Embryonic stem cells have attracted tremendous attention based on their ability to become any of the 220 types of cell in the human body. Ethical issues, as well as the problem of cancer formation, have impeded their practical utilization. Recently scientists have been creating embryonic-like stem cells by inserting specific genes into skin cells so as to "reverse their age" and create cells that in many ways resemble embryonic stem cells. These cells are called inducible pluripotent stem cells, or iPS cells.

This approach is highly interesting to many researchers because: 1) It allows creation of stem cells that are of the same tissue type as the patient that may in the future receive them; 2) Their generation can be performed under defined conditions. This is in contrast to many of the existing embryonic stem cell lines which have been created years ago and contain animal products or mutations; and 3) They can be made from tissues containing rare genes, so as to be able to examine the effect(s) of the gene in every cell of the body. There are still limiting factors to the use of iPS: like embryonic stem cells, they cause cancer, and they are difficult to produce.

An advancement has been made in the issue of their production. Professor Sheng Ding from the Scripps Research Institute, also one of the founders of the company Fate Therapeutics, has recently published in the journal Nature Methods that administration of three chemicals to cells undergoing the iPS process makes their generation 200 times more efficient and in double the speed. Using the previous technique only 1 in 10,000 cells would become iPS and it would take a month.

Dr. Ding stated: "Both in terms of speed and efficiency, we achieved major improvements over conventional conditions, this is the first example in human cells of how reprogramming speed can be accelerated." He continued "I believe that the field will quickly adopt this method, accelerating research significantly."

The bone marrow contains several stem cell populations that are capable of healing numerous tissues after injury. One interesting question has been whether different types of "semi-artificial" organs can be generated by combining bioengineering with stem cells.
In a recent publication in the Proceedings of the National Academy of Sciences, researchers from Columbia University described the creation of a jaw bone (temporomandibular joint) made in the laboratory.

According to the researchers, this is the first time a complex, anatomically-sized bone has been accurately created in this way. The process involved creation of a "scaffold" that was based on a computer-generated image of the patient, and subsequently stem cells were added to the scaffold to allow them to generate tissue. This process was performed under conditions that replicate the inside of the body, using a device called a bioreactor.

Dr Gordana Vunjak-Novakovic, lead researcher of the study stated: "The availability of personalised bone grafts engineered from the patient’s own stem cells would revolutionise the way we currently treat these defects." She continued "We thought the jawbone would be the most rigorous test of our technique; if you can make this, you can make any shape."

Unfortunately, the laboratory creation only was made of bone and did not contain other body parts such as cartilage, which would have been needed to implant this into a patient. However this does not seem to be very far away.

Last year a beating heart was created using a similar approach in which a scaffold was made with heart tissue that was treated to remove cellular component, and subsequently seeded with stem cells. A video of this heart can be seen at http://www.stemcell.umn.edu/stemcell/faculty/Taylor_D/home.html

In a study that appeared today in the Journal Cell Stem Cell, Dr Kevin Eggan’s group from Harvard reported a novel way of generating stem cells from adult cells. The procedure of generating stem cells from skin cells and other adult cells was originally reported by a Japanese group that demonstrated introduction of 4 genes into adult tissue resulted in cells that resembled embryonic stem cells. We made a video describing this procedure http://www.youtube.com/watch?v=_RLlUdJLy74 . Essentially, the genes act on the DNA to “reprogram” it, causing the adult cells to be capable of becoming different tissues in a similar manner in which an embryonic stem cell can become different tissues. This was a great breakthrough for two reasons: Firstly it opens the door to performing stem cell therapy using the patient’s own cells; and secondly, the very fact that an adult cell can be made back into a younger cell demonstrates that it is possible, at least at a cellular level, to reverse aging.

Unfortunately the genes used to “retrodifferentiate” adult cells and make these stem cells, which are called “inducible pluripotent stem cells” (iPS), are also involved in formation of cancer. So besides the fact that iPS cells themselves cause cancers because they are similar to embryonic stem cells, the very methodology used for creating iPS cells involves introduction of cancer causing genes into the cells. This of course would make it very difficult to perform clinical trials because of the risk for cancer. The other main problem with this iPS approach is that in order to get the genes into the adult cells, the genes had to be transported by viruses. Giving genes by viruses into cells has several potential problems, including the possibility of contaminating the patient.

