Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Department of Surgery, Yale School of Medicine New Haven, New Haven, CT, USA.
Nature. 2022 Aug;608(7922):405-412. doi: 10.1038/s41586-022-05016-1. Epub 2022 Aug 3.
After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.
在血流停止或类似的缺血暴露后，有害的分子级联反应在哺乳动物细胞中开始，最终导致细胞死亡。然而，通过有针对性的干预，这些过程可以被减轻或逆转，即使在死后几分钟或几小时，正如使用 BrainEx 技术在离体猪脑中所报道的那样。迄今为止，将单一器官干预转化为完整的全身应用仍然受到循环和多系统生理挑战的阻碍。在这里，我们描述了 OrganEx，这是对 BrainEx 体外搏动灌注系统和细胞保护灌注液的一种适应，用于猪的全身设置。在 1 小时的温热缺血后，OrganEx 的应用保持了组织的完整性，减少了细胞死亡，并在多个重要器官中恢复了选定的分子和细胞过程。相应地，单细胞转录组分析揭示了特定于器官和细胞类型的基因表达模式，这些模式反映了特定的分子和细胞修复过程。我们的分析包括在定义的缺血间隔和灌注干预期间跨越多个器官的细胞类型特异性变化的综合资源，它揭示了在大型哺乳动物中长时间全身温热缺血后细胞恢复的潜在作用被低估。
