how much energy the cancer is “eating” to drive its growth.

Zach noted: “We were very happy to see that four tumors were completely gone and the rest had regressed, both by measuring their size and actually seeing their metabolic activity through PET.” Zack said.

This approach has the advantage of engineering only a few cells that can produce a veritable army of cancer-fighting T-cells. Furthermore, these cells can exist in the circulating blood in low numbers, but if they detect the melanoma antigen, they can replicate and expand their numbers quickly and home to the tumor where they will fight it. Other advantages of this strategy are that the function of the engineered T-cells is not long-lasting in most cases. More engineered T-cells ultimately are needed to sustain a response, but some of these cells will probably become “memory cells.” Memory cells are inactive cells that remember the infection they recently fought, but can be reactivated if they encounter the antigen once again. This suggests that “fresh” cancer-killing cells could be easily generated when needed, perhaps protecting against cancer recurrence later.

The team would like to test this approach in clinical trials. One possible approach would be to engineer both the circulating T-cells and the blood stem cells that give rise to T-cells. The peripheral T-cells would serve as the front line cancer fighters, while the blood stem cells are creating a second wave of warriors to take up the battle as the front line T-cells are losing function. Zack also said that he hopes that this technique could adapted for protocols the battle other cancers like breast and prostate cancers.

Still Unconvinced?

Apparently I’m not the only one who thinks that Geron’s move to table its embryonic stem cell division is solely due to money. See comments by Daniel Salomon, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute in San Diego in a story by ABC News.

Cardiac Stem Cells Replace Heart Muscle In Heart Attack Patients

Two research teams have shown that stem cells harvested from a patient’s own heart can reverse heart attack damage. Roberto Bolli, director of the division of cardiology at the University of Louisville in Louisville, Ky., and colleagues presented their initial results from an ongoing clinical trial at a national meeting.  This trial treated 16 heart attack patients with infusions of cardiac stem cells that had been harvested from their own hearts during bypass surgery. In this experiment, 14 patients had improved cardiac function four months after the procedure, eight of these patients had further improvements a year after infusion, and their heart attack scars shrank.  Data from this clinical trial published in the journal The Lancet.

Director of the Cedars-Sinai Heart Institute in Los Angeles, Eduardo Marbán, discussed final results from a different Phase I clinical trial.  In this second trial, physicians harvested cardiac tissue using a minimally invasive technique, cultivated the stem cells from the cardiac tissue, and then administered them to 17 study subjects. Marbán said that his team’s cells also shrank heart scars, but also caused increases in living heart muscle in the patients (~600 million new heart cells per subject).

The two studies approach the same question; namely the ability of the heart to regenerate using its own stem cell populations. These two studies, however, use distinct approaches to answer this question. Blocked arteries deprive heart muscle, and if the heart muscle cells are kept without sufficient oxygen for a period time, they will start to die, which is the cause of heart attacks. If sufficient numbers of heart muscle cells die, the heart will not be able to service the needs of the body, and the patient will die from heart failure. In the U.S. alone, it is estimated that about six million people have heart failure. These new results provide hope for these patients, many of whom have been waiting for regenerative therapies to mend damaged heart tissue for more than a decade.

Depending on the Food and Drug Administration’s approach to the new therapy, Marbán said, a product based on his team’s work could be available to patients as soon as 2015 or 2016.

It’s All About Money?

According to the Los Angeles Times, Geron abandoned embryonic stem cell research and clinical trials solely of money. Wesley Smith does not believe it for a minute, as he writes in the Weekly Standard. Read them both and decide for yourself.

Having formerly lived in Southern California, I for one do trust the LA Times to get a story straight. Not only that, I simply do not trust the LA Times to put their biases aside and report the facts about a case. I can believe that Geron was strapped for cash, but with the potential for this research and the money-bags at the California Institute for Regenerative Medicine, I find it difficult to believe that private investors were not dumping wads of cash into their laps. I think somethings else is going on and I would love to see the media dig to bottom of it.

Biomaterials to Treat Heart Attacks

A field of experimental, regenerative medicine that has not received much press to date is the field of “biomaterials.” Simply put, bio-materials are organic compounds that can self-assemble and form polymers that reinforce damaged tissues. Such biomaterials are also used to form molds of organs that are seeded with stem cells that form an artificially assembled organ. These stem cells then degrade the biomaterial to leave a newly formed organ. This use of biomaterials is termed “tissue engineering,” and it is one of the most innovative and fascinating new fields of medical research.

Recently, biomaterials have been used to treat the hearts of laboratory animals that have suffered a heart attack, and the results are more than hopeful, even if the biomaterials themselves are not yet ready for human trials.  Furthermore, biomaterials can enhance the healing activities of stem cells.

