Christophe Heinrich received a PhD in Neuropharmacology from the University of Strasbourg (France), where he studied the role of BDNF and adult hippocampal neurogenesis in Mesial-Temporal Lobe Epilepsy. Afterwards, he joined the lab of Prof. Magdalena Götz at the Ludwig-Maximilian University of Munich (Germany) for his postdoctoral training. He focused on direct lineage reprogramming of glial cells into clinically-relevant induced neurons as a promising cell-based strategy for brain repair. He showed that astroglia from the cerebral cortex can be reprogrammed in vitro into functional, synapse-forming neurons of distinct phenotypes by forced expression of specific neurogenic transcription factors. He next showed that reactive glial cells within the injured adult cerebral cortex can also be instructed in vivo to generate induced neurons. After his postdoc, he moved back to France where he was recruited as assistant professor at CNRS (National Centre for Scientific Research). He was awarded in 2016 the Attraction Package from the Laboratory of Excellence (LabEx) CORTEX at the University of Lyon, where he has now established his own research group at the Stem Cell and Brain Research Institute (SBRI, INSERM). His lab is currently exploring the functional impact of in vivo lineage reprogramming as a promising cell-replacement strategy in regenerative medicine to induce functional recovery in neurological disorders.  

RESEARCH PROJECTS

In mammals, acute invasive brain injury and chronic neurodegenerative diseases are characterized by acute or progressive death of neurons. The discovery that neurogenesis occurs throughout life in the adult brain of most mammals including humans raised hopes as a potential source for new neurons. However, in most brain areas, the vast majority of lost neurons are not replaced and the endogenous response of the adult human CNS fails to promote functional recovery. Of note, the majority of neurological diseases associated with neuronal death are also accompanied by a reactive gliosis characterized by an early activation/proliferation of microglia and NG2 glia followed by an astrocyte response (Dimou and Gotz, 2014; Robel et al., 2011).

Which strategies can be developed to repair the damaged brain?

During my postdoc in the lab of Prof. Magdalena Götz (Munich, Germany), we explored a very innovative strategy aiming at reprogramming reactive glial cells residing at the injury site into clinically relevant neurons, with the underlying rationale to recruit glia as an endogenous cellular source for brain repair, thus replacing lost neurons directly within the injured tissue. In addition we aimed at exploring an exciting question in the field of reprogramming whether glial cells can be directly reprogrammed into functional induced neurons (iNs).

Glial cells as a source of new neurons in the injured brain

First, we showed that astroglia from the postnatal mouse cerebral cortex can be directly reprogrammed in vitro to generate functional, synapse-forming iNs following forced expression of transcription factors (TFs) known to instruct neurogenesis in neural stem cells (Heinrich et al, 2010; Heinrich et al, 2011). Importantly, the neurotransmitter identity of astroglia-derived iNs can be controlled by selective expression of distinct TFs: Neurogenin2 converts astroglia into glutamatergic neurons, while Ascl1 or Dlx2 induces a fate switch toward a GABAergic phenotype. This was the first time that the generation of functional iNs could be achieved by direct conversion across cell lineages induced by a single neurogenic TF. Next, a major challenge was the translation of these findings obtained in the culture dish into the context of the adult mouse brain in vivo. We showed that NG2 glia proliferating in the cortex of adult mice in response to acute invasive injury can be converted into functional iNs in vivo by forced expression of Ascl1 and Sox2 (Heinrich et al, 2014). Together these proof-of-principle studies show that glia-to-neuron conversion can be achieved in vivo in the injured adult brain, opening new avenues for cell-based therapies in regenerative medicine and the use of endogenous glial cells for brain repair (Heinrich et al, 2015; Vignoles et al, 2019).

Current projects

Based on these studies our current research aims now at further exploring whether glia-to-neuron reprogramming could emerge as a promising therapeutic tool. To this end, we aim 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.

PUBLICATIONS  

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RESEARCH SUPPORT

Current Research Support

• LabEx CORTEX Attraction Package  PI: C. Heinrich
• ARC - Région Rhône-Alpes-Auvergne: Qualité de Vie et Vieillissement  PI: C. Heinrich

Completed Research Support

• ANR JCJC - Agence Nationale de la Recherche - ReprogramEpi  PI: C. Heinrich
• FRC-FFRE - Fédération pour la Recherche sur le Cerveau - Fondation Française pour la Recherche sur l’Epilepsie  PI: C. Heinrich
• LFCE - Ligue Française Contre l'Epilepsie PhD Fellowship Célia Lentini
• CURE Innovator Award - Citizens United for Research in Epilepsy  PI: C. Heinrich
• PEPS-CNRS -Projet Exploratoire Premier Soutien  Co-Investigator (PI: C. Villard)

HONORS & AWARDS

• 2016      Laureate of the LabEx CORTEX Attraction Package
• 2016      Junior Group Leader at the Grenoble Institute of Neurosciences
• 2013      Recruited as Chargé de Recherche CR1 at CNRS 
• 2013      CURE Innovator Award  
• 2013      Heinrich et al, PLoS Biology (2010) recommended by Faculty of 1000 Biology
• 2010      Heinrich et al, PLoS Biology (2010) highlighted by Nature  
• 2006      Heinrich et al, J. Neuroscience (2006) recommended by Faculty of 1000 Biology and ranked as “exceptional” 
• 2006      Heinrich et al, J. Neuroscience (2006) highlighted in “This Week in The Journal”  
• 2004      NEUREX Fellowship, International PhD Program (1 year), France - Germany
• 2001      PhD Fellowship (3 years), Ministry of Education and Research, France
• 2001      Servier Award for Best Communication, NEUREX Meeting, Strasbourg, France