Fusion of Reprogramming Factors Alters the Trajectory of Somatic Lineage Conversion

Simultaneous expression of Oct4, Klf4, Sox2, and
cMyc induces pluripotency in somatic cells (iPSCs).
Replacing Oct4 with the neuro-specific factor Brn4
leads to transdifferentiation of fibroblasts into
induced neural stem cells (iNSCs). However, Brn4
was recently found to induce transient acquisition
of pluripotency before establishing the neural fate.
We employed genetic lineage tracing and found
that induction of iNSCs with individual vectors leads
to direct lineage conversion. In contrast, polycistronic
expression produces a Brn4-Klf4 fusion protein
that enables induction of pluripotency. Our study
demonstrates that a combination of pluripotency and
tissue-specific factors allows direct somatic cell
transdifferentiation, bypassing the acquisition of a
pluripotent state. This result has major implications
for lineage conversion technologies, which hold potential
for providing a safer alternative to iPSCs for
clinical application both in vitro and in vivo.