Matteo Bergami - C 3

Role of astrocytes in microvasculature remodeling following brain injury

Summary

Astrocytes regulate essential aspects of brain energy metabolism via specialized perivascular compartments controlling the transfer of metabolites between the blood-brain-barrier and brain parenchyma. Under physiological conditions the overall role of these specialized compartments is relatively well understood, but their contribution following injury, particularly with regard to tissue repair, is unclear. This project aims to reveal whether and how astrocytes may play an active role in vasculature remodelling after brain injury.  

Introduction

Most if not all functions of the mature central nervous system essentially depend upon a highly coordinated activity of several cell types constituting the so-called neurovascular unit. Besides endothelial cells, which form the actual blood-brain-barrier (BBB), and the critical recruitment of pericytes during BBB formation, astrocytes have recently emerged for their possible co-regulatory role on vasculature permeability sustaining neurovascular coupling and brain energy metabolism. Following brain injury, the coordinated activity of these cell types becomes disrupted, eventually resulting in vascular dysfunction, BBB breakdown, neuroinflammation and spreading of secondary degeneration. In this setting, astrocytes invariably enter a state of reactivity (astrogliosis) which has been reported to underlie important functions in the progression of the injury and its possible resolution, including confining macrophage extravasation and spread of pro-inflammatory mediators. Interestingly, during this response astrocytes exhibit traits of pronounced structural plasticity by acquiring polarized morphologies and – in a subset of juxtavascular cells – resuming proliferation. They also undergo major changes in their metabolic state (Gobel et al., 2018), including mitochondrial energy metabolism, mirroring corresponding alterations in gene expression. Interestingly, very little is known on the actual changes reactive astrocytes may experience with regard to their perivascular compartment in vivo, and in particular whether these changes can contribute to restore the microvasculature structure and function. In this proposal we tackle the question whether astrocytes may play an active role in the local structural remodeling of the microvasculature following brain injury. In particular, we will investigate whether sub-cellular, compartmentalized metabolic microdomains within astrocytic end-feet exert key roles on vascular reorganization and BBB maintenance after damage.

Region-specific remodelling of astrocyte mitochondrial network following injury

Astrocytes respond to brain injury and the ensuing inflammation by entering a state of reactivity characterized by marked changes in gene expression and cell metabolism. Intriguingly, development of innovative genetic tools, including  virus-based approaches to target specific cell populations (Deshpande et al., 2013) has made possible to investigate with high resolution the mitochondrial network architecture of astrocytes in vivo (Figure 1)(Gobel et al., 2018).  

By means of these approaches, we have been recently able to reveal that injury-induced reactive astrocytes in vivo undergo differential and time-dependent structural changes of their mitochondrial network, mirroring corresponding alterations in their energy state (Figure 2) (Motori et al., 2013). While so far the ultimate significance of this regionalized mitochondrial network reorganization has remained elusive, our ongoing work may reveal if distinctive metabolic states might be necessary to sustain locally metabolic/energy needs functional to the resolution of the lesion. Given the substantial accumulation of mitochondria in both peri-synaptic and peri-vascular processes in astrocytes, in this part we pursue the hypothesis that these organelles may have a central role in regulating regionalized metabolic adaptations underlying tissue repair following injury.      

Region-specific subcellular changes in astrocyte metabolism following injury

In this part, we take advantage of in vivo and ex-vivo experiments to visualize by 2-photon live-cell imaging the sub-cellular Ca2+ dynamics in astrocytes. The aim is that of identifying injury-induced functional alterations in Ca2+ domains in relation to microvascular repair. Work performed so far reveals that alterations in Ca2+ signalling are long-lasting, and correlate with tissue repair at the vascular level.

Perspectives 

We are currently introducing genetic manipulations aimed at corroborating our ongoing observations in vivo. We expect to identify new potential mechanisms underlying functional astrocyte and perivascular changes following lesion. On a broader level, we hope to reveal key pathways of relevance for tissue repair.

Selected publications

Deshpande, A.*, Bergami, M.*, Ghanem, A., Conzelmann, K.K., Lepier, A., Gotz, M., and Berninger, B. (2013). Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc Natl Acad Sci U S A. *, equal contribution.

Gobel, J., Motori, E., and Bergami, M. (2018). Spatiotemporal control of mitochondrial network dynamics in astroglial cells. Biochemical and biophysical research communications 500, 17-25.

Motori, E., Puyal, J., Toni, N., Ghanem, A., Angeloni, C., Malaguti, M., Cantelli-Forti, G., Berninger, B., Conzelmann, K.K., Gotz, M., et al. (2013). Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance. Cell Metab 18, 844-859.


Prof. Dr. Matteo Bergami

CECAD Cologne / RG location

Prof. Dr. Matteo Bergami

Principal Investigator C 3

matteo.bergami@uk-koeln.de

Work +49 221 478 84250

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

http://cecad.uni-koeln.de/Dr-Matteo-Bergami.323.0.html?&L=qstfwjrc

Publications - Matteo Bergami

Link to PubMed

Group Members

Vignesh Sakthivelu (PostDoc)
Hannah Jahn (PostDoc)
Jana Göbel (doctoral student)
Gulzar Wani (doctoral student)
Sandra Wendler (doctoral student)
Esther Engelhardt (doctoral student)
Kristiano Ndoci (doctoral student)
Milica Jevtic (lab manager)
Sabine Manz (technician)

Figure 1

Mitochondrial network architecture in astroglial cells in vivo. Schematic illustration of a viral-based approach to express mitochondrial-targeted GFP (mtGFP) in astrocytes. On the right, representative confocal pictures show the elaborated mitochondrial network of reconstructed mtGFP-expressing astrocytes across different layers of the neocortex.

Figure 2

Regionalized changes in astrocyte mitochondrial network after injury. (A) Overview of a cortical stab-wound (SW) injury in mouse combined with a virus injection to label the mitochondrial network (by mito-GFP) specifically in astrocytes (labelled with S100β and GFAP). (B) Magnifications of resting and reactive astrocytes showing regionalized alterations in mitochondrial network morphology a few days after injury.