Capturing epidermal stemness for regenerative medicine

Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

“…These cultures comprise a heterogeneous cell population as the clonogenic cells are endowed with different proliferative potential. They can be classified as holoclones, meroclones and paraclones by clonal analysis 3 : the holoclone is generated from SC and has the highest proliferative capacity; meroclones and paraclones are originated from young and old TA-cells, respectively. Specifically, paraclones derive from the largest colonyforming keratinocytes and generate aborted colonies containing only terminally differentiated cells.…”

“…Indeed, none of the identified cell surface proteins is a keratinocyte SC specific marker even though some of them are able to capture subpopulations that also contain SCs. 3 Different from replicative senescence, which is related to doubling number, clonal conversion occurs independently from telomere shortening and affects SC fate within a single cell division until the exhaustion of TA proliferative potential. 3 Moreover, clonal conversion might be abruptly accelerated by endogenous (overproduction of ROS, mutation accumulation) or microenvironmental (extracellular matrix modification, growth factor and cytokine modulation) insults.…”

“…The increase of paraclones of primary human keratinocyte cultures is a direct measure of clonal evolution accomplishment and, in turn, SC depletion. 3,4 Clonal conversion is a unidirectional process and is irreversible under normal conditions. However, an impairment of clonal evolution can be obtained by loss of tumor suppressors, such as 14-3-3sigma, 4 or oncogene activation, such as human papillomavirus (HPV) E6 and E7 oncogenes, 3 and might induce an uncontrolled proliferation.…”

“…They are cells endowed with a high proliferative capacity and able to generate a differentiated progeny. 2,3 Whenever SCs are activated, they enter into a transient state of rapid proliferation, giving rise to TAcells, the largest group of dividing cells. After several divisions, these cells withdraw from cell cycle and generate post-mitotic keratinocytes, which migrate upwards and form suprabasal layers executing their terminal differentiation program.…”

“…2 Thus, the clonal evolution or conversion, i.e., the transition from SCs to TA and post-mitotic cells, is a continuous process that builds up the epidermis. 3 …”