Adult Stem Cells for Tissue Repair

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Primary authors: Kaitlin Baker, Sam Feely, Chen Tao, Billy Tran

 

Outline

1. Motivation

     1.1 Adult Stem Cells in Therapeutic Medicine

     1.2 Diseases it will treat

     1.3 Tissue Repair

2. Background on Adult Stem Cells

     2.1 Adult Stem Cells

     2.3 Adult Stem Cells and what they Differentiate to

3. Past Research

4. Recent Breakthroughs

     4.1 Skin Tissue repair

     4.2 Muscle Drived Stem Cells and Repair of Myoblasts

     4.3 Stem Cells to Repair Heart Tissue

     4.4 Using Stem Cells for Bone Replacement

5. Future Research

6. Citations

 

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1. Motivation

1.1

     Recent research has shown many possible therapeutic advantages that come from the use of adult stem cells, particularly in the area of tissue repair. Adult stem cell research is also less controversial compared to embryonic stem cell research, therefore garnering much interest from scientists, governments, and private companies.

 

     Adult stems cells are being studied as to their ability to form new cells of differing organs, this is called cell plasticity. Since stem cells have the ability to self renew as well as differentiate into other cells of interest across germ layers, there is great potential for their use in disease treatment as well as tissue repair. These stem cells have been found to treat genetic diseases with the most success. Advancements in adult stem cell treatments have led to new technologies on the repair of cardiac tissue, liver tissue, skin tissue, lung tissue, gastrointestinal tissue and blood. These tissues can be harmed by numerous diseases and are effecting millions of people around the world.By learning how to better control the proliferation and differentiation of adult stem cells, there is an enourmous amount of medicinal potential waiting to be used.

1.2

      One such disease is the Ischaemic heart disease and is desinguished by reduced blood flow to the heart. Ischaemic heart disease is ususally due to atherosclerosis, or the hardening of arteries; contributers of increased risk include smoking, diabetes, obesity and hypertenion (high blood pressure). This disease is very prevalent in the US; in fact it is one of three most common diseases in patients over 65 years of age. [1] An estimated 80,700,000 American adults have some form of cardiovasular disease, of these heart disease accounts for 16,000,000. Half of this 16,000,000 population has myocardial infraction (or a heart attack) which is also being studied for stem cell repair. Heart disease is the number one cause of death in Americans today. These statistics prove that it is very important for continued studies in the field of adult stem cell research because the stem cells have the possibility to replace this damaged tissue and benefiting millions of people. [2]      

     Many other diseases can be treated using adult stems cells. These can include osteogenesis imperfecta, tyrosinemia type I, hepatitis B or C, liver cirrhosis, chronic limb ischemia, and ischemic vascular disease. [3]

   

           

[2]

fig 1. Percentage of people affected by Cardiovascular Diseases in different age group

 

1.3

     Adult stem cells for tissue repair are in the beginning stages of research, there is still a lot to study and understand before they can be used regularly in the treatments. However when stem cell research becomes more refined the advantages of them will become far and wide. They include the fact that the adult stem cells can self-renew with no biocompatibility issues and they are multipotient. The procedure will also be less painful than other leading procedures and it can probably be less expensive. Research of tissue repair is already showing signs of having great possibilities, adult stem cell multipotency has sucessfully created cells for skin layers as well as muscle tissues. With advancements in this field many injuries to tissues, such as ulcers caused by diabetes, can be easily treated and giving millions of patients access to an easy remedy.

 

2. Background of Adult Stem Cells

           Adult stem cells can be found throughout a person's body. They are undifferentiated cells and are used by the body to replace dying cells and repair damaged cells in various parts natually.  [18] Adult stem cells were initially thought to be restricted to a certain lineage of cells, however recent breakthroughs have shown that multipotent adult stem cells exist in certain regions of the body. New research has found multipotent cells in the skin, neuronal tissue, adipose tissue, and bone marrow. [4]

 

Currently many different factors contribute to the development of adult stem cells research:

·         Advantages:

o   Self-renewal, no biocompatibility issues.

o   Multipotency , plasticity

o   Less painful then other procedures, such as bone marrow transplant.

o   Not as controversial as embryonic stem cells research.

o   Really effective in treating genetic disorders

·         Disadvantages:

o   cost

o   Not easily accessible, and not a lot of research have been done. Current research is under way and results are pending.

o   Frequency of cell fusion is rare. Need a lot of stem cell to work with to get what you want.

o   Getting stem to target area for it to work.

o   Less developmental potential then embryonic stem cells.

