Small molecule inhibitors or agonists can help the direct conversion process by simultaneously accelerating neuronal fate commitment and pruning unwanted side differentiations. For example, Ladewig and coworkers reported up to 200% and 80% in neuronal yield and purity respectively by dual inhibition of GSK-3β and SMAD signaling [44]. Ambasudhan [22] and Yoo [45] used bFGF and dibutyrl cyclic AMP/Forskolin to increase neuronal yield. These reports suggest three pathways critical for iN cell reprogramming: TGFβ/BMP inhibition, FGF activation and increasing the level of intracellular cyclic AMP. Given the conserved roles of BMP inhibition and FGF activation during neural induction [46], it is not surprising that modulating those two pathways leads to an enhancement of iN cell reprogramming. Future studies will have to show whether those two pathways enhance iN cell reprogramming via a similar mechanism as early neural induction.
