Direct Conversion of Dermal Fibroblasts into Neural Progenitor Cells by a Novel Cocktail of Defined Factors

C.      Tian; R.J.      Ambroz; L.      Sun; Y.      Wang; K.      Ma; Q.      Chen; B.      Zhu; J.C.      Zheng

Abstract

The generation of functional neural progenitor cells (NPCs) independent of donor brain tissue and embryonic tissues is of great therapeutic interest with regard to regenerative medicine and the possible treatment of neurodegenerative disorders. Traditionally, NPCs are derived through the differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, the induction of NPCs from ESCs and iPSCs is a complicated process that increases the risk of neoplasia and undesired cell types. This process can be circumvented through the direct conversion of somatic cells from one cell type to another by ectopic expression of specifically defined transcription factors. Using gene expression profiling and parental cells from E/Nestin:EGFP transgenic mice as a monitoring system, we tested nine factors with the potential to directly convert fibroblasts into NPCs. We found that five of these factors can directly convert adult dermal fibroblasts into NPC-like cells (iNPCs), and the resulting iNPCs possessed similar properties as primary NPCs including proliferation, self-renewal and differentiation. Significantly, iNPCs also exhibit chemotactic properties similar to those of primary NPCs. These provide an important alternative strategy to generate iNPCs for cell replacement therapy of neurodegenerative diseases.

Keywords: Direct conversion, iNPCs, neural progenitor cells, neurodegenerative disease, regenerative medicine, fibroblasts, transcription factors, hepatocytes, melanocytes, cardiomyocytes, phenotypes, nervous system, brain injuries, proneural genes, Notch ligand genes