Multimodal decoding of human liver regeneration

Abstract

The liver has a unique ability to regenerate however in the setting of acute liver failure (ALF) this regenerative capacity is often overwhelmed and emergency liver transplantation is the only curative option. To advance our understanding of human liver regeneration and to inform design of pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNAseq)combined with spatial profiling of healthy and ALF explant human livers to generate the first single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation which emerges during human liver regeneration, and a corollary migratory hepatocyte subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Importantly, interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. 4-D intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 expression reduces HGF-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Taken together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation which mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may open up new areas of therapeutic discovery in regenerative medicine.

Liver regeneration requires reciprocal release of tissue vesicles to govern rapid hepatocyte proliferation

“…Our findings, together with others’ findings and despite preliminary, suggest that hepatocytes might sacrifice metabolic activity for safeguarding regenerative expansion, and that hepatocytes are equipped with flexible metabolic machinery able to adapt dynamically to tissue regeneration [31]. It is also noteworthy that our data revealed involvements of the immune, endothelial and stromal cell components in liver regeneration, which are in accordance with the current understanding [3, 10, 32], and that communication between hepatocytes and various cell populations through EVs potentially contributed to liver regeneration. Future research is needed to examine in-depth the multimodal paracrine regulation mechanisms via Hep-EVs that safeguard liver regeneration.…”

Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication

“…Of note, we observed that QC6352 treatment increased the expression of several cytochrome transcripts that are considered markers of hepatocyte function in drug detoxification ( 88 ). We found that CYP3A4 was KDM4 regulated, and has been shown to be enriched in the pericentral region of the human liver, consistent with oxygen-driven liver zonation ( 89 ). Interestingly, in vitro assays have manipulated cytochrome expression to regulate the differentiation of hepatocyte-like cells from induced pluripotent stem cells ( 44 , 46 , 58 ).…”

Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration

“…50 ANXA2 þ hepatocytes increased following APAP injection, peaking at 42 hours in the peri-necrotic region. 50 Surviving hepatocytes adjacent to the necrotic lesions increasingly express CXCR2, which is required for hepatocyte recovery and regeneration after APAP administration. 51 HSCs are activated and proliferate earlier after APAP injection.…”