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Induced pluripotent stem cells (view source)

Revision as of 03:02, October 10, 2012

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final edit for the night, will add section explaining mechanism tomorrow
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'''Induced pluripotent stem cells''', also known as '''iPSCs''', are pluripotent [[stem cells]] derived from [[cell differentiation|fully-differentiated]] ("adult") somatic cells.  While they are often mistakenly referred to as "[[adult stem cells]]", this is not the proper term for them because biologists more commonly use the phrase "adult stem cells" to refer to the partially-differentiated stem cells residing in somatic tissues.
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'''Induced pluripotent stem cells''', also known as '''iPSCs''', are pluripotent [[stem cells]] derived from [[cell differentiation|fully-differentiated]] ("adult") somatic cells<ref>http://genesdev.cshlp.org/content/22/15/1987.full.pdf+html</ref>.  While they are often mistakenly referred to as "[[adult stem cells]]", this is not the proper term for them because biologists more commonly use the phrase "adult stem cells" to refer to the partially-differentiated stem cells residing in somatic tissues.
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iPSCs are generated by [[transfection|transfecting]] fully differentiated cells with a combination of [[transcription factors]] that cause the cells to de-differentiate into a pluripotent state, mimicking the pluripotency of [[embryonic stem cells]] (ES cells).  As pluripotent cells, iPSCs can generate cells of any type; they can even be used to generate "organoids" (structures mimicking the organization of complex tissues) in-vitro (in [[cell culture|culture]]).
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iPSCs are generated by [[transfection|transfecting]] fully differentiated cells with a combination of [[transcription factors]] that cause the cells to de-differentiate into a pluripotent state, mimicking the pluripotency of [[embryonic stem cells]] (ES cells).  As pluripotent cells, iPSCs can generate cells of any type; they can even be used to generate "organoids" (structures mimicking the organization of complex tissues) in-vitro (in [[cell culture|culture]])<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226288/pdf/scrt58.pdf</ref><ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236565/pdf/nihms-339822.pdf</ref>.
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Current methods of generating iPSCs are not without limitations.  While the process of inducing de-differentiation does yield pluripotent cells, these cells retain some [[epigenetics|epigenitic]] imprinting of the cell type from which they were derived.  As such, iPSCs do not perfectly recapitulate the behavior of ES cells.  Additionally, cell transplantation studies have demonstrated that iPSCs are significantly (~3-4 times, depending on the source tissue and method of induction) more tumorigenic in-vivo than embryonic stem cells, limiting their current therapeutic potential.
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Current methods of generating iPSCs are not without limitations.  While the process of inducing de-differentiation does yield pluripotent cells, these cells retain some [[epigenetics|epigenitic]] imprinting of the cell type from which they were derived.  As such, iPSCs do not perfectly recapitulate the behavior of ES cells.  Additionally, cell transplantation studies have demonstrated that iPSCs are significantly (~3-4 times, depending on the source tissue and method of induction) more tumorigenic in-vivo than embryonic stem cells, limiting their current therapeutic potential<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419439/pdf/SCI2012-521343.pdf</ref><ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457607/pdf/CFG2012-538639.pdf</ref>.
    
==History==
 
==History==
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The first iPSCs were produced in 2006 in the lab of Shinya Yamanaka at Kyoto University in Japan.  Yamanaka and colleagues transfected mouse [[fibroblasts]] (in this case, skin cells) with a combination of four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) to generate cells with similar morphology, gene expression, and "growth properties" to ES cells<ref>http://www.cell.com/retrieve/pii/S0092867406009767</ref>.  A year later, a team led by James Thomson at the University of Wisonsin generated the first human iPSCs by applying the same technique to human fibroblasts<ref>http://www.sciencemag.org/content/318/5858/1917.long</ref>.
 
