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Human embryonic stem (hES) cells can generate cells expressing p63, K14, and involucrin, which have been proposed to be keratinocytes. Although these hES‐derived, keratinocyte‐like (hESderK) cells form epithelioid colonies when cultured in a fibroblast feeder system optimal for normal tissue‐derived keratinocytes, they have a very short replicative lifespan unless engineered to express HPV16 E6E7. We report here that hESderK cells undergo senescence associated with p16 INK4A  expression, unrelated to telomere status. Transduction to express bmi1, a repressor of the p16 INK4A /p14 ARF  locus, conferred upon hESderK cells and keratinocytes a substantially extended lifespan. When exposed to transforming growth factor beta or to an incompletely processed form of Laminin‐332, three lifespan‐extended or immortalized hESderK lines that we studied became directionally hypermotile, a wound healing and invasion response previously characterized in keratinocytes. In organotypic culture, hESderK cells stratified and expressed involucrin and K10, as do epidermal keratinocytes in vivo. However, their growth requirements were less stringent than keratinocytes. We then extended the comparison to endoderm‐derived, p63 + /K14 +  urothelial and tracheobronchial epithelial cells. Primary and immortalized lines of these cell types had growth requirements and hypermotility responses similar to keratinocytes and bmi1 expression facilitated their immortalization by engineering to express the catalytic subunit of telomerase (TERT). In organotypic culture, they stratified and exhibited squamous metaplasia, expressing involucrin and K10. Thus, hESderK cells proved to be distinct from all three normal p63 +  cell types tested. These results indicate that hESderK cells cannot be identified conclusively as keratinocytes or even as ectodermal cells, but may represent an incomplete form of, or deviation from, normal p63 +  lineage development. S TEM  C ELLS  2009;27:1388–1399

stem cells

Epithelial Cells Derived from Human Embryonic Stem Cells Display P16 INK4A  Senescence, Hypermotility, and Differentiation Properties Shared by Many P63 +  Somatic Cell Types