If biomaterials are used on their own, they can shore up a failing heart. Alginate hydrogels, are based on compounds extracted from brown seaweeds called “alginic acids.”  When crosslinked by positively charged ions like calcium, alginic acids form solid or semi-solid materials.  called a hydrogel.  Injection of alginate hydrogels into the heart muscle after a heart attack increases the thickness of the heart wall and decreases the amount of blood left in the large chambers of the heart after they have been filled with blood (also known as “end diastolic volume” or EDV; see Landa, et al. Circulation 2008; 117: 1388-96, and Leor, et al., J Am Coll Cardiol 2009; 54: 1014-23). In unhealthy hearts, the EDV is high because the heart beats sluggishly and waits longer before each beat. If the EDV goes down after a heart attack, it is usually evidence that the heart has recovered somewhat. Because hydrogels are biodegradable, these positive effects are temporary. For example, polyethylene glycol hydrogels also lower EDV 4 weeks after a heart attack, but this effect goes away after 3 months (Dobner, et al., J Card Fail 2009; 15: 629-36). Therefore, by themselves, biomaterials buy the heart time, but do not promote long-term healing.

In order for biomaterials to work within the heart, they must not activate the immune system to attack them, they must have similar properties to heart muscle, and be liquid at the time of injection into the heart but solid once they achieve their proper location in the heart. Matrigel, for example, was originally extracted from soft tumors, and is composed of several proteins already found in the body (laminin, collagen IV, heparan sulfate proteoglycan, and entactin for those who want to know). Matrigel is liquid at low temperatures but forms a hydrogel at 37 degrees Celsius (our body temperature). Also, because matrigel is made by living cells, is usually imbued with growth factors that can aid the ailing heart and assist the work of implanted stem cells. In fact, experiments with matrigel and embryonic stem cells in mice have shown that matrigel increases the retention of embryonic stem cells that have been injected into the heart after a heart attack and the functional efficiency of the heart compared to injections of just cells (Kofidis, et al., Circulation 2005; 112: I173-7). Matrigel, however, is extracted from mouse tumor cell lines and is not appropriate for use in human patients.

Another potential biomaterial is collagen, which is use to make the scars in the heart after a heart attack. This protein is inexpensive, nontoxic, biodegradable, and friendly to the immune system. Collagen gels have been used to prevent mesenchymal stem cells from redistributing to other organs after they have been injected into the wall of the heart after a heart attack (Dai, et al., Regen Med 2009; 4: 387-95, and Danovic, et al., PloS One 2010; 5: e12077). In large animals, collagen gels have been used to deliver mesenchymal stem cells to precise locations around the heart (Ladage, et al., Gene Therapy 2011; 18(10): 979-85). Tissue engineers have also made vascular beds from collagen gels and “endothelial progenitor cells” or EPCs (stem cells that form blood vessels). Implantation of these engineered tissues into sick rodent hearts improved heart function by increasing blood delivery to heart tissue (Frederick et al., Circulation 2010; 122: S107-17).

Another protein that can potentially serve as a biomaterial for heart attacks is fibrin, which is the material found in blood clots. Fibrin has a major advantage in that it is already recognized by the Food and Drug Administration (FDA) as a product approved for use in human patients. Fibrin can serve as a patch (like a bandage) for hearts, or it can be injected into the heart itself with stem cells. Fibrin acts as a kind of glue that helps retain stem cells in the heart after their delivery (See Breen, O’Brien and Pandit, Tissue Engineer Part B Rev. 2009; 15: 201-14; Terrovitis et al., J Am Coll Cardiol 2009; 54: 1619-26; and Lui, et al., Am J Physiol Heart Circ Physiol 2004; 287: H501-11).

Finally, there are a few artificial biomaterials that are presently being tested. These include self-assembling peptides, PLGA (polylactic-coglycol acid, which is FDA approved), and other similar compounds. These other compounds typically show dosage-dependent toxicities, and some even tend to activate the immune system. Nevertheless, some of these compounds have been used to culture heart muscle cells in the laboratory and others can be injected directly into the heart. Some self-assembling peptides that form protein nanofibers can stimulate the differentiation of bone marrow stem cells into blood vessels (Lin et al., Circulation 2010; 122: S132-41).

Biomaterials have other advantages in that they can bind protein growth factors that promote the survival or even differentiation of implanted stem cells. For this reason, some labs are investigating biomaterials for use in gene therapy.

Biomaterials may provide an adjuvant to stem cell treatments in the heart, and for that reason, biomaterials research deserves more attention than it has been receiving.