Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program.
Marisa Karow, J Gray Camp, Sven Falk, Tobias Gerber, Abhijeet Pataskar, Malgorzata Gac-Santel, Jorge Kageyama, Agnieska Brazovskaja, Angela Garding, Wenqiang Fan, Therese Riedemann, Antonella Casamassa, Andrej Smiyakin, Christian Schichor, Magdalena Götz, Vijay K Tiwari, Barbara Treutlein, Benedikt Berninger
Author Information
Marisa Karow: Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, Mainz, Germany. marisa.karow@med.uni-muenchen.de. ORCID
J Gray Camp: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. ORCID
Sven Falk: Physiological Genomics, Biomedical Center, Ludwig Maximilians University Munich, Planegg/Martinsried, Germany.
Tobias Gerber: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Abhijeet Pataskar: Institute of Molecular Biology (IMB), Mainz, Germany.
Malgorzata Gac-Santel: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Jorge Kageyama: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Agnieska Brazovskaja: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Angela Garding: Institute of Molecular Biology (IMB), Mainz, Germany.
Wenqiang Fan: Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, Mainz, Germany.
Therese Riedemann: Physiological Genomics, Biomedical Center, Ludwig Maximilians University Munich, Planegg/Martinsried, Germany. ORCID
Antonella Casamassa: Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, Mainz, Germany.
Andrej Smiyakin: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
Christian Schichor: Department of Neurosurgery, Ludwig Maximilians University, Munich, Germany.
Magdalena Götz: Physiological Genomics, Biomedical Center, Ludwig Maximilians University Munich, Planegg/Martinsried, Germany. ORCID
Vijay K Tiwari: Institute of Molecular Biology (IMB), Mainz, Germany.
Barbara Treutlein: Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany. barbara_treutlein@eva.mpg.de. ORCID
Benedikt Berninger: Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University Mainz, Mainz, Germany. benedikt.berninger@kcl.ac.uk. ORCID
Ectopic expression of defined transcription factors can force direct cell-fate conversion from one lineage to another in the absence of cell division. Several transcription factor cocktails have enabled successful reprogramming of various somatic cell types into induced neurons (iNs) of distinct neurotransmitter phenotype. However, the nature of the intermediate states that drive the reprogramming trajectory toward distinct iN types is largely unknown. Here we show that successful direct reprogramming of adult human brain pericytes into functional iNs by Ascl1 and Sox2 encompasses transient activation of a neural stem cell-like gene expression program that precedes bifurcation into distinct neuronal lineages. During this transient state, key signaling components relevant for neural induction and neural stem cell maintenance are regulated by and functionally contribute to iN reprogramming and maturation. Thus, Ascl1- and Sox2-mediated reprogramming into a broad spectrum of iN types involves the unfolding of a developmental program via neural stem cell-like intermediates.
