Closer to fine: fewer steps to endothelial stemness.

Yamanaka’s pioneering work demonstrating the ability of fully differentiated cells to reprogram into embryonic stem cells with just four factors (c-Myc, Oct3/4, Sox2, and Klf4) ushered in a new era of regenerative biology.1 Although it is currently thought that reprogramming of differentiated cells to a pluripotent state involves multiple stochastic epigenetic events, progenitors with some degree of unior multipotency can be reprogrammed more easily with fewer factors.2 Mouse neural stem cells can be reprogrammed to a pluripotent state with the addition of only one factor, Oct4.3 The endogenous expression of Sox2, Klf-4, and c-Myc, as well as other intermediate reprogramming genes, by endogenous neural stem cells perhaps enables Oct4 to drive these cells to a pluripotent state. Even in reprogramming with nuclear transfer technology, nuclei donated from less differentiated cells or progenitor cells induce a higher efficiency of reprogramming than nuclei from terminally differentiated cells, suggesting that the epigenetic landscape of a less differentiated cell is more amenable to reprogramming than that of a terminally differentiated cell.4 However, endogenous expression of reprogramming genes in somatic cells is not sufficient for inducing reprogramming with fewer factors. For instance, fibroblasts express c-Myc as well as Klf-4 but still require exogenous introduction of these genes or addition of small molecules to enhance the reprogramming process.2,5 Successful reprogramming with exogenous introduction of factors depends on multiple variables, including the epigenetic landscape of the cell to be reprogrammed, expression levels, correct balance, and continuity of transgene expression, as well as appropriate temporal silencing of transgene expression.2