Future of Animal Modeling for Poststroke Tissue Repair
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CitationModo, MM. Jolkkonen, J. Zille, M. Boltze, J. (2018). Future of Animal Modeling for Poststroke Tissue Repair. STROKE, 49 (5) , 1099-1106. 10.1161/STROKEAHA.117.018293.
Numerous preclinical animal studies have shown beneficial effects of cell therapies after stroke, including reduction of functional deficits and lesion size. Early stage clinical studies currently aim to confirm this therapeutic potential. Despite the progress in translating cell therapy for stroke, true cell replacement and stem cell-based tissue regrowth have not been achieved yet. Multimodal regeneration improving effects, such as immunomodulation or paracrine growth factor support, are considered the primary mechanisms of action in cell therapies.1 This is not surprising for systemically administered adult progenitor or mixed populations, which typically do not enter brain tissue. However, even brain tissue-derived cells that, in principle, have the ability to give rise to neurons and glia are thought to exert their therapeutic benefits mainly via multimodal regeneration improving effects.2 Current clinical trials are designed to reflect this supportive role of cell therapy rather than tissue reconstruction.3
Our increasing understanding of brain development on the one hand and poststroke pathophysiology on the other illustrate the challenges in true tissue restoration. First, tissue replacement requires a perfect synchronization between participating cells and the host tissue in spatial, temporal, and functional dimensions.1 Second, anatomic cues being decisive for brain tissue growth during embryo/fetogenesis rapidly decline in postnatal brain maturation.4 Third, major brain lesions cause a hostile local environment that detrimentally impacts graft survival and integration. Fourth, restoring brain tissue requires an adequate blood supply, posing a major challenge in larger lesions and bigger brains.5 Fifth, lack of adequate functional interaction between host tissue and the graft leads to tissue restoration failure.6
To go beyond multimodal regeneration improving effects, a careful orchestration of therapeutic approaches relying on and promoting endogenous (eg, neurogenesis-based) or exogenous (eg, stem cell transplantation-based) tissue restoration need to be established. Selection of appropriate, restoration-permissive target lesions will also be required to enhance chances for successful tissue regeneration. Herein, we propose a 4-component in vivo research strategy with the potential to foster tissue repair and replacement in stroke.