Researchers from the Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences found that human fibroblasts can be directly converted into neuronal cells by a chemical cocktail of seven small molecules. These chemical-induced neuronal cells (hciNs) were similar to hiPSC-derived neurons and TF-iNs with respect to morphology, gene expression profiles, and electrophysiological properties. This approach was further applied to generate hciNs from familial Alzheimer's disease patients. 

Terminally differentiated somatic cells could be reprogrammed into pluripotent stem cells by forced expression of a specific set of transcription factors, indicating that the cell fates determination is reversible. Further, different combination of lineage-specific transcription factors could directly convert cardiomyocytes, hepatocytes or neurons from mouse or human somatic cells bypassing pluripotent state, providing alternative avenues for disease modeling and regenerative medicine. However, the introduction of ectopic transgenes limits their current therapeutic application. Thus, tightly controlled expression of ectopic genes and reducing the number of transcription factors have been tried. Cell-permeable small molecules have been shown to promote cell reprogramming. Recent report has even showed that small molecules alone can induce mouse fibroblasts into a pluripotent state. Their previous report also showed that NPCs can be induced from mouse fibroblasts or human urinary cells with proper chemical cocktails. Moreover, chemical-promoted transdifferentiation from mouse or human fibroblasts to different cell lineages has been reported.  

Under the guidance of Prof. PEI Gang, ZHAO Jian and YU Yongchun, Dr. HU Wenxiang, graduate student QIU Binlong and GUAN Wuqiang found that human fibroblasts were directly converted into neuronal cells by small molecules. These hciN cells exhibited physiological properties like repetitive trains of action potential, fast inward sodium currents and spontaneous postsynaptic currents. Moreover, resembling hiPSC-derived neurons and TF-induced neurons, hciNs showed similar electrophysiological properties including calcium transients.  

To further characterize the genes expression signature, HU et al used Fluidigm Biomark platform and microarray to analyzed the gene expression, which also proved that hciN cells was similar to that of TF-induced neurons or hiPSC-derived neurons, but distinguished from that of initial fibroblasts. Further, this chemical-induction protocol was applied to generate Alzheimer’s disease patient fibroblast derived neuronal cells for disease modeling. 

Their findings indicate that this study present another strategy for generation of patient-specific neuronal cells, thus providing desirable neuron recourses for personalized disease modeling or even potential cell replacement therapy of neurological disorders.. 

This work was published in Cell Stem Cell entitled “Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules” on Aug. 6, 2015.  

The study was done in collaboration with Tongji University, Fudan University, Shanghai East Hospital, Central South University, Institute of Health Sciences and CAS-MPG Partner Institute for Computational Biology. It was funded by the grants from Chinese Academy of Sciences, the Ministry of Science and Technology of China, Shanghai Zhangjiang Stem Cell Research Project, the National Natural Science Foundation of China and the National Science and Technology Support Program. 

Fig. The graphical abstract of direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. (Image by Prof. PEI Gang’s group)   

Contact:
PEI Gang
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai 200031, P. R. China.
Phone: 86-21-54921371
E-mail: gpei@sibs.ac.cn