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Mfsd2a + hepatocytes repopulate the liver during injury and regeneration

View Article: PubMed Central - PubMed

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.

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Reduction of pre-labelled PP hepatocytes after injury induced by BDL.(a) Schematic figure showing strategies for PP hepatocytes labelling and injury model induced by BDL. (b) Whole-mount bright view of sham and BDL livers. Scale bars, 2 mm. (c) Sirius red staining of liver sections. Scale bars, 200 μm. (d) Whole-mount fluorescence view of sham and BDL livers. Inserts are bright-field images of the same liver. Scale bars, 500 μm. (e) Immunostaining for RFP, CK19 and HNF4a on sham or BDL liver sections. Boxed regions are magnified in lower panels. Insertions indicate the quantification of the percentage of RFP+ hepatocytes in sham or BDL livers. n=4. Error bars are s.e.m. of the mean. Scale bars, 500 μm. Each image is a representative of four individual samples.
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f10: Reduction of pre-labelled PP hepatocytes after injury induced by BDL.(a) Schematic figure showing strategies for PP hepatocytes labelling and injury model induced by BDL. (b) Whole-mount bright view of sham and BDL livers. Scale bars, 2 mm. (c) Sirius red staining of liver sections. Scale bars, 200 μm. (d) Whole-mount fluorescence view of sham and BDL livers. Inserts are bright-field images of the same liver. Scale bars, 500 μm. (e) Immunostaining for RFP, CK19 and HNF4a on sham or BDL liver sections. Boxed regions are magnified in lower panels. Insertions indicate the quantification of the percentage of RFP+ hepatocytes in sham or BDL livers. n=4. Error bars are s.e.m. of the mean. Scale bars, 500 μm. Each image is a representative of four individual samples.

Mentions: In addition to the two-third PH and chronic liver injury models, we also employed the biliary injury model via bile duct ligation (BDL), to study the cellular dynamics of hepatocyte repopulation during cholestatic injures (Fig. 10a). Whole-mount view of liver and Sirius red staining of liver sections confirmed that BDL injury led to severe liver jaundice and excessive fibrosis (Fig. 10b,c). Immunostaining for the ductal cell markers CK19, EPCAM and A6 showed strong ductal reaction in BDL injury (Supplementary Fig. 14). We then induced labelling of Mfsd2a+ PP hepatocytes 2 weeks before injury by tamoxifen injection into Mfsd2a-CreER;Rosa26-RFP mice. Lineage tracing of Mfsd2a+ PP hepatocytes in cholestatic liver showed a significant reduction in pre-labelled PP hepatocytes after BDL injury, with only two or three layers of RFP+ hepatocytes remaining in the PP regions compared with that of the sham-operated littermate controls within the same time window (%RFP+ hepatocytes: 31.89±2.62% versus 7.14±0.35%, respectively, n=4; Fig. 10d,e). It is likely to be that PP hepatocytes were prone to injury induced by bile duct obstruction and replaced by non-labelled hepatocytes such as PC hepatocytes during cholestasis.


Mfsd2a + hepatocytes repopulate the liver during injury and regeneration
Reduction of pre-labelled PP hepatocytes after injury induced by BDL.(a) Schematic figure showing strategies for PP hepatocytes labelling and injury model induced by BDL. (b) Whole-mount bright view of sham and BDL livers. Scale bars, 2 mm. (c) Sirius red staining of liver sections. Scale bars, 200 μm. (d) Whole-mount fluorescence view of sham and BDL livers. Inserts are bright-field images of the same liver. Scale bars, 500 μm. (e) Immunostaining for RFP, CK19 and HNF4a on sham or BDL liver sections. Boxed regions are magnified in lower panels. Insertions indicate the quantification of the percentage of RFP+ hepatocytes in sham or BDL livers. n=4. Error bars are s.e.m. of the mean. Scale bars, 500 μm. Each image is a representative of four individual samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5120209&req=5

f10: Reduction of pre-labelled PP hepatocytes after injury induced by BDL.(a) Schematic figure showing strategies for PP hepatocytes labelling and injury model induced by BDL. (b) Whole-mount bright view of sham and BDL livers. Scale bars, 2 mm. (c) Sirius red staining of liver sections. Scale bars, 200 μm. (d) Whole-mount fluorescence view of sham and BDL livers. Inserts are bright-field images of the same liver. Scale bars, 500 μm. (e) Immunostaining for RFP, CK19 and HNF4a on sham or BDL liver sections. Boxed regions are magnified in lower panels. Insertions indicate the quantification of the percentage of RFP+ hepatocytes in sham or BDL livers. n=4. Error bars are s.e.m. of the mean. Scale bars, 500 μm. Each image is a representative of four individual samples.
Mentions: In addition to the two-third PH and chronic liver injury models, we also employed the biliary injury model via bile duct ligation (BDL), to study the cellular dynamics of hepatocyte repopulation during cholestatic injures (Fig. 10a). Whole-mount view of liver and Sirius red staining of liver sections confirmed that BDL injury led to severe liver jaundice and excessive fibrosis (Fig. 10b,c). Immunostaining for the ductal cell markers CK19, EPCAM and A6 showed strong ductal reaction in BDL injury (Supplementary Fig. 14). We then induced labelling of Mfsd2a+ PP hepatocytes 2 weeks before injury by tamoxifen injection into Mfsd2a-CreER;Rosa26-RFP mice. Lineage tracing of Mfsd2a+ PP hepatocytes in cholestatic liver showed a significant reduction in pre-labelled PP hepatocytes after BDL injury, with only two or three layers of RFP+ hepatocytes remaining in the PP regions compared with that of the sham-operated littermate controls within the same time window (%RFP+ hepatocytes: 31.89±2.62% versus 7.14±0.35%, respectively, n=4; Fig. 10d,e). It is likely to be that PP hepatocytes were prone to injury induced by bile duct obstruction and replaced by non-labelled hepatocytes such as PC hepatocytes during cholestasis.

View Article: PubMed Central - PubMed

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.

No MeSH data available.