 

     From experiements done on animals, adult stem cells can adapt to its environment and differentiate into the type of cells that surround them [7] This cell to cell contact method is useful in therapy since it is not invasive and relatively easy to work with. 

fig. 2 Adult stem cells differentiating into different cells of the body. [19]

 

3. Past Research

·              In the case of a heart tissue failure, current procedure would call for bypass, heart transplants or heart valve repair.  The disadvantage of the current treatment is the lack of compatibility and the supply of available human hearts for transplant, and the fact that using a replacement heart valve cannot completely fix the problem indefinitely; previous treatments have not been proven to be long term. Another disadvantage would be that treantments used in the past may require more surgeries if the replacement fails or another problem arises; this leads to more medical bills, as well as a higher risk of death and pain.

           The only advantages to these procedures would be that they are more cost efficient than stem cell-generated-organ replacementat the moment and that there is more knowledge on the treatments from years of experience. The average heart trasplant costs the patient $148,000 with actual prices varying from $50,000 to $287,000. [5] Adult stem cell replacements for the heart are still in clinical trials and cost estimates haven't actually been prepared, however, since the costs of prodution of Mesenchymal Precursor Cells, MPC, which has the same abilities as other adult stem cells, have become cheaper, it is likely that the procedure for other adult stem cell production will become less expensive in the future. 

·              When skin tissue becomes damaged, such as with diabetic ulcers, Apligraf, an artificial skin, is currently used to repair the skin. This has the advantage of being simple, only requiring to be sutured to the damaged area, and a relatively cheap procedure to perform, costing $30 per square centimeter. [8]

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4. Recent breakthroughs

 

4.1 Skin Tissue Repair

 

Converting skin cells into adult stem cells [6]

     Last year, two separate teams of researchers independently converted skin cells into cells that behave like embryonic stem cells. One is a Japanese research team, led by Shinya Yamanaka, that was successful in reprogramming skin cells from mice tails into an embryonic state, as well as cells from a 36 year old Caucasian woman's and a 69 year old male's face.The other is an American research team, led by James Thomson, at the University of Wisconsin, that was successful at achieving the same feat with skin cells from the foreskins of newborn babies. These induced pluripotent stem (iPS) cells are very similar to embryonic stem cells, and with embryonic stem cell properties. [20]

     Both teams used a similar technique to transform these skin cells into stem cells. Each team manipulated four key genes, two of which they had in common, and used viral vectors to transform the cells with them [20]. Cells that were successfully transformed acted like multipotent stem cells. This technique however is not without risk: the need to transform cells using viruses can cause mutation, possibly causing cancerous tissue to form.

 

Using adult stem cells from stem cell niche for skin repair [7]

     Another current breakthrough was the use of Mesenchymal stem cells for skin wound regeneration. Mesenchymal stem cells, or MSC's, are multipotent stem cells that live in the stem cell niche. They are advantageous because of their multipotency, as well as their easy isolation and culture, and immunosuppression properties.

     MSC's have been seen to work successfully in animals, able to differentiate into the type of cells that surround them, thereby repairing damage to the surrounding tissue, and partially restoring normal function. These cells have been able to differentiate into not only cells of mesenchymal lineages, such as cartilage, but also other embryonic layers, such as skin.

     In humans, MSC's have been used to treat Diabetic Foot Ulcers. One 29 day study used a treatment with a biograft made of skin fibroblasts combined with MSC's. This biograft was applied directly to the wound, and injected on the edges of the wound on days 1, 7, and 17. As the treatment proceeded, it was seen that wound size decreased, and the vascularity of dermis and dermal thickness increased.

     As mentioned above, one of the more recent, non stem cell treatments for Diabetic Foot Ulcers is Apligraf. Apligraf is an engineered skin made from the biological ingredients in actual human skin. Treatment with this product is similar to the treatment with MSC's, in that it is placed directly on the wound, sutured and then starts the healing cycle. Improvement with this product is usually seen within a few weeks, and the cost of Apligraf is $30.00 per square centimeter, so a treatment with MSC's that can occur as effectively with a lower price than this would be a large improvement over current treatments of problems such as Diabetic Foot Ulcers. [8]

     In order to make this a more viable treatment, however, there are many issues that must be addressed in the future. First of all, the mechanism by which MSC's facilitate wound repair is currently unclear. Secondly, current data is not sufficient to show that skin appendages regenerated through this method are functional. As with adult stem cells in general, isolation of these cells is difficult, and their large differentiation capability could lead to the production of malignant cells and the deterioration of function and structure of the repaired tissue.

