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Brain Trauma Stroke
Immunoregulatory Neuroprotection of Cerebral Ischaemia by
Haematopoietic Stem and Precursor Cells
Sönke Schwarting
1
and Harald Neumann
2
1. Medical Resident, Department of Neurology, University of Heidelberg;
2. Professor, Neural Regeneration, Institute of Reconstructive Neurobiology, University of Bonn
Abstract
Cerebral ischaemia leads to early immune system activation followed by delayed immunosuppression. Post-ischaemic inflammation
contributes to neurodegeneration. Although experimental approaches using adult stem or precursor cells have repeatedly demonstrated
neuroprotective effects in cerebral ischaemia, the underlying mechanism of cell-mediated neuroprotection is still debated. It was
suggested that stem or precursor cells invade ischaemic brain regions and act locally. However, recent data demonstrate that systemically
transplanted stem or precursor cells have strong immunoregulatory effects leading to reduced post-ischaemic brain tissue inflammation.
This article argues that the systemic balance of the immune system might explain the reduced neurodegeneration observed after stem cell
treatment in cerebral ischaemia. Consequently, systemic immunoregulatory neuroprotection using stem and precursor cells should be
considered an important therapeutic option to prevent post-ischaemic neurodegeneration in cerebral ischaemia.
Keywords
Stroke, cerebral ischaemia, neuroinflammation, neuroimmunology, neuroprotection, neurodegeneration, haematopoietic stem cells,
haematopoietic precursor cells, stem cell therapy
Disclosure: The Neural Regeneration Group at the Institute of Reconstructive Neurobiology of the University of Bonn is supported by the Hertie Foundation, the Walter und
Ilse Rose Foundation, Deutsche Forschungsgemeinschaft (SFB704, KFO177) and the EU (LSHM-CT-2005-018637). The authors have no conflicts of interest to declare.
Received: 16 February 2009 Accepted: 29 June 2009
Correspondence: Harald Neumann, Neural Regeneration, Institute of Reconstructive Neurobiology, University of Bonn and Hertie Foundation, Sigmund-Freud-Str. 25,
53127 Bonn, Germany. E: hneuman1@uni-bonn.de
Evidence-based stroke therapy using the thrombolytic agent Indeed, subsequent studies detected most of the grafted cells primarily
recombinant-tissue plasminogen activator (rt-PA) aims at rapid in secondary immune organs, such as the spleen and lymph nodes.
11
The
recanalisation of the occluded vessel within the acute phase of authors’ experiments confirmed early and numerous detection of
cerebral ischaemia, thereby lacking direct neuroprotective or systemically injected green-fluorescent-protein-positive haematopoietic
neuroregenerative properties to restrict subsequent ischaemic stem cells (HSCs) in the spleen. This was followed by a delayed and
damage.
1
In the search for promising neuroregenerative tools, stem limited cell migration into ischaemic brain parenchyma and significant
cell treatment has come into the spotlight during the last decade of neuroprotection after focal cerebral ischaemia in mice.
12
However, the
experimental stroke research. Since then, various kinds of stem and authors’ data suggest that systemic immunomodulatory mechanisms
progenitor cell from different kinds of tissue have been exploited for are responsible for the substantial neuroprotection observed after stem
their neurorestorative and neuroregenerative properties and value in cell treatment in stroke experiments.
cerebral ischaemia.
2–5
This review re-visits recent studies on post-ischaemic inflammatory
Despite all efforts, none of these studies has convincingly achieved the neurodegeneration, involvement of the peripheral immune system
ultimate goal: stem cell differentiation into neuronal phenotypes and interference by transplantation of stem and precursor cells in
accompanied by functional integration into neuronal networks. cerebral ischaemia.
However, evidence of graft-cell-mediated neuroprotection in stroke has
emerged in many studies.
6–8
Skepticism remained as most of the data Neuroprotection in Ischaemia
failed to convincingly demonstrate in vivo neuronal transdifferentiation. Sudden blockage of the oxygen and glucose supply in cerebral
Consequently, other mechanisms were propagated, such as stimulation ischaemia initiates various cascades of pathophysiological events
of endogenous neurogenesis via neoangiogenesis in peri-infarct terminating in neuronal cell death.
13
Within the ischaemic penumbra
tissues.
9
Surprisingly, neuroprotection following cell treatment after tissue, aggressive processes take place including excessive activation
experimental stroke was observed despite the absence of central of glutamate receptors, accumulation of intracellular calcium cations,
nervous system invasion of exogenous stem cells. Thus, functional recruitment of inflammatory cells and excessive production of free
recovery was suggested to be due to graft cell release of soluble radicals.
14,15
Such secondary autodestructive reactions, which are
mediators that cross the post-ischaemic blood–brain barrier and act on activated over a period from seconds to days after the primary insult,
the lesion site.
10
cause an exacerbation of cell death.
13
42 © TOUCH BRIEFINGS 2009
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