stem-cell-therapy-in-the-usa

 

Producing stem cells has always been a convoluted process. That's why the discovery of key transcriptional networks are helping to pave the way for new culturing methods and further advancements in the field of cell therapy (see also,Pluripotent Stem Cells What we know today) [1]. According to the Journal of Molecular Endocrinology, these new mechanisms are fundamentally reforming the in vitro strategies currently used to generate and sustain iPS cells in culture [2]. Several methods have already been developed. The process roughly goes like this: take almost any differentiated cell, induce pluripotency, and you have a stem cell. Then, maintain and proliferate the stem cell line until there are enough cells to be used therapeutically. Since the success of cell therapy, in many ways, hinges upon the cultivation of hundreds of millions of SCs per patient, developments like these are allowing researchers to produce induced pluripotent stem cells (iPS cells) in greater supply and variety.

 

Stem Cell Treatments for Alzheimer's Disease

neuron resized 600Stem cells are the only cells to divide throughout life and likely are the main cells to age through time. The most widely held view is that as stem cells age and divide they tend to accumulate DNA mutations and pass on any such epigenetic events to their descendants. Since these cells go on to support organ-specific tissues, it stands to reason that the organism itself will feel the consequences of aging [3].

Another symptom associated with aging is the loss of neurons in the brain, a burden shared by Alzheimer's patients. Alzheimer's disease is a progressive neural degenerate disorder that disrupts normal brain function such as, memory, communication, and judgement. Previous experiments have shown that various factors in the blood of old mice can impair the cognitive function in young mice. However, a new collaborative study led by researchers at Stanford and the University of California, San Francisco suggest that factors in the blood of young mice can reverse learning and memory impairments in old mice by improving the neuron function of the brain [4].

Researcher and study author Tony Wyss-Coray of Stanford said in a recent news release, This [research] could have been done 20 years ago. You don't need to know anything about how the brain works. You just give an old mouse young blood and see if the animal is smarter than before. It's just that nobody did it. He also said that treating the big-picture issue of aging could in turn ease the burden of many diseases, not just Alzheimer's disease. Quite intriguingly, their research reaffirms a long-standing scientific position that the aging process is reversible and that the endocrine system can be repurposed to mediate these changes later in life [5, 6]. It is important to note, that this study explores the unwanted consequences of Alzheimer's, such as the degenerate loss of neural function, and does not necessarily correct the root cause.

 

Improving Stem Cells in the Current Era

So while our understanding of the aging process and the many factors that contribute to producing stem cells has improved, many limiting ethical and biological factors remain. This is particularly true for embryonic stem cells (ESCs) and for the less productive adult stem cell (ASC) lines, which are not immediately pluripotent. Still, only limited progress has been made through available ESC lines despite their ability to become any cell in the human body.

embryonic stem cellESCs hold great promise for developing cell therapy techniques. Their use, however, posed two serious problems to researchers. Biologically, they can easily adapt in many cellular environments, and their high rate of proliferation leads to an increased risk for cancerous tumors. There are also the ethical considerations since the only source is from embryos (albeit at the early blastocyst stage weeks before fetal development begins).

As an alternative, ASCs were seen as the most likely candidate to replace ESCs, but they must first be artificially reprogrammed and maintained in culture in order to be used for rehabilitative therapy. Because ASCs are not immediately pluripotent, success with these cell lines will depend to a large extent on our ability to identify and then manipulate the genetic factors that underlie their growth and proliferation a goal that modern methods promise to achieve.

The current reprogramming protocols call for twice the amount of OCT4 and KLF4 when compared with SOX2 and cMYC. The results produce iPS cells that are genetically and epigenetically stable and are fully pluripotent. More importantly, when this reprogramming method were tested in mice, these iPS cells did not produce tumors when compared to the original protocol and appeared to be immune tolerant [7].

