Abstract
Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery. To advance its therapeutic usefulness, it is important to understand the mechanisms through which IRE induces cell death and the role of the innate immune system in mediating subsequent regenerative repair. Through intravital imaging of the liver in mice, we show that IRE produces distinctive tissue injury features, including delayed yet robust recruitment of neutrophils, consistent with programmed necrosis. IRE treatment converts the monocyte/macrophage balance from pro-inflammatory to pro-reparative populations, and depletion of neutrophils inhibits this conversion. Reduced generation of pro-reparative Ly6CloF4/80hi macrophages correlates with lower numbers of SOX9+ hepatic progenitor cells in areas of macrophage clusters within the IRE injury zone. Our findings suggest that neutrophils play an important role in promoting the development of pro-reparative Ly6Clo monocytes/macrophages at the site of IRE injury, thus establishing conditions of regenerative repair.
Highlights
Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery
PECAM-1 staining of sinusoidal endothelium remained bright and contiguous after IRE treatment, and neutrophils coursed through patent PECAM-1+ sinusoids deep within the IRE injury zone
Whereas in thermal injury neutrophil numbers rapidly declined by 24 h25, neutrophils persisted at the site of IRE injury much longer and remained a major myeloid population for the first 3 days
Summary
Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery. To advance its therapeutic usefulness, it is important to understand the mechanisms through which IRE induces cell death and the role of the innate immune system in mediating subsequent regenerative repair. The mode of cell killing is nonthermal; the surrounding extracellular matrix is not denatured and remains intact This feature is likely important for the ability of IRE-ablated tissues, including normal s kin2, intestine[3], and liver[4,5,6], to regenerate with minimal formation of scar. Because of these non-thermal and extracellular matrix-preserving properties, IRE has become a valuable clinical modality to ablate tumors near critical structures, such as blood vessels, ducts, and nerves[7,8,9,10]. Inflammation is advantageous for IRE-mediated in vivo organ decellularization to facilitate engraftment of stem cell-derived cells for regenerative s urgery[13]
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