Direct conversion of astrocytes into neuronal cells by drug cocktail

Direct conversion of astrocytes into neuronal cells by drug cocktail Cell Research advance online publication 2 October 2015; doi:10.1038/cr.2015.120 Dear Editor, Neurological disorder is one of the greatest threats to public health according to the World Health Organization. Because neurons have little or no regenerative capacity, conventional therapies for neurological disorders yielded poor outcomes. While the introduction of exogenous neural stem cells or neurons holds promise, many challenges still need to be tackled, including cell resource, delivery strategy, cell integration and cell maturation. Reprogramming of fibroblasts into induced pluripotent stem cells or directly into desirable neuronal cells by transcription factors (TFs) or small molecules can solve some problems, but other issues remain to be addressed, including safety, conversion efficiency and epigenetic memory [1, 2]. Astrocytes are considered to be the ideal starting candidate cell type for generating new neurons, due to their proximity in lineage distance to neurons and ability to proliferate after brain damage. Many studies have already revealed that astrocytes of the central nervous system can be reprogrammed into induced neuronal cells by virus-mediated overexpression of specific TFs in vitro and in vivo [3-6]. However, application of this virus-mediated direct conversion is still limited due to concerns on clinical safety. We have previously reported direct conversion of somatic cells into neural progenitor cells (NPCs) in vitro by cocktail of small molecules under hypoxia [7]. Here we set out to explore whether astrocytes can be induced into neuronal cells by the chemical cocktail in vitro

Direct Generation of Human Neuronal Cells from Adult Astrocytes by Small Molecules

Astrocytes, due to the proximity to neuronal lineage and capability to proliferate, are ideal starting cells to regenerate neurons. Human fetal astrocytes have been successfully converted into neuronal cells by small molecules, which offered a broader range of further applications than transcription factor-mediated neuronal reprogramming. Here we report that human adult astrocytes could also be converted into neuronal cells by a different set of small molecules. These induced cells exhibited typical neuronal morphologies, expressed neuronal markers, and displayed neuronal electrophysiological properties. Genome-wide RNA-sequencing analysis showed that the global gene expression profile of induced neuronal cells resembled that of human embryonic stem cell-differentiated neurons. When transplanted into post-natal mouse brains, these induced neuronal cells could survive and become electrophysiologically mature. Altogether, our study provides a strategy to directly generate transgene-free neuronal cells from human adult astrocytes by small molecules