Several research groups have tried to circumvent the problems with the current technology. For example, one approach was to use the antiepileptic medication valproic acid in combination with only 2 of the genes. In a publication last year (Huangfu et al. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol. 2008 Nov;26(11):1269-75) skin cells were made into iPS by administration of valproic acid with the genes Sox-2 and Oct-4. These two genes do not cause cancer. The reason why this strategy seemed to work was because valproic acid, in addition to having neurological effects, seems to modify the DNA of adult cells. DNA in adult cells is usually very compact. In the embryonic stem cell the DNA is more spreadout, and also is like a blank slate. As embryonic stem cells develop into liver cells, for example, certain parts of the DNA become “silenced” either because they are modified by chemicals that adult cells make, or because the DNA is more compacted in certain areas. Valproic acid has the ability to “loosen up” the DNA in adult cells and thereby allow them to act more like embryonic stem cells.

The use of chemicals like valproic acid for modifying stem cells is a very exciting area with practical consequences. For example, after a heart attack there are stem cells that reside in the cardiac muscle that try to heal the injured tissue. Valproic acid, by its ability to reprogram stem cells, albeit at a low level, actually seems to increase the ability of the heart to heal itself after injury, at least in animal models (Lee et al. Inhibition of Histone Deacetylase on Ventricular Remodeling in Infarcted Rats. Am J Physiol Heart Circ Physiol. 2007 Mar 30).

Another practical application of valproic acid’s ability to modulate stem cells is its potential use in the area of bone marrow transplantation. In patients with leukemias one of the commonly used procedures is autologous transplantation. This means taking out the patient’s bone marrow stem cells, the cells that make blood, giving the patient a very high dose of chemotherapy and radiation to kill the leukemic cells, and then giving back the patient’s own stem cells after they have been “cleaned up” so that they don’t have any more contaminating cells. One of the issues with this procedure is that sometimes there is not enough bone marrow stem cells to keep giving them back if the patient needs more. So for example, after the stem cells are administered, if the blood counts are too low, it would be ideal to have the patient’s own stem cells stored so that more can be given. Unfortunately it has been very difficult to expand stem cells outside of the body. In a recent publication, (Seet et al Valproic acid enhances the engraftability of human umbilical cord blood hematopoietic stem cells expanded under serum-free conditions. Eur J Haematol. 2009 Feb;82(2):124-32.) it was demonstrated that treatment of umbilical cord blood stem cells with valproic acid outside of the body led to increased expansion and ability to make the different types of blood cells needed after chemotherapy/radiation therapy. We actually made a video about an older paper in which valproic acid was used to expand bone marrow derived stem cells http://www.youtube.com/watch?v=3Hc4LCUOSiA

So based on the above two examples of chemical agents that modify “stemness” of cells, it is obvious that if newer methods were developed to make old cells young using chemical compounds instead of genes administered by viruses, these methods would have many potential applications and benefits. In the paper by Eggan, a new compound called RepSox was demonstrated to have ability of to take away the need for two of the genes when making iPS cells. With RepSox the investigators only needed to administer the genes Oct-4 and KLF, thus taking away the need for the cancer causing gene c-myc, and Sox-2.

It will be interesting to see if this new compound RepSox has similar activity to valproic acid, or to other compounds that have been demonstrated to activate patient’s own stem cells such as lithium, G-CSF, or the food supplement StemKine.

Scientists at the University of Wisconsin-Madison announced today that they have succeeded in generating retinal cells from stem cells. The retina is the light-sensitive portion of the eye that is responsible for seeing. Many types of blindness are caused by the cells in the retina not functioning properly. For example, in the disease wet macular degeneration, blood vessels start growing over the retina and induce death of the neurons that transmit light. Another conditions causing retinal damage include diabetic retinopathy and long term glaucoma. While treatmetns exist that slow down progression of conditions that cause retinal damage, to date, no treatments exist that reverse damage once it has occurred.

Dr. David Gamm was the head of the research group that successfully created retinal cells outside of the body, is a member of the Ophthalmology and Visual Sciences Department, and of the UW Eye Research Institute. He used a new type of stem cell called inducible pluripotent stem cells (iPS) as the starting material for the experiments. These iPS cells are stem cells created from the skin. By introducing certain pieces of DNA into skin cells, the cells literally “become younger” and take the characteristics of stem cells. These “artificial” stem cells have been previously used for generating a variety of tissues in the test tube and even in some animal experiments. For example, iPS cells have been previously made into pancreatic islets that produce insulin (Zhang et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009 Apr;19(4):429-38) and could one day be used in the treatment of diabetes. The advantage of iPS cells is that they can be made from the same individual for which they will be used. In other words people are able to use their own cells as stem cells.
Unfortunately, the disadvantage of iPS cells is that they are very similar to embryonic stem cells. While obviously they do not have the ethical concerns associated with embryonic stem cells, since they come from the skin, iPS cells cause cancer. There is a specific type of cancer, called a teratoma, that forms when embryonic stem cells or iPS cells are injected into animals. One of the reasons for this type of cancer is because the cells are very primitive and do not know how to interact with the body around them. To date there as been one approval by the FDA for an embryonic stem cell based clinical trial by the Menlo Park company Geron Inc, but that approval was withdrawn due to concerns about some of the animal safety data without any patients being treated.

