To The Editor:

The zonation of liver functions across the hepatic acinus from the periportal region (zone 1) to the pericentral region (zone 3) is marked by patterns of gene expression, enzyme activity, and redox state.1, 2 The hepatic lineage starts within the stem cell compartment, the canals of Hering located periportally, progresses through the midacinar region, and terminates with mature polyploid hepatocytes in the pericentral zone.3 Clues to the mechanisms governing the maturational process and the functional differentiation across the hepatic lobule are highlighted in the recent discovery of a metabolic pathway underlying the control of embryonic stem cell (ESC) fate by Yanes et al.4 These authors found that experimentally maintained high levels of unsaturated molecules perpetuatd ESC pluripotency, whereas a downstream increase of oxidized metabolites and pro-oxidative substrates promoted differentiation, highlighting the metabolome relevance on stem cell biology. The higher activity of redox enzymes found in the pericentral zone, and the metabolic adaptation to the pericentral lower oxygen concentration related to increased NADH/NAD and NADPH/NADP ratios,1, 2 could be in tight connection with a gradient of molecular saturation through the hepatic lobule, being the highly unsaturated molecules predominant in the periportal zone.

The human hepatic stem cell differentiation and maturational lineage organization could be regulated and maintained by the gradient of saturation of small molecules (oxidized and polyunsaturated) along the zones of the acinus, depending primarily on an oxygen gradient metabolic adaptation. Dezso et al.5 have proposed a model of progenitor cell-driven liver regenerative growth. Applying the 2-acetylaminofluorene/partial hepatectomy experimental model in the rat, they discovered how the regeneration is initiated by proliferation of so-called “oval cells” in the periportal region, resulting in the formation of a seemingly random collection of small hepatocytes called foci. Interestingly, the polarized lobular vasculature architecture and the hepatic zonation were preserved in this model, and the foci can easily remodel to reconstitute a normal lobular structure. These results suggest that the preservation of the normal vasculature organization as well as the oxygen gradient along the acinus zones could drive the refolding of the foci and the entrance of the small hepatocytes in the lineage by sustaining the metabolites saturation gradient. In conclusion, the effect of metabolome on stem cell fate could be a pivotal phenomena regulating the hepatic lineage in physiologic conditions and during liver regeneration, and a candidate mechanism responsible for the progressive failure of cirrhotic liver.


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  • 1
    Gaudio E, Onori P, Franchitto A, Sferra R, Riggio O. Liver metabolic zonation and hepatic microcirculation in carbon tetrachloride-induced experimental cirrhosis. Dig Dis Sci 1997; 42: 167177.
  • 2
    Dicker E, Cederbaum AI. Increased oxidation of dimethylnitrosamine in pericentral microsomes after pyrazole induction of cytochrome P-4502E1. Alcohol Clin Exp Res 1991; 15: 10721076.
  • 3
    Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E, Alpini G, et al. Human hepatic stem cell and maturational liver lineage biology. HEPATOLOGY 2011; 53: 10351045.
  • 4
    Yanes O, Clark J, Wong DM, Patti GJ, Sanchez-Ruiz A, Benton HP, et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat Chem Biol 2010; 6: 411417.
  • 5
    Dezsõ K, Papp V, Bugyik E, Hegyesi H, Safrany G, Bodor C, et al. Structural analysis of oval cell mediated liver regeneration in rats. HEPATOLOGY 2012; 56: 14571467.

Vincenzo Cardinale M.D.*, Guido Carpino M.D.† ‡, Alfredo Cantafora M.D.*, Lola M. Reid M.D.§, Eugenio Gaudio M.D.†, Domenico Alvaro M.D.* ¶, * Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza University of Rome, Rome, Italy, † Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy, ‡ Department of Health Sciences, University of Rome “Foro Italico”, Rome, Italy, § Department of Cell and Molecular Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, ¶ Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy.