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Induced pluripotent stem cells (view source)
Revision as of 18:52, October 10, 2012
, 18:52, October 10, 2012saving progress, will add sources in a few minutes
'''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.
'''Induced pluripotent stem cells''', also known as '''iPSCs''', are pluripotent [[stem cells]] derived from [[cell differentiation|fully-differentiated]] ("adult") somatic cells<ref>This video is a good introduction to the topic: http://www.jove.com/video/3804/reprogramming-human-somatic-cells-into-induced-pluripotent-stem-cells</ref><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.
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>.
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>.
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.
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.
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>.
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 and reduce tumorigenicity (c-Myc and Klf4 being [[oncogenes]])<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>.
Some recent methods have dispensed with transfection altogether, using recombinant protein growth factors instead<ref>http://masspec.scripps.edu/publications/news_art/2009_04_CellSteml.pdf</ref>. These methods are safer for therapeutic use, as the resulting cells are much less tumorigenic than transfected iPSCs; however they are usually far less efficient than methods relying on transfection.
Regardless of the method used, the mechanism of de-differentiation is the same. The cultured cells are induced to epigenetically reprogram themselves from a non-dividing (or slowly dividing) terminally differentiated state into an actively [[cell cycle|cycling]] pluripotent state.
==Applications==
Currently, iPSCs are primarily used in research. They often function as a substitute for human [[embryonic stem cells|ES cells]] (the use of which is tightly regulated) in studies on cell differentiation and tissue development. More commonly, iPSCs are used in experiments where the use of ES cells would be inappropriate (e.g. lab animal models requiring perfectly [[histocompatibility|histocompatible]] cell grafts).
Because patient-derived iPSCs would allow for perfectly histocompatible autografts, they are preferred over ES cells by researchers working to develop stem cell therapies. Several iPSC therapies are in clinical trials around the world (most in the United States), however none of them are currently widely available or routinely used. The major barriers to developing iPSC therapies are the tumorigenicity of iPSCs generated using current techniques, as well as the low efficiency, labor intensiveness, and relatively high cost (compared to other modern therapies) of these techniques. However, as researchers continue to develop better methods for producing iPSCs, it is thought that iPSC therapies for various diseases (ranging from type 1 diabetes to cardiomyopathies) will become more clinically viable.
Tumorigenicity of iPSCs is a real concern. Many studies transplanting iPSC derived cells into animal models report subsequent cancer rates approaching 100% (as opposed to ~10 to 25% for grafts derived from ES cells). Grafts from iPSCs generated using newer techniques are demonstrated to be safer, but are still generally 2 to 4 times as tumorigenic as similar grafts derived from ES cells. Until this problem is overcome, the clinical use of iPSCs will remain reserved for treatments of "last resort".
==References==
==References==