High-Mobility Group Box 1: An Amplifier of Stem and Progenitor Cell Activity After Stroke
Stroke induces a highly complex web of pathophysiology that usually leads to serious long-term disability. Molecules from the damage-associated molecular pattern (DAMP) family immediately increase after stroke. DAMPs are known to cause massive inflammati
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Abstract Stroke induces a highly complex web of pathophysiology that usually leads to serious long-term disability. Molecules from the damage-associated molecular pattern (DAMP) family immediately increase after stroke. DAMPs are known to cause massive inflammation and brain damage. Thus, they may be targets for neuroprotection. However, emerging data now suggest that DAMPs may not always be detrimental. The high-mobility group box1 (HMGB1) protein is discussed as an example of this idea. During the acute phase after stroke, HMGB1 amplifies neuroinflammation. But during the brain remodeling phase of stroke recovery, HMGB1 can mediate beneficial plasticity and enhance stem and progenitor cell recruitment, proliferation, and differentiation within damaged brain. These emerging findings support the hypothesis that HMGB1 might be an important molecule for regulating stem and progenitor cell therapies in stroke patients. Keywords Stroke • HMGB1 • Inflammation • Stem cells • Brain remodeling
Introduction Stroke is the second leading cause of death worldwide and is a very challenging clinical and scientific problem. Therapeutic options for stroke patients are still limited. For example, in ischemic stroke, acute treatments are limited to reperfusion with tissue plasminogen activator or mechanical catheter devices [56]. Many targets and drugs seem exciting at the level of molecular, cellular and animal models. But it has K. Hayakawa, L-D.D. Pham, K. Arai, and E.H. Lo (*) Neuroprotection Research Laboratory, Harvard Medical School, Massachusetts General Hospital East, 149-2401, Charlestown, MA 02129, USA e-mail: [email protected]
been exceedingly difficult to translate these pre-clinical ideas into clinical efficacy [47, 57]. The biological processes after cerebral ischemia are complicated. Energy deprivation and excitotoxicity are the main causes of the initial tissue damage. In response to initial injury, damage-associated molecular patterns (DAMPs) released into the extracellular micro-environment amplify the secondary processes of blood–brain barrier (BBB) disruption and post-ischemic inflammation [50]. Nevertheless, damaged brain can be surprisingly plastic, and neurogenesis, angiogenesis, and dendritic and axonal remodeling may all provide substrates for compensation and repair. A paradigm shift from symptomatic control for secondary prevention against stroke to amplifying brain regenerative mechanisms may provide a therapeutic opportunity to improve long-term disability after stroke [57]. As a potential concept in brain regenerative medicine, cell-based therapies may become an exciting new frontier for promoting endogenous brain plasticity after stroke [10, 44]. Accumulating evidence suggests that the recruitment of endogenous stem and progenitor cells or exogenously transplanted cells may support brain remodeling following stroke. Intriguingly, high-mobility group box 1 (HMGB1, a member of the DAMP family) can act as a key regulator of stem cell migration, proliferation and differentiation. In this minireview
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