Automatic identification of small molecules that promote cell conversion and reprogramming

• DOI: 10.1016/j.stemcr.2021.03.028
• Publication Date: 2021-04-22T16:38:22Z
• Authors: Francesco Napolitano; Trisevgeni Rapako...; Patrizia Annunziata; Akira Hasegawa; Melissa Cardon; Sara Napolitano; Lorenzo Vaccaro; Antonella Iuliano; Luca Giorgio Wand...; Takeya Kasukawa; Diego L. Medina; Davide Cacchiarelli; Xin Gao; Diego di Bernardo; Erik Arner
• Keywords: Resource; 0301 basic medicine; 0303 health sciences; bioinformatic; Induced Pluripotent Stem Cells; reprogramming; Reproducibility of Results; cell conversion; bioinformatics; Cellular Reprogramming; 3. Good health; Small Molecule Libraries; small molecules; Automation; Mice; 03 medical and health sciences; bioinformatics; cell conversion; reprogramming; small molecules; Animals; Cluster Analysis; Algorithms

AbstractControlling cell fate has great potential for regenerative medicine, drug discovery, and basic research. Although numerous transcription factors have been discovered that are able to promote cell reprogramming and trans-differentiation, methods based on their up-regulation tend to show low efficiency. The identification of small molecules that can facilitate conversion between cell types can ameliorate this problem working through safe, rapid, and reversible mechanisms. Here we present DECCODE, an unbiased computational method for the identification of such molecules solely based on transcriptional data. DECCODE matches the largest available collection of drug-induced profiles (the LINCS database) for drug treatments against the largest publicly available dataset of primary cell transcriptional profiles (FANTOM5), to identify drugs that either alone or in combination enhance cell reprogramming and cell conversion. Extensivein silicoandin vitrovalidation of DECCODE in the context of human induced pluripotent stem cells (hIPSCs) generation shows that the method is able to prioritize drugs enhancing cell reprogramming. We also generated predictions for cell conversion with single drugs and drug combinations for 145 different cell types and made them available for further studies.