The direct conversion of accessible cells such as human fibroblasts to inaccessible cells, particularly neurons, opens up many opportunities for using the human model system to study diseases and discover therapies. Previous studies have indicated that the neuronal conversion of adult human skin fibroblasts is much harder than that for human lung fibroblasts, which are used in many experiments. Here we formally report this differential plasticity of human skin versus lung fibroblasts in their trans differentiation to induced neurons. Using RNAseq of isogenic and non-isogenic pairs of human skin and lung fibroblasts at different days in their conversion to neurons, we found that several master regulators (TWIST1, TWIST2, PRRX1 and PRRX2) in the fibroblast Gene Regulatory Network were significantly downregulated in lung fibroblasts, but not in skin fibroblasts. By knocking down each of these genes and other genes that suppress the neural fate, such as REST, HES1 and HEY2, we found that the combined attenuation of HEY2 and PRRX2 significantly enhanced the transdifferentiation of human skin fibroblasts induced by ASCL1 and p53 shRNA. The new method, which overexpressed ASCL1 and knocked down p53, HEY2 and PRRX2 (ApH2P2), enabled the efficient transdifferentiation of adult human skin fibroblasts to MAP2+ neurons in 14 days. It would be useful for a variety of applications that require the efficient and speedy derivation of patient-specific neurons from skin fibroblasts. (C) 2019 Elsevier Inc. All rights reserved.