New approaches for direct conversion of patient fibroblasts into neural cells

摘要

Recent landmark studies have demonstrated the production of disease-relevant human cell types by two different methods; differentiation of stem cells using external morphogens or lineage conversion using genetic factors. Directed differentiation changes embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) into a desired cell type by providing developmental cues in an in vitro environment. Direct reprogramming is achieved by the introduction of exogenous lineage specific transcription factors to convert any somatic cell type into another, thereby bypassing an intermediate pluripotent stage. A variety of somatic cell types such as blood, keratinocytes and fibroblasts can be used to derive iPSC cells. However, the process is time consuming, laborious, expensive and gives rise to cells with reported epigenetic heterogeneity even amongst different iPSC lines from same patient which could propagate phenotypic variability. A major concern with the use of pluripotent cells as starting material for cell replacement therapy is their incomplete differentiation and their propensity to form tumors following transplantation. In comparison, transcription factor mediated reprogramming offers a direct route to target cell types. This could allow for rapid comparison of large cohorts of patient and control samples at a given time for disease modeling. Additionally, transcription factors that drive maturation may yield more functionally mature cells than directed differentiation. Several studies have demonstrated the feasibility of generating of cell types such as cardiomyocytes, hepatocytes, and neurons from fibroblasts. Here, we will discuss recent advances and key challenges regarding direct reprogramming of somatic cell types into diverse neural cells.