Acclimatized induction reveals the multipotency of adult human undifferentiated keratinocytes

It has been demonstrated that several types of somatic stem cells have the remarkable capacity to differentiate into other types of tissues. However, the promise of keratinocyte stem cells seems slim for generating nonepidermal tissues. Using our recently developed acclimatization induction strategy, we demonstrate the multipotency of adult human undifferentiated keratinocytes (UKs). The UKs were isolated from the basal layer of adult human foreskin and cultured in Epilife medium, which allows for the growth of only keratin-positive keratinocytes, promotes high proliferation of UKs, and prevents their differentiation. Induction of the UKs by either serum or lineage-committed medium only produce differentiated epidermal cells. Hence, serum or lineage-committed medium was added to Epilife to acclimate UKs to differentiate to other cell types. Unexpectedly, serum acclimatization can induce UKs to produce a large number of smooth muscle cells and fewer of adipocytes and neurocytes within 3 weeks. In contrast, except for the terminally differentiated epidermal cells, committed acclimatization can induce UKs to differentiate exclusively into the adipocytic, myogenic, or neurogenic lineages. These data indicate that human UKs represent a novel multipotent adult stem cell, and suggest that they may provide an accessible, therapeutically promising cell source for regenerative medicine.