 

4.2 Muscle Derived Stem Cells and Repairing Myoblast

     Stem cells that are derived from muscle cells have been shown to be able to divide into different lineages. Scientists are looking into ways to make these stem cells into a therapeutic treatment. Recently studies have shown the possibilities to treat many diseases and tissue damage ranging from muscle and heart diseases to the regeneration of bone and cartilage[9].

                    

fig. 3 differentiation of stem MDSCs and the corresponding inducing factors [10]

 

     Muscle Derive Stem Cells, (MDSC), are stem cells that originate in muscle tissue. MDSCs have different levels of pluripotency, or types of cell differentiation. They have been shown to be able to divide into different lineages of cells and have a high degree of hematopoietic potential, or give rise to many blood cell types.[10] These cells show a great possibility to regenerate muscle cells.

      Stem cells are continuing to show their new importance in the repair of muscle tissue. Although muscle repair usually comes with few difficulties, there are cases where fibrous muscle can occur and limit the function of the regeneration of muscle tissue. Stem cells are able to directly repair the muscle fibers as well as bring the necessary proteins that aid the regeneration of muscle tissue. One such protien is IGF-1, an autocrine regulating growth factor. [11].

     Other then healing injuries, scientists are also investigating the possibility of treating tissue related genetic diseases. Treatments such as myoblast transportation has a low success rate. [12]

     Stem cells that are from different sources in the body other then muscle have been researched to show that they too can aid in the regeneration of muscle tissue.[13, 14] But the amount to which certain stem cells from various organs can repair myofibers is under serious investigations. As of recently, only a certain percent of function was able to be repaired. This however does give scientists hope that there are adult stem cells that have plasticity and can differentiate into other cell types.

 

4.3 Stem Cells to Repair Heart Tissue

     Studies have been done to show that stem cell have helped to improve the function of heart tissue. Heart tissue can sometime lose function after an event such as a heart attack. If the heart attack was severe enough, it can result in permanent damage in heart tissue.  In tests done with lab mice, stem cells that were placed in contact with damaged heart tissue helped to improved contraction. These experiments were done with both embryonic stem cells as well as adult stem cells. They have yielded similar results.

     Treatment of cardiac tissue with stem cells are still in the development stage. Although it has been shown that stem cells used in the repair of human tissue such as cardiac tissue is safe, there is still extensive research going on. Also, there is still more to be discovered about the long term effects, permanent treatments, and other advances that stem cells can provide.

     The Arizona Heart Institute is currently conducting research on myoblast transplantation. The institute used stem cells from skeletal muscle for the repair of cardiac tissue, proving that the use of adult stem cell is a very viable method to repair tissue.

 

Video courtesy of YouTube from the Arizona Heart Insititute.

http://www.prnewswire.com/mnr/ahi/35313/

 

 

4.4 Using Adult Stem Cells from Fat Tissue for Bone Replacement

     In February 2008, Finnish doctors successfully operated an upper jaw replacement for a man using a jaw developed from his own stem cells. The cells were taken from fat stem cells in his abdomen and grew in a controlled culture dish into bones. The new jaw is a perfect fit and the patient needed very little recovery time and did not have a negative immune response.  [15]

 

 

Future Works/Conclusion

 

     Work done by researchers around the world has proved that adult stem cells have great potentials in the future. It is believed that stem cell therapies may be able to permanently cure genetic disease and to repair damage to various body tissues. Since adult stem cell therapy is more effective in the long term and has less compatibility problems, it has the potential to be used regularly in clinics. Since most governments prohibit and/or have very limited state funding for embryonic stem cell research, adult stem cell research is viewed to be more available. The Australian government has already announced in 2006 that they will provide $22 million over the next four years towards the establishment of a National Adult Stem Cell Research Center. The major focus will be on Parkinson's disease. [16] In the US, President-elect Obama has promised to reverse a policy made by the Bush administration which restricts federal funding towards research of stem cells. The new administration will allow more government sponsorship for stem cell research. [17] Many private companies have taken a greater interest in stem cell research and are providing more financial sponsorships to researchers as well.

