The double-edged sword of transforming growth factor β 1: a systematic review of pre-clinical stroke models

Stroke is a leading cause of death, with those that survive often suffering significant disability. Strokes are classified as ischemic, occlusion of a blood vessel leading to reduction in cerebral blood flow, or hemorrhagic, the rupture of a vessel causing bleeding into the brain. Transforming growth factor beta 1 (TGF-β1), a pleiotropic cytokine, has been investigated in stroke due to its wide-ranging effects on proliferation, extracellular matrix deposition and inflammation. This systematic review examined the role of TGF-β1 in pre-clinical studies of both ischemic and hemorrhagic stroke. A search was performed across PubMed, Web of Science and Scopus, including English-language animal studies which examined TGF-β1 signaling as an outcome or intervention. 89 studies were ultimately included: 68 ischemic and 21 hemorrhagic stroke. Studies were assessed for bias following the SYRCLE guidelines for pre-clinical studies, followed by extraction of the methodology and the role of TGF-β1. Compliance with SYRCLE guidelines was found to be low and the methodological approaches for creating stroke models were variable. A range of interventions were shown to modify TGF-β1 expression or signaling, with exogenous TGF-β1 improving outcomes in all included ischemic stroke studies. TGF-β1 was found to play a protective role in 76% of ischemic stroke studies whereas it was only protective in 33% of hemorrhagic stroke studies, with likely involvement in fibrosis development in the latter. Our findings suggest a marked difference in the function of TGF-β1 between these types of stroke, and it is hypothesized that blood cytotoxicity following hemorrhagic stroke may generate a more sustained expression of TGF-β1 than seen in ischemic stroke. This may lead to TGF-β1 mediated fibrosis and post-hemorrhagic hydrocephalus, as opposed to the neuroprotective role played by the same molecule following ischemic stroke. These findings highlight the possible clinical utility of exogenous TGF-β1 therapies after ischemic stroke, and TGF-β1 inhibitors after hemorrhagic stroke, to reduce morbidity and disability caused by these events.