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Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts
Wakao, Shohei; Kitada, Masaaki; Kuroda, Yasumasa; Shigemoto, Taeko; Matsuse, Dai; Akashi, Hideo; Tanimura, Yukihiro; Tsuchiyama, Kenichiro; Kikuchi, Tomohiko; Goda, Makoto; Nakahata, Tatsutoshi; Fujiyoshi, Yoshinori; Dezawa, Mari
The stochastic and elite models have been proposed for the mechanism of induced pluripotent stem (iPS) cell generation. Inthis study we report a system that supports the elite model. We previously identified multilineage-differentiating stress-enduring(Muse) cells in human dermal fibroblasts that are characterized by stress tolerance, expression of pluripotency markers, self-renewal,and the ability to differentiate into endodermal-, mesodermal-, and ectodermal-lineage cells from a single cell. They canbe isolated as stage-specific embryonic antigen-3/CD105 double-positive cells. When human fibroblasts were separated intoMuse and non-Muse cells and transduced with Oct3/4, Sox2, Klf4, and c-Myc, iPS cells were generated exclusively from Muse cells but not from non-Muse cells. Although some colonies were formed fromnon-Muse cells, they were unlike iPS cells. Furthermore, epigenetic alterations were not seen, and some of the major pluripotencymarkers were not expressed for the entire period during iPS cell generation. These findings were confirmed further using cellstransduced with a single polycistronic virus vector encoding all four factors. The results demonstrate that in adult humanfibroblasts a subset of preexisting adult stem cells whose properties are similar in some respects to those of iPS cells selectivelybecome iPS cells, but the remaining cells make no contribution to the generation of iPS cells. Therefore this system seemsto fit the elite model rather than the stochastic model.
