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Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration.

ABSTRACT: Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation: the periportal and pericentral hepatocytes. During liver injury and regeneration, the cellular dynamics of these two distinct populations remain largely elusive. Here we show that major facilitator super family domain containing 2a (Mfsd2a), previously known to maintain blood-brain barrier function, is a periportal zonation marker. By genetic lineage tracing of Mfsd2a⁺ periportal hepatocytes, we show that Mfsd2a⁺ population decreases during liver homeostasis. Nevertheless, liver regeneration induced by partial hepatectomy significantly stimulates expansion of the Mfsd2a⁺ periportal hepatocytes. Similarly, during chronic liver injury, the Mfsd2a⁺ hepatocyte population expands and completely replaces the pericentral hepatocyte population throughout the whole liver. After injury recovery, the adult liver re-establishes the metabolic zonation by reprogramming the Mfsd2a⁺-derived hepatocytes into pericentral hepatocytes. The evidence of entire zonation replacement during injury increases our understanding of liver biology and disease.

SUBMITTER: Pu W

PROVIDER: S-EPMC5120209 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration.

Pu Wenjuan W Zhang Hui H Huang Xiuzhen X Tian Xueying X He Lingjuan L Wang Yue Y Zhang Libo L Liu Qiaozhen Q Li Yan Y Li Yi Y Zhao Huan H Liu Kuo K Lu Jie J Zhou Yingqun Y Huang Pengyu P Nie Yu Y Yan Yan Y Hui Lijian L Lui Kathy O KO Zhou Bin B

Nature communications 20161118

Hepatocytes are functionally heterogeneous and are divided into two distinct populations based on their metabolic zonation: the periportal and pericentral hepatocytes. During liver injury and regeneration, the cellular dynamics of these two distinct populations remain largely elusive. Here we show that major facilitator super family domain containing 2a (Mfsd2a), previously known to maintain blood-brain barrier function, is a periportal zonation marker. By genetic lineage tracing of Mfsd2a<sup>+ ...[more]

PMID: 27857132

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Project description:Background & aimsLiver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration.MethodsHepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice.ResultsPrecision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice.ConclusionsOur data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming.Impact and implicationsBy using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.

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Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration.

Publications

Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration.

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