 

     So far, some countries like China have already applied adult stem cell research in the treatment of diseases on a regular basis. Major breakthroughs are occuring more often in the labs, and there has been more public interest generated than ever. In the near future, researchers anticipate that they will be able to use stem cell therapy to treat a greater variety of diseases.

 

 

 

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Citations:

 

 

[1] Mielnik , M. "Cardiovascular diseases, medical apocalypse of the 21st century?." Przegl Lek (2004): 159-64.

 

[2] American Heart Association. Heart Disease and Stroke Statistics — 2008 Update. Dallas, Texas: American Heart Association; 2008. ©2008, American Heart Association.

 

http://www.americanheart.org/downloadable/heart/1200078608862HS_Stats%202008.final.pdf

 

[3]   Korbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med. 2003; 349: 570–582.

 

[4] Snykers, S., J. De Kock, V. Rogiers, and T. Vanhaecke. "In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art." In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. 4 Dec. 2008. PubMed. 6 Dec. 2008 <http://www.ncbi.nlm.nih.gov/pubmed/19056906?ordinalpos=1&itool=entrezsystem2.pentrez.pubmed.pubmed_resultspanel.pubmed_defaultreportpanel.pubmed_rvdocsum>.

[5] Source: Battelle Institute/Seattle Research Center. http://www.chfpatients.com/tx/transplant.htm

 

 

[6] McIlroy, Anne. "Stem-cell method hailed as 'massive breakthrough'" Stem-cell method hailed as 'massive breakthrough' 21 Nov. 2007. Globe and Mail. 6 Dec. 2008 <http://www.theglobeandmail.com/servlet/story/rtgam.20071121.wstemcells21/bnstory/science/home>.

 

[7] Fu, Xiaobing, and Haihong Li. "Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions." Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions: 1-4. 26 Nov. 2008. NCBI. U.S. National Library of Medicine. 6 Dec. 2008 <http://www.ncbi.nlm.nih.gov/pubmed/19034523?ordinalpos=3&itool=entrezsystem2.pentrez.pubmed.pubmed_resultspanel.pubmed_defaultreportpanel.pubmed_rvDocSum

                < http://www.springerlink.com/content/6m57860848685hq5/fulltext.pdf>

 

[8] "Apligraf: Hope for healing even the most resistant sores." Apligraf: Hope for healing even the most resistant sores. 2008. Organogenesis. 2008 <http://www.apligraf.com/>.

 

 

[9] Hairong Peng, Johnny Huard, Muscle-derived stem cells for musculoskeletal tissue regeneration and repair, Transplant Immunology, Volume 12, Issues 3-4, Organogenesis and Tissue Engineering in Transplantation Medicine, April 2004, Pages 311-319, ISSN 0966-3274, DOI: 10.1016/j.trim.2003.12.009.

(http://www.sciencedirect.com/science/article/B6W6V-4BP9MW3-4/2/4e96ebfc2c5b707615d46e8a278f051f) 

   

 

[11] Sato K, Li Y, Foster W, Fukushima K, Badlani N, Adachi N, et al. Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis. Muscle Nerve 2003;28(3):365 –372.

 

 

[12] Partridge TA. Invited review: myoblast transfer: a possible therapy for inherited myopathies? Muscle Nerve 1991;14(3):197–212.

 

 

[13] Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E,

Stornaiuolo A, Cossu G, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science 1998;279(5356):1528 –1530.

[14] LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 2002;111(4):589 – 601.

 

 [15] ABC news. Retrived on Dec. 9th, 2008. Finnish patient gets new jaw from own stem cells: http://www.abc.net.au/news/stories/2008/02/02/2152899htm

 

[16] http://www.sport.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2006-ta-abb052.htm?OpenDocument&yr=2006&mth=5

 

[17] Newsweek. Retrived on Dec. 11th, 2008. Will Stem Cells Finally Deliver? Major breakthroughs are propelling the field. Science becomes medicine.  http://www.newsweek.com/id/172563

 

[18] Wikipedia. Retrived on Dec. 15th, 2008. Adult stem cell. http://en.wikipedia.org/wiki/Adult_stem_cells

 

 

[19] BBC news. A guide to Stem cells. Adult Stem Cells. Retrived on Dec. 15th, 2008. http://news.bbc.co.uk/nol/shared/spl/hi/pop_ups/03/health_stem_cell_guide/img/4.jpg