 

Clinical aspects

Advancements in stem cell therapy have been gaining steam over the last decade. This is a promising indication that adult and embryonic stem cells will be used in the coming decade to treat and possibly cure cancer, paralysis, cardiac failure, stroke, type 1 diabetes mellitus, and many more. Recent breakthroughs in cellular and molecular biology have widened the scene in which new stem cells can be developed and used alongside existing clinical approaches. In the near future, hospitals and clinics will be able to regenerate a patient's tissue, ranging from their own heart muscle, lung, liver, and kidney tissue, eyes, even hair. They will also be able to help people with baldness, missing teeth, deafness, blindness, birth defects, wound healing, and infertility.

For example, research conducted in 2012 to repair spinal cord damage in rats and mice led to partial recovery in motor function after SC injections [8]. Similar models with stroke have led to a similar functional recovery after mesenchymal stem cells (MSCs) were injected into the carotid artery. But, just to illustrate the difficulties researchers face, when cells were injected intravenously to repair damaged brain tissue, results showed a substantially diminished cellular uptake, possibly due to the blood-brain barrier [9].

Another difficulty is that if and when iPS cells are reprogrammed using traditional methods, either with a virus or episome vector, the residual foreign proteins it contains elicits an immune response to destroy the stem cells. So, until an improved vector can be developed, researchers have proposed using MSCs as an alternative for therapy due to their ability to successfully mitigate the immune response. However, the limited number of trials using MSCs and difficulty producing a sufficient quantity of cells are the current limitations to a widespread application.

The reported successes of cell therapy in patients are due, only in part, to the regeneration of cells after injection. The primary mechanism is really the ability of SCs to first repair the existing tissue, which will ultimately improve organ function.

So, while a number of advancements are clearly being made, cell therapy is a dynamic process, and deviating from the precise procedure in any one step, such as how stem cells are produced and cultured, how cells are handled, or how they are injected, can all lead to significant statistical variations in clinical tests [10].

Right now, there approximately 3,400 controlled clinical trials registered as Cell Therapy in the NIH database (http://clinical-trials.gov/). In total, almost 1,900 trials have finished, although only about 125 have presented their results. Less than 50 trials are currently focused on endocrinology.

It is obvious to many that we not only want but need improvements to the applications of cell therapy. Cooperation between the private and public sectors will be important for applying stem cell technologies to improve cell therapy in the future. Traditional and progressive approaches will need to be used to promote such advancements.

 

SOURCES

[1] Saha K, Mei Y, Reisterer CM, Pyzocha NK, Yang J, Muffat J, Davies MC, Alexander MR, Langer R, Anderson DG et al. 2011 Surface- engineered substrates for improved human pluripotent stem cell culture under fully defined conditions. (doi:10.1073/pnas.1114854108)

[2] Blasco MA, Serrano M & Fernandez-Capetillo O. 2011. Genomic instability in iPS: time for a break. EMBO Journal 30 991-993. (doi:10.1038/emboj.2011.50)

[3] Liu L & Rando TA 2011 Manifestations and mechanisms of stem cell aging. Journal of Cell Biology 193 257-266. (doi:10.1083/jcb. 201010131)

[4, 5] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A et al. 2011 The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477 90-94. (doi:10.1038/nature10357)

[6] Rando TA 2005 The adult muscle stem cell comes of age. Nature Medicine 11 829-831. (doi:10.1038/nm0805-829)

[7, 10] Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells. Journal of Molecular Endocrinology R89-111. 2012. (http://jme.endocrinology-journals.org/content/49/2/R89.full.pdf).

[8] Sakai K, Yamamoto A, Matsubara K, Nakamura S, Naruse M, Yamagata M, Sakamoto K, Tauchi R, Wakao N, Imagama S et al. 2012 Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro- regenerative mechanisms. Journal of Clinical Investigation 122 80-90. (doi:10.1172/JCI59251)

[9] Gutierrez-Fernandez M, Rodriguez-Frutos B, Alvarez-Grech J, Vallejo-Cremades MT, Exposito-Alcaide M, Merino J, Roda JM & Diez-Tejedor E 2011 Functional recovery after hematic administration of allogenic mesenchymal stem cells in acute ischemic stroke in rats. Neuroscience 175 394-405. (doi:10.1016/j.neuro- science.2010.11.054)