Cellular reprogramming in the brain
Until the last half of the 20th century, it was commonly believed that cell differentiation was unidirectional and irreversible. Strikingly, Gurdon and Yamanaka then made groundbreaking discoveries demonstrating instead that the identity of differentiated cells is not irreversibly determined but can be reprogrammed to a pluripotent state under appropriate signals. Importantly, seminal studies also showed that it is possible to turn one differentiated cell type directly into another without transitioning through a pluripotent ground state. This process has been termed direct lineage reprogramming.

Direct reprogramming or cell-fate conversion across cell lineages emerges as an innovative approach toward cell-based therapies for regenerative medicine. In the CNS, direct lineage reprogramming of non-neuronal cells into clinically relevant neurons represents a highly innovative strategy to regenerate lost neurons for brain repair in several neurological disorders (for review see Heinrich et al., Nature Cell Biol, 2015 and Vignoles et al., Trends Mol Med, 2019). Along this line, we contributed important work by demonstrating that mouse astroglia can be directly reprogrammed in vitro to generate functional induced neurons (iNs) with different neurotransmitter identity (Heinrich et al., 2010; Heinrich et al., 2011). A major challenge was the translation of these findings obtained in the culture dish into the context of the adult brain in vivo. We showed that NG2 glia can be converted into iNs in the adult mouse cortex in vivo and following acute invasive injury (Heinrich et al., 2014).

Based on these studies our current research aims now at reprogramming glial cells residing within the injured brain –in pathological conditions– into functional iNs that:

  • Acquire the same molecular identity and phenotype as lost neurons
  • Functionally integrate into endogenous neuronal networks
  • Modulate the pathological network activity with beneficial effects.
2022Studer F, Jarre G, Pouyatos B, Nemoz C, Brauer-Krisch E, Muzelle C, Serduc R, Heinrich C*, Depaulis A*, *equal participationAberrant neuronal connectivity in the cortex drives generation of seizures in rat Absence Epilepsy.Brain
2021Célia Lentini, Marie d'Orange, Nicolás Marichal, Marie-Madeleine Trottmann, Rory Vignoles, Louis Foucault, Charlotte Verrier, Céline Massera, Olivier Raineteau, Karl-Klaus Conzelmann, Sylvie Rival-Gervier, Antoine Depaulis, Benedikt Berninger, Christophe HeinrichReprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsyCell Stem Cell
2019Vignoles R, Lentini C, d'Orange M, Heinrich CDirect Lineage Reprogramming for Brain Repair: Breakthroughs and ChallengesTrends Mol Med
2018Zweifel S, Marcy G, Lo Guidice Q, Li D, Heinrich C, Azim K, Raineteau OHOPX Defines Heterogeneity of Postnatal Subventricular Zone Neural Stem CellsStem Cell Reports
2016Gascon S, Murenu E, Masserdotti G, Ortega F, Russo GL, Petrik D, Deshpande A, Heinrich C, Karow M, Robertson SP, Schroeder T, Beckers J, Irmler M, Berndt C, Angeli JP, Conrad M, Berninger B, Götz MIdentification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal ReprogrammingCell Stem Cell
2015Heinrich C, Spagnoli FM, Berninger BIn vivo reprogramming for tissue repairNat Cell Biol
2014Heinrich C, Bergami M, Gascón S, Lepier A, Viganò F, Dimou L, Sutor B, Berninger B, Götz MSox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortexStem Cell Reports
2011Heinrich C, Gascón S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, Schroeder T, Götz M, Berninger BGeneration of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortexNat Protoc
2010Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger BDirecting astroglia from the cerebral cortex into subtype specific functional neuronsPLoS Biol