Lentiviral hTERT overexpression extends the lifespan of primary human epidermal melanocytes and reshapes transcriptional programs

Lentiviral hTERT overexpression can generate expandable epidermal melanocyte models that preserve closer global similarity to primary melanocytes than melanoma cell lines. Nevertheless, hTERT overexpression and subsequent clonal selection induced broad remodeling of genes and pathways associated with cell-cycle progression, telomere regulation, antiviral immune response, extracellular matrix organization, cell adhesion, dendrite-associated structures, and pigmentation. These findings indicate that lentiviral hTERT overexpression extends the lifespan of human epidermal melanocytes but is not functionally neutral. Instead, this process promotes dedifferentiation and compromises key melanocytic functions. Moreover, single-cell cloning appears to impose additional selection pressure and may further drive model drift. hTERT-extended melanocytes should therefore be used cautiously in studies involving pigmentation, adhesion, differentiation, and normal melanocyte physiology.