A Better Way to Make Pluripotent Cells From Liver Cells
Researchers have identified an efficient method for creating pluripotent stem cells from differentiated liver cells, according to the April issue of Gastroenterology. This technology could lead to new methods for therapeutic regeneration of diseased or damaged tissues.
Embryonic stem cells are pluripotent, in that they can form the 3 germ layers of the embryo and therefore any tissue in the body. Researchers have been looking for various ways to generate pluripotent cells from differentiated cells, for studies of tissue repair and tumor development.
Alexander Kleger et al. showed that mouse liver progenitor cells (which have the capacity to regenerate only liver cells) could be reprogrammed to become pluripotent (called induced pluripotent or iPS cells). These iPS cells expressed many factors in common with embryonic stem cells, and were able to differentiate, in vitro and in vivo, into different germ layers.
To create the iPS cells, Kleger et al. isolated progenitor cells from livers of adult (6–8 weeks old) and fetal (embryonic day 14.5) mice and expressed 3–4 transcription factors that have been previously shown to convert differentiated cells into iPS cells. However, they found that their liver progenitor cells produced iPS cells at higher efficiency than more fully differentiated liver cells. The differentiation stage of mouse liver cells therefore affected their efficiency of reprogramming into iPS cells.
Similar findings have been reported only for hematopoietic cells—this was the first study to show that progenitor cells isolated from solid organs, such as the liver, have higher reprogramming efficiency than differentiated cells from the same organ. Kleger et al. observed that the increased reprogramming efficiency of liver progenitor cells occurred independently of proliferation rates.
The mechanisms that mediate reprogramming of progenitor into pluripotent cells are not clear. Tissue stem or progenitor cells are closer to the embryonic stage than differentiated cells—epigenetic modifications in tissue stem cells more closely resemble those of embryonic cells, compared with differentiated tissue cells. The higher reprogramming efficiency of the liver progenitor cells, compared with differentiated liver cells, required some endogenous factors, such as Klf4, c-Myc, and BAF complex members Baf155 and Brg1, which mediate epigenetic changes during reprogramming.
Overexpression of the BAF complex has been shown to increase reprogramming efficiencies in mouse embryonic fibroblasts by demethylating promoter regions of genes that encode pluripotency factors. These findings might also apply to the dedifferentiation of somatic stem cells that occurs during tumor development.
The authors conclude that identifying subpopulations of organ cells that can undergo highly efficient reprogramming could improve the use of iPS cells for translational research and increase our understanding of the reprogramming process itself.
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Kleger A, Mahaddalkar PU, Katz S-F, et al. Increased reprogramming capacity of mouse liver progenitor cells, compared with differentiated liver cells, requires the BAF complex. Gastroenterology 2012;142:907–917.