Neurogenesis and Regeneration Group

We focus on basic and translational research in the field of the central nervous system (CNS) repair and regeneration aiming at novel strategies for brain repair and regeneration by modulating the function of glial cells. We aim at providing a basis for the development of new therapies for patients affected by stroke, neurotrauma or neurodegenerative diseases. In the mammalian CNS, spontaneous regeneration and repair taking place during development of are lost and a CNS injury during adulthood is often irreversible. Regenerative therapies face two major challenges: a) how to how to improve connectivity of spared neurons or replace lost neurons to improve functional recovery (restorative neurogenesis) and b) how to prevent or limit the glial scar formation. A scar is non-functional tissue interfering not only with the function of the brain area at the place of its deposition, but also creating an adverse environment for the attempts of new neurons to integrate. In contrast to mammals, zebrafish is a great model for neuronal replacement and scarless regeneration. Effective mechanisms are in place to activate a restorative neurogenic program in a specific set of glia (ependymoglia) in the injured forebrain (Ayari et al., 2010; Barbosa et al., 2015; Baumgart et al., 2012; Kroehne et al., 2011; Kyritsis et al., 2012; Viales et al., 2015) as well as implement scarless regeneration (Baumgart et al., 2012; Kroehne et al., 2011; Marz et al., 2011). We utilize a translational trans-species approach by comparing two animal models (zebrafish and mouse) for identifying predictive biomarkers and novel therapeutic approaches applicable to human brain injury. We use combination of in vivo cell imaging methods and cell-type specific OMICS analysis to understand multi-gene interactions in vivo and in real-time in the regenerating adult zebrafish brain and implement them in the mammalian brain for the regeneration purposes.

In the long term, our work aims at developing approaches to aid neuronal regeneration and functional recovery after the CNS damage.

EXPERIMENTAL APPROACHES

The Ninkovic group is pursuing 3 main lines of research:

1. Understanding and implementation of mechanisms to induce restorative neurogenesis from glial cells

We were the first to implement live imaging of adult ependymoglia in the intact and injured zebrafish telencephalon. Our discovery in this model uncovered the cellular basis for studying molecular roadblocks preventing direct reprogramming of glia into neurons with two major new conceptual insights. We discovered a novel mode of neurogenesis, namely the direct conversion of an ependymoglia into a neuron without cell division (Barbosa et al., 2016; Barbosa and Ninkovic, 2016; Barbosa et al., 2015). This process is an endogenous correlate of direct reprogramming of glia into neurons in the injured mouse brain (Gascon et al., 2016; Guo et al., 2014; Heinrich et al., 2010). Building on these novel discoveries we now focus to examine, in a comparative manner, the molecular mechanisms of ependymoglia fate progression in reaction to injury in the zebrafish. Understanding the direct fate conversion of ependymoglia into neurons in the zebrafish will allow determining adequate processes in smooth fate conversion that can consequently be implemented in the mammalian brain to achieve efficient restorative neurogenesis. The second major insight from our recent work was the identification of the cellular mechanisms increasing the neuronal output after injury at the expense on the ependymoglia maintenance, including activation of quiescent ependymoglia and change in the mode of their division (Barbosa et al., 2015) that are also shared with the mouse neural stem cells (Calzolari et al., 2015). We are currently investigating underlying molecular mechanisms as potential targets for the regenerative therapies.

2. Understanding and inhibition of glial scar formation in the vertebrate brain

Traumatic brain injury induces an orchestrated reaction of resident glial cells to remodel the extracellular matrix (ECM) around injury. This reaction is initially instrumental for the healing process (wound healing), but later leads to the formation of non-functional tissue (glial scar) with detrimental effects for functional restoration (Anderson et al., 2016; Burda and Sofroniew, 2014). Therefore, taking apart and eliminating pathways involved specifically in the prolonged glial reaction and scaring is one of the major challenges for setting up regenerative therapies in mammalian brain, including humans.  To tackle this problem we have for the first time, used two different injury models in the zebrafish telencephalon to delineate wound-healing processes from the pathways leading to the scar formation. We now investigate signalling pathways specific for these processes and means to interfere with scar formation in both zebrafish and mouse.

3. Recovery of functional neuronal circuits after brain injury

We investigate the contribution of newly generated neurons to the functional recovery of neuronal circuits using the optokinetic reflex (OKR) as an experimental paradigm. Towards this end, we developed a robust methodology to analyze the cellular basis for the OKR recovery after stab wound injury. The OKR ensures the precision of gaze-stabilizing reflexes through sensory-motor transformation of residual visual error signals into extraocular motor commands. The horizontal optokinetic reflex in zebrafish is direction-specifically impaired after a unilateral stab wound injury of a pretectal nucleus that causes cell death in this area. We aim to decipher post-lesional processes such as neurogenesis, inflammation, glial reactivity and sensory substitution leading to the successful OKR recovery. We expect to reveal the role of cellular/molecular alterations and principles of cross-modal plasticity for a functional recovery after brain injury.

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