A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells

• Published in: Nature communications 2016-04, Vol.7 (1), p.11247-14, Article 11247
• Main Authors: Saxena, Pratik, Heng, Boon Chin, Bai, Peng, Folcher, Marc, Zulewski, Henryk, Fussenegger, Martin
• Format: Article
• Language: English
• Subjects: 631/136/532/2064; 631/45/612/822; 631/553/338/552; 631/61/490; Cell Differentiation - drug effects; Cell Lineage - drug effects; Gene Expression Profiling; Gene Expression Regulation - drug effects; Glucose - pharmacology; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - cytology; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Middle Aged; multidisciplinary; Reproducibility of Results; Science; Science (multidisciplinary); Transcription Factors - metabolism; Vanillic Acid - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11247

Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine. Synthetic biology offers the potential for the design and implementation of rationally designed, complex genetic programmes. Here the authors design a genetic network to trigger the differentiation of patient derived IPSCs into beta-like cells.