Friday, August 2, 2013

Shedding the viral (pay) load: generation of CiPSCs using small compounds

The potential for the use of human embryonic stem cells (hESCs) to cure or repair a wide variety of diseases and regenerative methods has been well resounded since first reported by Drs. James Till and Ernest McCulloch on February 1, 1961 as cells with the ability to self-renew for a variety of purposes. The nature of these cells as pluripotent, having the ability to mature into all cell types comprising the source organism, is invaluable. However, as the field of stem cell research began to gain momentum the 93rd US Congress, on July12, 1974, implemented a ban limiting the use of federal research dollar for studies using fetal tissue, the primary source of hESCs, until the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research could draft guidelines pertaining to ethical means of their procurement and use. The controversy continues with fervor today while the public, scientists and politicians grapple with coming to terms with the morality of issues involving the destruction of embryos, cloning, and genetic engineering.

Since the initial discovery of stem cells additional sources have been discovered. None have been more indispensable than the discovery of methods to induce pluripotent stem cells (iPSCs) from somatic cells. iPSCs can be derived by several methods with the first mouse iPSCs created in 2006 by Shinya Yamanaka’s team closely followed by the generation of human iPSCs in 2007 by both Yamanaka’s and James Thompson’s team. The initial work was achieved by viral transfection of four key reprogramming genes and subsequent integration into the host cell genome. Obviously, cells derived from somatic cells can provide patient or disease specific cells greatly enhancing the researches ability to generate more relevant model systems with the added benefit of foregoing the reliance on the need for fetal tissue as a source.

While the discovery of iPSCs has proved to be a milestone achievement it did come with the added complication of the potential for inducing cancer-causing oncogene expression. In 2008, it was shown that the removal of the incorporated genes could be achieved thus reducing the risks associated with therapeutic use of cells generated using viral transfection. The next major stride occurred the following year when researchers demonstrated the ability to induce pluripotency by delivery of the required proteins directly into cells. In the following years efforts increasingly have focused on improving the efficiency of reprogramming using a mixture of small compounds. Earlier this month, July, 2013, Deng et al from the University of Beijing reported the first evidence of the induction of pluripotent stem cells of mouse origin using a cocktail of seven (7) small-molecule compounds without any genetic modification to the cells. These induced pluripotent stem cells have been coined CiPSCs (chemically induced PSCs) with reprogramming efficiencies of 0.2% (comparable to standard methods) and the ability to contribute to all major cell types when introduced into the developing mouse embryo. One can only assume that human CiPSCs will soon be on the horizon.

Hou, Pingping; Li, Yanqin; Zhang, Xu; Liu, Chun; Guan, Jingyang; Li, Honggang et al. (2013): Pluripotent Stem Cells Induced from Mouse Somatic Cells by Small-Molecule Compounds. In Science.

By: BioTek Instruments, Peter J. Brescia, Jr., MSc, MBA, Applications Scientist

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