Immunoregulatory Neuroprotection of Cerebral Ischaemia by Haematopoietic Stem and Precursor Cells
Immunoregulatory Neuroprotection of Cerebral Ischaemia by Haematopoietic Stem and Precursor Cells
European Neurological Review, 2009;4(2):42-5
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 beconsidered 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 recombinant-tissue plasminogen activator (rt-PA) aims at rapid recanalisation of the occluded vessel within the acute phase of cerebral ischaemia, thereby lacking direct neuroprotective or neuroregenerative properties to restrict subsequent ischaemic damage.1 In the search for promising neuroregenerative tools, stem cell treatment has come into the spotlight during the last decade of experimental stroke research. Since then, various kinds of stem and progenitor cell from different kinds of tissue have been exploited for their neurorestorative and neuroregenerative properties and value in cerebral ischaemia.2–5
Despite all efforts, none of these studies has convincingly achieved the ultimate goal: stem cell differentiation into neuronal phenotypes accompanied by functional integration into neuronal networks.However, evidence of graft-cell-mediated neuroprotection in stroke has emerged in many studies.6–8 Skepticism remained as most of the data failed to convincingly demonstrate in vivo neuronal transdifferentiation. Consequently, other mechanisms were propagated, such as stimulation of endogenous neurogenesis via neoangiogenesis in peri-infarct tissues.9 Surprisingly, neuroprotection following cell treatment after experimental stroke was observed despite the absence of central nervous system invasion of exogenous stem cells. Thus, functional recovery was suggested to be due to graft cell release of soluble mediators that cross the post-ischaemic blood–brain barrier and act on the lesion site.10
Indeed, subsequent studies detected most of the grafted cells primarily in secondary immune organs, such as the spleen and lymph nodes.11 The authors’ experiments confirmed early and numerous detection of systemically injected green-fluorescent-protein-positive haematopoietic stem cells (HSCs) in the spleen. This was followed by a delayed and limited cell migration into ischaemic brain parenchyma and significant neuroprotection after focal cerebral ischaemia in mice.12 However, the authors’ data suggest that systemic immunomodulatory mechanisms are responsible for the substantial neuroprotection observed after stem cell treatment in stroke experiments.
This review re-visits recent studies on post-ischaemic inflammatory neurodegeneration, involvement of the peripheral immune system and interference by transplantation of stem and precursor cells in cerebral ischaemia.
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Stroke, cerebral ischaemia, neuroinflammation, neuroimmunology, europrotection, neurodegeneration, haematopoietic stem cells, haematopoietic precursor cells, stem cell therapy
