Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver

Abstract

The adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cellcell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand-receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver..

The influence of tissue spatial geometry and functional organisation on liver regeneration

“…In addition, the increased proliferation capacity of midlobular/zone 2 hepatocytes may be a way to preserve liver metabolic functions, which are exerted predominantly by hepatocytes in zone 1 and 3. Supporting this, i) single-cell RNA-sequencing showed that periportal/zone 1 and pericentral/zone 3 hepatocytes maintain their metabolic competence, while midlobular/zone 2 hepatocytes proliferate after partial hepatectomy [20]; ii) ATAC-sequencing combined with RNA-sequencing showed that, after partial hepatectomy, a subset of hepatocytes retain chromatin accessibility and expression of genes involved in metabolic functions [19]. Together, this suggests that the peculiar spatial organisation allows the liver to preserve its vital metabolic functions in response to both tissue resection and toxic damage.…”

“…This gradient of proliferation ensures restoration of the tissue mass while maintaining liver functionality, since proliferation is associated with reduced expression of functional hepatocyte genes [4]. Proliferation is also accompanied by the transient re-acquisition of chromatin and transcriptional profiles of foetal progenitors [19] and early postnatal hepatocytes [20]. This is consistent with the fact that adult hepatocytes can de-differentiate into bipotent liver progenitors after toxic damage [21][22][23], as they are capable to give rise to both hepatocytes and cholangiocytes, resembling the liver epithelial embryonic progenitors, the hepatoblasts [2,3,24].…”

“…Are all hepatocytes equally competent to proliferate and regenerate the liver? Recent findings highlight midlobular/zone 2 hepatocytes as the most proliferative hepatocyte population [20,25,31,32]. Fate-mapping of 14 different hepatocyte populations in the mouse liver revealed that midlobular/zone 2 hepatocytes are the main proliferative hepatocyte population in homeostasis [31].…”

“…Fate-mapping of 14 different hepatocyte populations in the mouse liver revealed that midlobular/zone 2 hepatocytes are the main proliferative hepatocyte population in homeostasis [31]. EdU labelling showed that midlobular/zone 2 hepatocytes exhibit higher proliferation potential in response to partial hepatectomy [20]. Midlobular/zone 2 hepatocytes also contribute to liver regeneration both after periportal injury induced by the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) diet, which damages zone 1 hepatocytes, and pericentral injury induced by Carbon tetrachloride (CCl4), which damages zone 3 hepatocytes [31].…”

Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

“…8C). Instead, a decrease in phosphorylated eIF2α was noted in 4-week acSRSF1 HKO and 10-day SRSF1 HKO hepatocytes, which likely reflects regeneration-associated surge in protein synthesis (54,55).…”