However, re-differentiation effects (expression level of thyroid-specific genes) were modest compared to PT. We are currently seeking the better method enabling more efficient differentiation. In addition, these cells do not have unlimited proliferative capacity: all targets the cells will stop growing until 3�C4 months, due to cellular senescence. Conversion of differentiated cells into multipotent progenitor or different lineage has been reported by several groups. Adult hepatocytes were converted into insulin-producing cells by transgenes, Pdx-1 and Ngn-3 [26]; retinal pigment epithelium into retinal neurons by Sox-2 [27]; and interfollicular epidermal basal keratinocytes into the cells capable of differentiating into neuronal cells by Oct-4 [28].

The aforementioned studies used exogenous trangenes, some of which are key transcription factors for generating iPS cells. To our knowledge, there is only one report describing conversion from differentiated cells into multilineage progenitor cells without any gene delivery. Adult intestinal epithelial cells were dedifferentiated into nestin-positive cells that have multilineage differentiation capacity into neuronal, pancreatic and hepatic lineages [29]. The authors cultured intestinal epithelial cells on mouse embryonic fibroblasts (feeder layer) in medium supplemented with leukemia inhibitory factor, EGF and bFGF. For generating iPS cells, two key transcription factors Klf-4 and Sox-2 could be replaced by chemical compounds [30], [31]. SAGM contains EGF, insulin, other growth factors and chemicals.

These findings suggest that a particular combination of growth factors/chemicals probably changes transcriptional profiling, leading to dedifferentiation of thyrocytes. Microarray analysis revealed that the expression of ABCG2, Oct-4 and CD133 which have been used to identify stem cells in a number of tissues, were not up-regulated in the SAGM-grown cells, suggesting that the cells were a bit far from genuine pluripotent stem cells. Rather, they seem to be more committed stem/progenitor cells. In fact, mesenchymal stem cell markers CD106, CD105 and CD90 but not CD73 were highly up-regulated. Taken together with down-regulation of E-cadherin, these results suggest that the SAGM-grown cells acquired properties prior to cells committed to thyroid epithelial lineage. GO enrichment analysis was performed and revealed differentially regulated cellular processes.

Embryo implantation had the lowest p value among the up-regulated GO processes. Other up-regulated processes were endoplasmic reticulum, sterol/steroid/lipid biosynthesis/metabolic processes, cell cycle and oxidoreductase activity. These processes are generally related to protein/membrane synthesis presumably linked Carfilzomib to cell proliferation. Regarding down-regulated GO processes, protein binding and cell adhesion processes were impacted.