Small molecules increase direct neural conversion of human fibroblasts
Ulrich Pfisterer1,2, Fredrik Ek3, Stefan Lang2,4
1Department of Experimental Medical Science, Wallenberg Neuroscience Center 221 84, Lund, Sweden.
Scientific Reports
|December 6, 2016
Summary
Researchers developed a new screening assay to identify compounds that improve the generation of human induced neurons (hiNs). Six potent compounds were found, increasing hiN reprogramming efficiency over six-fold and accelerating neuronal gene activation.
Area of Science:
- Neuroscience
- Biotechnology
- Genetics
Background:
- Human induced neurons (hiNs) offer a patient-specific model for neurological diseases.
- Current methods for generating hiNs require optimization for efficiency and scalability.
- hiNs hold potential for disease modeling, drug screening, and regenerative medicine.
Purpose of the Study:
- To develop an unbiased screening assay for small molecules that enhance hiN generation efficiency.
- To identify novel compounds that potentiate the reprogramming of fibroblasts into neurons.
Main Methods:
- Utilized hiNs to establish an unbiased screening assay.
- Screened 307 compounds from five annotated libraries.
- Performed global gene expression and CellNet analysis at various reprogramming timepoints.
Main Results:
- Identified six potent compounds that significantly enhance the neuronal reprogramming process.
- Achieved a >6-fold increase in reprogramming efficiency using an optimal combination of these compounds.
- Observed accelerated upregulation of neuronal genes and activation of neuronal gene regulatory networks (GRNs).
- Noted the downregulation of fibroblast-specific GRNs and increased expression of genes related to transcriptional activity and cellular stress response.
Conclusions:
- The developed screening assay effectively identified compounds that boost hiN generation.
- The identified compounds accelerate neuronal differentiation and enhance the efficiency of reprogramming.
- These findings contribute to advancing the potential of hiNs for therapeutic and research applications.
