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Posted: Apr 04, 2014
Additional factors improve stem cell generation
(Nanowerk News) Induced pluripotent stem (iPS) cells are created by ‘reprogramming’ specialized adult cells into embryonic stem-like cells. Although a remarkable process, the procedure remains slow and inefficient, involving induced expression of four specific protein factors found at high levels in embryonic stem cells. By adding two further proteins found in unfertilized egg cells, or oocytes, to this standard recipe of reprogramming factors, a collaborative team of researchers led by Shunsuke Ishii and colleagues from the Molecular Genetics Laboratory at the RIKEN Tsukuba Institute have now discovered a way to generate iPS cells with increased speed and efficiency ("Histone Variants Enriched in Oocytes Enhance Reprogramming to Induced Pluripotent Stem Cells").
Adding TH2A and TH2B to the standard reprogramming recipe promotes the production of induced pluripotent stem cells (green). (Image: Shunsuke Ishii, RIKEN Tsukuba Institute)
There are many ways to coax terminally differentiated adult cells into a pluripotent state. One of the most commonly used methods is based on expression of the four ‘Yamanaka factors’. These proteins—Oct3/4, Sox2, Klf4 and c-Myc—are found in embryonic stem cells but not in oocytes.
Through cloning studies using a technique known as somatic cell nuclear transfer, scientists have shown that oocytes retain the natural ability to reprogram adult cells. Ishii and his colleagues hypothesized that the proteins found in oocytes might therefore assist in the generation of iPS cells.
The researchers focused on two proteins in particular, TH2A and TH2B. Both are variants of histone proteins that affect how tightly DNA is wrapped into chromatin—the complex of DNA and proteins that makes up the contents of the cell’s nucleus. By studying mice engineered to lack these proteins, Ishii and his colleagues showed that TH2A and TH2B are highly expressed in oocytes and, upon fertilization, help to activate the paternal genome of incoming sperm. These observations highlighted TH2A and TH2B as strong candidates for oocyte-specific reprogramming factors that might induce pluripotency through a different mechanism to that of the Yamanaka factors.
Working with mouse embryonic fibroblast cells, the researchers added TH2A and TH2B to the Yamanaka factors and obtained more than 20 times the number of iPS cells in less than half the normal time compared to using the Yamanaka factors alone. The researchers also showed that TH2A and TH2B could function as direct substitutes for two of the Yamanaka factors, allowing for an alternative four-part recipe.
“There are two ways to use these findings,” explains Ishii. “Firstly, use of TH2A/TH2B may help to increase the quality and differentiation capacity of iPS cells. Secondly, use of TH2A/TH2B may help to generate iPS cells from cell types, such as certain somatic cells, that have low efficiency for iPS cell generation.”
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