Cellular recovery after prolonged warm ischaemia of the whole body

David Andrijevic, Zvonimir Vrselja, Taras Lysyy, Shupei Zhang, Mario Skarica, Ana Spajic, David Dellal, Stephanie L. Thorn, Robert B. Duckrow, Shaojie Ma, Phan Q. Duy, Atagun U. Isiktas, Dan Liang, Mingfeng Li, Suel-Kee Kim, Stefano G. Daniele, Khadija Banu, Sudhir Perincheri, Madhav C. Menon, Anita Huttner, Kevin N. Sheth, Kevin T. Gobeske, Gregory T. Tietjen, Hitten P. Zaveri, Stephen R. Latham, Albert J. Sinusas and Nenad Sestan ()
Additional contact information
David Andrijevic: Yale School of Medicine
Zvonimir Vrselja: Yale School of Medicine
Taras Lysyy: Yale School of Medicine
Shupei Zhang: Yale School of Medicine
Mario Skarica: Yale School of Medicine
Ana Spajic: Yale School of Medicine
David Dellal: Yale School of Medicine
Stephanie L. Thorn: Yale School of Medicine
Robert B. Duckrow: Yale University School of Medicine
Shaojie Ma: Yale School of Medicine
Phan Q. Duy: Yale School of Medicine
Atagun U. Isiktas: Yale School of Medicine
Dan Liang: Yale School of Medicine
Mingfeng Li: Yale School of Medicine
Suel-Kee Kim: Yale School of Medicine
Stefano G. Daniele: Yale School of Medicine
Khadija Banu: Yale School of Medicine
Sudhir Perincheri: Yale School of Medicine
Madhav C. Menon: Yale School of Medicine
Anita Huttner: Yale School of Medicine
Kevin N. Sheth: Yale University School of Medicine
Kevin T. Gobeske: Yale University School of Medicine
Gregory T. Tietjen: Yale School of Medicine New Haven
Hitten P. Zaveri: Yale University School of Medicine
Stephen R. Latham: Yale University
Albert J. Sinusas: Yale School of Medicine
Nenad Sestan: Yale School of Medicine

Nature, 2022, vol. 608, issue 7922, 405-412

Abstract: Abstract After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. 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 technology3. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05016-1

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