Division of Pediatric Gastroenterology, Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
FASEB J. 2021 Apr;35(4):e21471. doi: 10.1096/fj.202002421R.
Acute liver failure constitutes a devastating condition that needs novel cell and molecular therapies. To elicit synergisms in cell types of therapeutic interest, we studied hepatocytes and liver sinusoidal endothelial in mice with acetaminophen-induced acute liver failure. The context of regenerative signals was examined by transplants in peritoneal cavity because it possesses considerable capacity and allows soluble signals to enter the systemic circulation. Whereas transplanted hepatocytes and liver sinusoidal endothelial cells engrafted in peritoneal cavity, only the former could rescue mice in liver failure by improving injury outcomes, activating hepatic DNA damage repair, and inducing liver regeneration. The cytokines secreted by donor hepatocytes or liver sinusoidal endothelial cells differed and in hepatocytes from mice undergoing acetaminophen toxicity major cytokines were even rendered deficient (eg, G-CSF, VEGF, and others). Significantly, recapitulating hepatotoxicity-related DNA damage response in cultured cells identified impairments in ATM and JAK/STAT3 intersections since replacing cytokines produced less from injured hepatocytes restored these pathways to avoid acetaminophen hepatotoxicity. Similarly, hepatocyte transplantation in acute liver failure restored ATM and JAK/STAT3 pathways to advance DNA damage/repair and liver regeneration. The unexpected identification of novel hepatic G-CSF receptor expression following injury allowed paradigmatic studies of G-CSF supplementation to confirm the centrality of this paracrine ATM and STAT3 intersection. Remarkably, DNA damage/repair and hepatic regeneration directed by G-CSF concerned rebalancing of regulatory gene networks overseeing inflammation, metabolism, and cell viability. We conclude that healthy donor hepatocytes offer templates for generating specialized cell types to replace metabolic functions and regenerative factors in liver failure.
急性肝衰竭是一种毁灭性的疾病，需要新型的细胞和分子治疗方法。为了在有治疗意义的细胞类型中产生协同作用，我们研究了乙酰氨基酚诱导的急性肝衰竭小鼠的肝细胞和肝窦内皮细胞。通过腹膜腔移植来研究再生信号的背景，因为腹膜腔具有相当大的能力，并允许可溶性信号进入体循环。虽然移植的肝细胞和肝窦内皮细胞在腹膜腔中植入，但只有前者可以通过改善损伤结局、激活肝 DNA 损伤修复和诱导肝再生来挽救肝衰竭小鼠。供体肝细胞或肝窦内皮细胞分泌的细胞因子不同，而且在经历乙酰氨基酚毒性的小鼠的肝细胞中，甚至有主要细胞因子缺失（例如，G-CSF、VEGF 等）。重要的是，在培养的细胞中重现与肝毒性相关的 DNA 损伤反应，确定了 ATM 和 JAK/STAT3 交点的损伤，因为从受损的肝细胞中替换产生较少的细胞因子会恢复这些途径，以避免乙酰氨基酚的肝毒性。同样，在急性肝衰竭中进行肝细胞移植可以恢复 ATM 和 JAK/STAT3 途径，以促进 DNA 损伤/修复和肝再生。损伤后新发现的肝脏 G-CSF 受体表达的意外鉴定，使得 G-CSF 补充的范例研究得以确认这种旁分泌 ATM 和 STAT3 交点的中心性。值得注意的是，G-CSF 指导的 DNA 损伤/修复和肝再生涉及监管基因网络的重新平衡，这些网络负责炎症、代谢和细胞活力的调控。我们得出结论，健康供体肝细胞为产生专门的细胞类型提供了模板，以替代肝衰竭中的代谢功能和再生因子。
