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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.

No MeSH data available.


Lineage tracing of Mfsd2a+ hepatocytes after single injection of CCl4.(a) Schematic figure showing strategy for tamoxifen induction (Tam), CCl4 treatment and time points for tissue analysis. (b) Haematoxylin and eosin staining of liver sections collected at day 2 or week 2 after after single CCl4 injection. C, central vein; P, portal vein. Scale bars, 100 μm. (c,d) Immunostaining for RFP, CK19 and HNF4a on liver sections collected at day 2 (c) and week 2 (d) after single CCl4 injection. Scale bars, 100 μm. Each image is a representative of four individual samples.
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f7: Lineage tracing of Mfsd2a+ hepatocytes after single injection of CCl4.(a) Schematic figure showing strategy for tamoxifen induction (Tam), CCl4 treatment and time points for tissue analysis. (b) Haematoxylin and eosin staining of liver sections collected at day 2 or week 2 after after single CCl4 injection. C, central vein; P, portal vein. Scale bars, 100 μm. (c,d) Immunostaining for RFP, CK19 and HNF4a on liver sections collected at day 2 (c) and week 2 (d) after single CCl4 injection. Scale bars, 100 μm. Each image is a representative of four individual samples.

Mentions: We next asked whether a single dose of CCl4 injection led to expansion of Mfsd2a+ PP hepatocytes after 2 weeks' recovery. Mfsd2a-CreER;Rosa26-RFP mice were treated with tamoxifen at 6 weeks old and injected with CCl4 at 8 weeks old (Fig. 7a). By examining liver samples using haematoxylin and eosin staining and immunostaining, we found severe liver injury at day 2 when almost no hepatocyte could be detected at the PC region (Fig. 7b,c). Haematoxylin and eosin staining and immunostaining for HNF4a showed that the liver had recovered 2 weeks after CCl4 injection. The percentage of RFP+ hepatocytes increased at week 2 compared with day 2 after injury (Fig. 7d). Unlike chronic injury with multiple CCl4 injections (Fig. 6d), Mfsd2a+ hepatocytes did not expand to replace the entire liver lobule (Fig. 7d). Therefore, our data suggested that complete hepatic zonation replacement happened only after chronic but not acute injury following CCl4 treatment. Altogether, our results demonstrated that the Mfsd2a-derived PP hepatocyte population completely replaced the PC hepatocyte population in the entire liver during CCl4-induced chronic injury (Fig. 6f).


Mfsd2a + hepatocytes repopulate the liver during injury and regeneration
Lineage tracing of Mfsd2a+ hepatocytes after single injection of CCl4.(a) Schematic figure showing strategy for tamoxifen induction (Tam), CCl4 treatment and time points for tissue analysis. (b) Haematoxylin and eosin staining of liver sections collected at day 2 or week 2 after after single CCl4 injection. C, central vein; P, portal vein. Scale bars, 100 μm. (c,d) Immunostaining for RFP, CK19 and HNF4a on liver sections collected at day 2 (c) and week 2 (d) after single CCl4 injection. Scale bars, 100 μm. Each image is a representative of four individual samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Lineage tracing of Mfsd2a+ hepatocytes after single injection of CCl4.(a) Schematic figure showing strategy for tamoxifen induction (Tam), CCl4 treatment and time points for tissue analysis. (b) Haematoxylin and eosin staining of liver sections collected at day 2 or week 2 after after single CCl4 injection. C, central vein; P, portal vein. Scale bars, 100 μm. (c,d) Immunostaining for RFP, CK19 and HNF4a on liver sections collected at day 2 (c) and week 2 (d) after single CCl4 injection. Scale bars, 100 μm. Each image is a representative of four individual samples.
Mentions: We next asked whether a single dose of CCl4 injection led to expansion of Mfsd2a+ PP hepatocytes after 2 weeks' recovery. Mfsd2a-CreER;Rosa26-RFP mice were treated with tamoxifen at 6 weeks old and injected with CCl4 at 8 weeks old (Fig. 7a). By examining liver samples using haematoxylin and eosin staining and immunostaining, we found severe liver injury at day 2 when almost no hepatocyte could be detected at the PC region (Fig. 7b,c). Haematoxylin and eosin staining and immunostaining for HNF4a showed that the liver had recovered 2 weeks after CCl4 injection. The percentage of RFP+ hepatocytes increased at week 2 compared with day 2 after injury (Fig. 7d). Unlike chronic injury with multiple CCl4 injections (Fig. 6d), Mfsd2a+ hepatocytes did not expand to replace the entire liver lobule (Fig. 7d). Therefore, our data suggested that complete hepatic zonation replacement happened only after chronic but not acute injury following CCl4 treatment. Altogether, our results demonstrated that the Mfsd2a-derived PP hepatocyte population completely replaced the PC hepatocyte population in the entire liver during CCl4-induced chronic injury (Fig. 6f).

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.