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Thrombin\u2010preconditioned mesenchymal stem cells (MSCs) exert neuroprotective effects by enriching cargo contents and boosting exosome biogenesis, thus showing promise as a new therapeutic strategy for HIE. This study was conducted to evaluate the tissue distribution and potential toxicity of thrombin\u2010preconditioned human Wharton's jelly\u2010derived mesenchymal stem cells (th\u2010hWJMSCs) in animal models before the initiation of clinical trials. We investigated the biodistribution, tumorigenicity and general toxicity of th\u2010hWJMSCs. MSCs were administered the maximum feasible dose (1\u00a0\u00d7\u00a010<jats:sup>5<\/jats:sup> cells\/10\u00a0\u00b5L\/head) once, or at lower doses into the cerebral ventricle. To support the clinical use of th\u2010hWJMSCs for treating brain injury, preclinical safety studies were conducted in newborn Sprague\u2010Dawley rats and BALB\/c nude mice. 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