Assistant Professor UCLA Los Angeles, California, United States
Abstract Text: Ischemia-reperfusion injury (IRI) is a significant clinical concern for recipients of liver transplantation, yet there are still no diagnostic or therapeutic strategies available to alleviate its significant influence on both short and long term allograft and patient survival. Myeloid cells are key players in the sustained tissue inflammation and damage associated with IRI, but mechanisms regulating these activities are unknown. Thus, there is a fundamental need for understanding the molecular pathways associated with myeloid cells present in either IRI- or IRI+ recipients of liver transplants. RNA-seq was performed on 80 longitudinal pre- and post-reperfusion biopsies from 40 human liver transplant recipients (23 IRI+, 17 IRI-). To further characterize myeloid involvement, we used transcriptional profiling and computational approaches to identify specific gene co-expression network modules which correlated with numbers of LYSO+ myeloid cells, MPO+ neutrophils and CD68+ monocytes/macrophages as determined by immunohistochemistry on sequential sections from the same patient biopsies. The global molecular map generated by this unique computational approach revealed markers of early myeloid activation in pre-reperfusion samples of IRI+ recipients coupled with subsequent lymphocyte activation post-reperfusion, which identified transcriptional programs associated with the transition to adaptive immunity. IRI- recipients had a less inflammatory profile pre- and post-reperfusion than IRI+ recipients, with pre-reperfusion samples dominated by myeloid genes related to a response to injury, followed by regeneration or repair signaling post-reperfusion. Strategies to therapeutically target these myeloid-specific genes and signaling pathways, as well as improve donor-recipient matching are urgently needed to limit IRI in the clinical setting of liver transplantation.
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