The first iPSCs were produced in 2006 in the lab of Shinya Yamanaka at Kyoto University in Japan.  Yamanaka and colleagues transfected mouse [[fibroblasts]] (in this case, skin cells) with a combination of four transcription factors (Oct3/4, Sox2, c-Myc, and Klf4) to generate cells with similar morphology, gene expression, and "growth properties" to ES cells<ref>http://www.cell.com/retrieve/pii/S0092867406009767</ref>.  A year later, a team led by James Thomson at the University of Wisonsin generated the first human iPSCs by applying the same technique to human fibroblasts<ref>http://www.sciencemag.org/content/318/5858/1917.long</ref>.
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Since then, researchers have been focused on addressing the shortcomings of the original technique, notably its low efficiency and the tumorigenicity of the resulting iPSCs, and many novel variations of the original method have been published.  No current protocol for generating iPSCs is capable of producing cells that perfectly (and reliably) mimic the behavior of ES cells; accordingly, techniques for generating iPSCs will remain an area of intense research for the forseeable future.
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Since then, researchers have been focused on addressing the shortcomings of the original technique, notably its low efficiency<ref>e.g. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448677/pdf/pone.0045633.pdf</ref> and the tumorigenicity <ref>e.g. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204002/pdf/281_2011_Article_266.pdf</ref> of the resulting iPSCs, and many novel variations of the original method have been published.  No current protocol for generating iPSCs is capable of producing cells that perfectly (and reliably) mimic the behavior of ES cells <ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457607/pdf/CFG2012-538639.pdf</ref><ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114956/pdf/10815_2011_Article_9552.pdf</ref><ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159104/pdf/ars.2010.3814.pdf</ref>; accordingly, techniques for generating iPSCs will remain an area of intense research for the forseeable future.
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In 2012, Shinya Yamanaka was awarded the Nobel Prize in Medicine for his 2006 paper describing the production of iPSCs<ref>http://www.washingtonpost.com/world/europe/2012-nobel-prize-announcements-being-with-medicine-award/2012/10/08/3f0284fe-110f-11e2-9a39-1f5a7f6fe945_story.html</ref>.
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==Generation of iPSCs==
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The original method for producing iPSCs used a [[retrovirus|retroviral]] vector to express Oct3/4, Sox2, c-Myc, and Klf4 in cultured fibroblasts.  Successfully induced cells were identified by their expression of Nanog (an ES cell marker) and isolated by selection for Fbx15<sup>+</sup> (another ES cell marker) cells.  iPSC lines established using this technique remain widely used in research.
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Newer approaches for generating iPSCs generally vary from the original method in the vector and/or genes used, they may also use a different selection protocol for isolating the resulting iPSCs.  For instance, one of the first variations on the original protocol, also published by Yamanaka, selected for Nanog<sup>+</sup> cells instead of Fbx15<sup>+</sup> cells to isolate iPSCs.  This had the effect of increasing "ES cell like" behavior and decreasing tumorigenicity in the resulting cells, at the expense of signficantly reducing the efficiency of induction<ref>http://www.ncbi.nlm.nih.gov/pubmed/17554338</ref>.
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Other variations have used lentiviral and plasmid vectors to transfect the cells.  Depending on the specific protocol used, these approaches can increase induction efficiency and ES cell characteristics in the resulting iPSCs, while at the same time somewhat reducing tumorigenicity.
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Varying the transfected genes has also shown promise in improving iPSC generation.  For example, culturing the cells with valproic acid allows c-Myc to be excluded from the transfection vector, greatly reducing tumorigenecity at the expense of efficiency.  Alternatively, substituting LIN28 for c-Myc and Klf4 has been shown to increase transduction efficiency<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159104/pdf/ars.2010.3814.pdf</ref><ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924949/pdf/nihms-219126.pdf</ref>.
    
==References==
 
==References==
 
<references/>
 
<references/>
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*Yu, J. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science. November 20, 2007.
         
[[Category:Biology]][[Category:Medicine]]
 
[[Category:Biology]][[Category:Medicine]]
JHunter
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