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Stem cells for neurorepair after stroke

Principal investigator: Dr. Holger Braun

During the last decade the literature has shown that neurogenesis can occur in the adult mammalian brain. We focus on possible regeneration after an ischemic insult, based on proliferation, migration and functional integration of endogenous and transplanted adult stem cells.

 A focal cerebral ischemia, induced by the insertion of a filament in the middle cerebral artery or the occlusion of the artery by endothelin-1, leads to a damage of cortical and striatal brain areas. A repair of these damaged areas might be possible by activating endogenous stem cells or by transplantation of exogenous stem cells. An increase of the endogenous cell proliferation was shown in the subventricular zone after the application of different factors such as growth factors or antiapototic substances. To what extent these factors can prevent the cells from death and/or lead the cells towards a neuronal differentiation, is the topic of the current investigations. Embryonic stem cells (ES-cells) as well as bone marrow cells are investigated for transplantation purposes after stroke. We showed that ES-cells are able to survive in the infarcted area of the rat brain. Further, they differentiated into neurons and glia, demonstrating that ES-cells can at least partly and for limited time replace lost neurons and astrocytes after stroke. Bone marrow cells are migrating to the lesion site and probably release trophic factors supporting the regeneration of the insulted brain.

Recently we have focused on the in vitro characterisation of different stem cell types and their potential usage for regenerative medicine especially for treatment of neurodegenerative disorders including stroke. In collaboration with colleagues from Hamburg and Giessen we demonstrated a few years ago that embryonic stem cells from mice differentiate into functioning neurons and astrocytes after transplantation into rats with experimental stroke Bühnemann et al., 2006). Further, we characterised in vitro mesenchymal stem cells from bone marrow of rats and human (BMSC). We could demonstrate that serum deprivation leads to the selective propagation of small cells present as a subpopulation of BMSC. These cells are characterized by small size and the expression of the neural  and embryonic stem cell markers nestin and Oct4 (Sauerzweig et al. 2008). The studies were continued in the frame of an BMBF-project (MARS). Currently we are investigating the influence of culture conditions on the expression profile of BMSC. This includes the co-culture of BMSC with cortical primary cultures.

Together with European partners (FP 6 STEMS) we have investigated induced human pluripotent stem cells (iPS-cells) under both in vivo and in vitro studies. After delivery into rats with stroke human cells survived up to 4 weeks and differentiated into cells with typical neuronal morphology and co-expression of ßIII-tubulin and DCX. These results were confirmed by in vitro investigations. By co-cultivation with cortical primary cultures we found that human iPS cells differentiated into DCX positive neurons within 2 days.

ES-cells 4 weeks after transplantation

Fig. 1: mouse ES-cells 4 weeks after transplantation in ischemic rats, many cells express the neuronal marker NeuN


Fig. 2: bone marrow mesenchymal stem cells (red-nestin; green-GFAP)

Role of neutrophil granulocytes and microglia in ischemic tissue damage in the CNS

Principle investigators:  Dr. Monika Riek-Burchardt and Dr. Jens Neumann

The acute cerebrovascular disorder stroke represents the third most frequent cause of death in Western industrial nations. The CNS damage caused by stroke is accompanied by an acute inflammatory reaction. During the early phase of this process it appears to an activation of microglia, resident brain specific immune cells, and to the recruitment of peripheral leucocytes, especially neutrophils and monocytes/macrophages. But, the nature and function of any interactions between microglia and invading immune cells is incompletely understood. Recently, we could identify new neuroprotective mechanisms of the CNS whereby microglia guards neurons by the engulfment of toxic neutrophil granulocytes and direct cell-cell contacts between microglia and neurons (capping) in an in vitro stroke model.

In our current work in the research cluster SFB 824 we investigate the in vivo relevance of these findings and elucidate the underlying cellular and molecular mechanisms, ultimately aiming at the development of novel neuroprotective treatment options. We investigate the post-ischemic changes of microglial morphology and the infiltration of neutrophils into the ischemic penumbra using intracranial live imaging via two-photon microscopy. Until now we found a rapid extravasation of neutrophils after ischemia and dramatic changes of microglia morphology in the first 24 h after experimental stroke. The near future plan is the visualisation of a neuro-immune cross-talk directly within vital tissue.


Visualization of microglia in vivo using intravital 2-Photon microscopy. A time laps movie from the cortex of a CX3CR1-EGFP x Lys EGFP mouse shows green fluorescent microglia with fine ramifications and a green fluorescent neutrophil granulocytes into the blood vessels. To visualize the blood vessels rhodamin labeled dextran (40kDa) was injected intravenously.

Long-term potentiation of synaptic response and its disorder-related disruption

Principle investigators:  Dr. Raik Rönicke and Prof. Klaus Reymann
Long-term potentiation (LTP) of synaptic response is a widely established model for learning and memory at the cellular level. We investigate synaptic plasticity in the hippocampus, a brain region that is involved in forms of spatial and associative learning and that possesses a number of anatomical advantages for such studies. We are mainly interested disease-related disturbances of learning and memory formation, in particular, the Alzheimer's disease (AD) related impairment of synaptic function, which is mediated by oligomeric forms of amyloid-beta. Our findings will help to develop new therapeutic strategies against learning and memory disorders. We showed that:
  • The Na+/H+ exchanger modulates LTP in rat hippocampal slices (Rönicke et al. 2009)
  •  LTP can be impaired by application of oligomeric forms of amyloid-beta (Rönicke et al. 2008)
  •  Inhibition of amyloid-beta aggregation rescues LTP (Müller-Schiffmann et al. 2010)
  •  Activation of the NMDA(NR2B) receptor subtype is critically involved in amyloid-beta mediated LTP disruption (Rönicke et al. 2011)
  •  Transgenic mice, developing amyloid-beta pathology, show hippocampal LTP disruption (Alexandru et al. 2011), as well as multifaceted cortical malfunction (Lison et al. submitted).
At present we deal with the following questions:
  • How does amyloid-beta impair LTP in vitro?
  • How can amyloid-beta-mediated disruption of LTP been rescued?
  • What physiological consequences arise from amyloid-beta pathology in vivo?

LTP of TBA2,1 mice

Fig. 1: At 5 months of age, LTP of TBA2.1 mice, which express the fast aggregating pE3Abeta, is significantly diminished compared with age-matched WT littermates.

Oligomeric A2 significantly reduced LTP in vitro

Fig. 2: Oligomeric Abeta significantly reduced LTP in vitro. The NMDA (NR2B) receptor antagonist ifenprodil did not influence potentiation significantly, but prevented the Abeta effect, when co-applied

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