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).
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).
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).
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:
|2011||42(1):35-47||Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy||Heinrich C, Lähteinen S, Suzuki F, Anne-Marie L, Huber S, Häussler U, Haas C, Larmet Y, Castren E, Depaulis A||Neurobiol Dis||-|
|2005||46(2):193-202||Glutamate receptor antagonists and benzodiazepine inhibit the progression of granule cell dispersion in a mouse model of mesial temporal lobe epilepsy||Suzuki F, Heinrich C, Boehrer A, Mitsuya K, Kurokawa K, Matsuda M, Depaulis A||Epilepsia||-|
|2008||49(10):1711-22||Granule cell dispersion develops without neurogenesis and does not fully depend on astroglial cell generation in a mouse model of temporal lobe epilepsy||Nitta N, Heinrich C, Hirai H, Suzuki F||Epilepsia||-|
|2011||52(12):2315-25||Inflammatory changes during epileptogenesis and spontaneous seizures in a mouse model of mesiotemporal lobe epilepsy||Pernot F, Heinrich C, Barbier L, Peinnequin A, Carpentier P, Dhote F, Baille V, Beaup C, Depaulis A, Dorandeu F||Epilepsia||-|
|2011||6(2):214-28||Generation of subtype-specific neurons from postnatal astroglia of the mouse cerebral cortex||Heinrich C, Gascón S, Masserdotti G, Lepier A, Sanchez R, Simon-Ebert T, Schroeder T, Götz M, Berninger B||Nat Protoc||-|
|2010||8(5):e1000373||Directing astroglia from the cerebral cortex into subtype specific functional neurons||Heinrich C, Blum R, Gascón S, Masserdotti G, Tripathi P, Sánchez R, Tiedt S, Schroeder T, Götz M, Berninger B||PLoS Biol||-|