For generating treatments based on either iPS or embryonic stem cells, it will be essential to make sure that the cells are made to mature in the test tube before implantation into humans. To date, this has been one of the major stumbling blocks.

The discovery of making retina from iPS cells is, however, a major finding. One reason is that by being able to make retina cells in large quantities, the possibility of using these cells to screen for drugs that may protect them from damage or death emerges.

Retinal-like cells have been previously made from other stem cells, including from bone marrow (Wang et al. Transplantation of quantum dot-labelled bone marrow-derived stem cells into the vitreous of mice with laser-induced retinal injury: Survival, integration and differentiation. Vision Res. 2009 Sep 25) and cord blood (Koike-Kiriyama et al. Human cord blood cells can differentiate into retinal nerve cells. Acta Neurobiol Exp (Wars). 2007;67(4):359-65) stem cells, which do not have the problems of cancer formation associated with embryonic or iPS cells.

Scientists at Johns Hopkins University are learning how to treat various diseases and injuries with the endogenous adult stem cells that naturally exist within each person’s own body. Under the direction of Dr. Jennifer Elisseef, associate professor in the deparment of biomedical engineering at Johns Hopkins, a number of therapies have already been developed and are currently being tested in clinical trials.

Dr. Elisseef’s lab focuses primarily on the stimulation of endogenous adult stem cells, rather than on the administration of adult stem cells derived from outside sources. As she explains, "It’s going to be cheaper and easier to deliver to patients. We wanted something off-the-shelf, that the surgeon can grab when he needs it."

The first condition for which Dr. Elisseef and her colleagues developed a new type of therapy was damaged knee cartilage – an increasingly common malady among the general public. The scientists found that there is no need to administer adult stem cells from an outside source when there are plenty of adult stem cells residing within each person’s own body, and which exist solely for the purpose of regenerating damaged tissue – although it was only recently that researchers have discovered how to stimulate and utilize these endogenous adult stem cells. Now, with the specific therapy that Dr. Elisseef and her colleagues have developed, patient improvement is rapid and dramatic. According to Dr. Elisseef, "And their function is better. They might not be star athletes, but they can go out and do something like play doubles tennis."

The scientists focused specifically on the holes that develop in knees when a piece of knee cartilage is damaged or missing altogether. Referring to them as "potholes", Dr. Elisseef explained that, "It will gradually get bigger and bigger, and you get a generalized arthritic process happening in the joint. You really want to treat them when they’re a reasonable size." The current, conventional medical treatment, known as "micro-fracture", involves surgically "tapping into" the surrounding bone, from which blood and marrow that are rich in mesenchymal stem cells are allowed to "ooze out", thereby repairing the holes, at least theoretically. In actuality, however, as Dr. Elisseef describes, "The problem is, it ends up making more scar tissue instead of the real cartilage, and it doesn’t fully fill the defects." In a new approach, her lab began developing a hydrogel which they derived from bovine cartilage and which serves as a matrix on which the human body’s endogenous stem cells can grow. After being solidified with ultraviolet light, the hydrogel is attached to the injured cartilage with a type of "glue" that was also developed in Dr. Elisseef’s lab, into which the porous material is allowed to absorb the stem cells from the blood and bone marrow that are released from the micro-fractures. Within a few months, the endogenous stem cells have formed new cartilage. In the first clinical trial – which was conducted in Europe in order to take advantage of lower costs and fewer regulatory hurdles – 15 adults were treated with this therapy, in whom 89% of cartilage defects were found to have healed after a year, which is a significant improvement over the 50% response rate that is found with the conventional treatment.

Dr. Elisseef’s lab is also testing a number of other therapies based upon endogenous adult stem cells, which include a new type of contact lens that can guide the patient’s endogenous stem cells to rebuild damaged corneal tissue, for which she has received a five-year, $4 million U.S. Department of Defense grant that was just awarded this week. As she explains, "Someone’s stable now. They’re in the hospital and have a corneal injury. How can we repair that? How can we rebuild that cornea? We’re hoping that, working with the Deparment of Defense, these people who really have a strong need for this will help move the technology forward." Preliminary studies on rabbits have shown encouraging results.

Her laboratory is also currently involved in the development of a new biomaterial that can be shaped and contoured with beams of light, which she is developing in collaboration with the California-based company Kythera, and which is expected to be useful in reconstructing lost tissue such as from combat injuries or breast lumpectomies. According to Dr. Elisseef, "We make it from fat tissue. We take the fat and process it with chemicals. We take out the cells. We don’t want any foreign DNA in there. And we take out the lipids." What remains is just the connective tissue scaffolding of collagen and proteins, on which the endogenous stem cells can grow and regenerate new tissue.

As Dr. Elisseef further adds, "People are working on the basic science of things and trying to understand how tissue develops but also at the same time developing practical technologies that can be used in the clinic today."

According to Dr. Barley Griffeth, chief of cardiac surgery at the University of Maryland Medical Center, whose own research focuses on the regeneration of cardiac muscle, "A cell in free space doesn’t know what to do. It looks for a comforter to get under."

Dr. Elisseef and her colleagues seem to have discovered just the right type of "comforter" under which endogenous adult stem cells can happily thrive and proliferate.

The U.S. company BioTime Inc. and the the Hong Kong company Nashan Memorial Medical Institute today announced the collabortive formation of a new BioTime subsidiary.

The new company, to be known as BioTime Asia, will be focused on the development and commercialization throughout China and other Asian nations of stem cell products for occular, hematologic and musculoskeletal treatments. Dr. Lu Daopei, who pioneered China’s first successful adult stem cell transplant from bone marrow, will advise BioTime Asia with the management of clinical trials. It is expected, however, that the emphasis of BioTime Asia’s future clinical trials throughout the Far East will be on human embryonic, not adult, stem cells.

Based in Alameda, California, BioTime is engaged in a number of various medical specializations which include the development of artificial blood plasma solutions for trauma and surgery, in addition to the R&D of low temperature "suspended animation" medicine, and, of course, ongoing embryonic stem cell research, for which the company is perhaps best known. Dr. Michael West, BioTime’s CEO, is also the founder of Geron which has frequently been in news headlines over the past year for its highly controversial human embryonic stem cell (hESC) clinical trials, which were brought to an abrupt halt before they even began, due to an FDA "hold" that was recently imposed. No doubt the decision to transfer hESC clinical trials outside of the U.S. to Asian countries – where regulatory agencies and laws are significantly different from those of the U.S. FDA – was an executive calculation not entirely uninfluenced by the recent FDA-imposed "hold" on Geron’s clinical trials.

Financial terms of the new agreement were not disclosed.

The U.S. company Stem Cell Therapy International Inc. (SCII) announced today a reorganization and stock purchase agreement with S. Korea’s leading stem cell company, Histostem. The agreement marks the first step in the completion of a merger between the two companies.

Following a finalization of the agreement, the U.S. operations of Histostem will be managed by AmStem International, a wholly owned subsidiary of SCII.

As reported in initial filings with the S.E.C. (Securities and Exchange Commission), SCII will acquire 90% of the issued and outstanding shares of Histostem in consideration for the issuance of 72.5 million shares of Histostem stock.

According to David Stark, president and CEO of SCII, the company is in the process of securing supply channels in order to strengthen cash flow, which include a worldwide distribution of already existing stem cell facial cream and cosmetics products.

As stated in the press release, "Additional revenue is expected from the development of proprietary technologies from Dr. Han Hoon, CEO of Histostem, who will be working together with AmStemm to bring new products to the U.S. and E.U. markets."

This merger announcement was not unexpected but in fact was a required condition of a litigation settlement to which both companies had previously agreed and which had been announced on September 10th of this year. (Please see the related news article on this website, entitled, "U.S. and S. Korean Stem Cell Companies Announce Litigation Settlement", dated September 10, 2009).

Based in Tampa, Florida, SCII is a regenerative medicine company that is "devoted to the treatment of patients with stem cell transplantation therapy as well as providing the supplies of biological solutions containing new lines of stem cell products," as described on their website. As further described on the company’s website, SCII uses a type of adult stem cell procedure which they refer to simply as "stem cell transplantation (SCT)", which uses exclusively adult stem cells and which, as they explain, "is a surgical procedure that has been used successfully for 70+ years as a treatment of many diseases for which modern medicine has had no therapy, or in which state-of-the-art therapies stopped being effective. A documented 5 million patients have been so treated worldwide to date, evidenced by over 120,000 publications in MEDLINE (see www.nlm.nih.gov) amongst others. SCT is approved for use by the German authorities and the EU."

AmStem International, a wholly owned subsidiary of SCII, is based in Northern California where it specializes in "biotherapeutic and cosmetic stem cell products".

Founded in 2000 and based in Seoul, S. Korea, Histostem houses the largest repository of cord blood stem cells in the world, from which the company has already treated more than 500 patients. The company currently has 56 full-time employees and 28 part-time employees, and an intellectual property portfolio that consists of 5 patents that have already been granted and 6 patent applications that are still pending.