Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis.
OBJECTIVE
In alcoholic hepatitis (AH), development of targeted therapies is crucial and requires improved knowledge of cellular and molecular drivers in liver dysfunction. The unique opportunity of using explanted livers from patients with AH having undergone salvage liver transplantation allowed to perform more in-depth molecular translational studies.


METHODS
We studied liver explants from patients with AH submitted to salvage transplantation (n=16), from patients with alcoholic cirrhosis without AH (n=12) and fragments of normal livers (n=16). Hepatic cytokine content was quantified. Hepatocyte function and proliferation and the presence of hepatic progenitor cells (HPCs) were evaluated by immunohistochemistry, western blot or quantitative PCR. Mitochondrial morphology was evaluated by electron microscopy.


RESULTS
Livers from patients with AH showed decreased cytokine levels involved in liver regeneration (tumour necrosis factor α and interleukin-6), as well as a virtual absence of markers of hepatocyte proliferation compared with alcoholic cirrhosis and normal livers. Electron microscopy revealed obvious mitochondrial abnormalities in AH hepatocytes. Importantly, livers from patients with AH showed substantial accumulation of HPCs that, unexpectedly, differentiate only into biliary cells. AH livers predominantly express laminin (extracellular matrix protein favouring cholangiocyte differentiation); consequently, HPC expansion is inefficient at yielding mature hepatocytes.


CONCLUSIONS
AH not responding to medical therapy is associated with lack of expression of cytokines involved in liver regeneration and profound mitochondrial damage along with lack of proliferative hepatocytes. Expansion of HPCs is inefficient to yield mature hepatocytes. Manoeuvres aimed at promoting differentiation of HPCs into mature hepatocytes should be tested in AH.
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Laurent
http://orcid.org/0000-0003-3596-5497
L
Dubuquoy
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Alexandre
A
Louvet
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Guillaume
G
Lassailly
CHRU Lille, Service de Chirurgie Digestive et Transplantation, Hôpital Huriez, Lille, France.
Stéphanie
S
Truant
CHRU Lille, Service de Chirurgie Digestive et Transplantation, Hôpital Huriez, Lille, France.
Emmanuel
E
Boleslawski
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Florent
F
Artru
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
François
F
Maggiotto
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Emilie
E
Gantier
CHRU Lille, Service d'Anatomo-Pathologie, Lille, France.
David
D
Buob
CHRU Lille, Service d'Anatomo-Pathologie, Lille, France.
Emmanuelle
E
Leteurtre
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Amélie
A
Cannesson
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Sébastien
S
Dharancy
Department of Gastroenterology and Hepato-pancreatology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Christophe
C
Moreno
CHRU Lille, Service de Chirurgie Digestive et Transplantation, Hôpital Huriez, Lille, France.
François-René
FR
Pruvot
Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
Ramon
R
Bataller
Inserm, UMR995 - LIRIC, Lille, France Univ Lille, UMR995 - LIRIC, Lille, France CHRU Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, Lille, France.
Philippe
P
Mathurin
D002454:Cell Differentiation; D049109:Cell Proliferation; D000074049:Cytokine TWEAK; D004249:DNA Damage; D004272:DNA, Mitochondrial; D006519:Hepatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008928:Mitochondria / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
D000074049:Cytokine TWEAK; D004272:DNA, Mitochondrial; D015850:Interleukin-6; D053552:Keratin-7; D019394:Ki-67 Antigen; D007797:Laminin; D016328:NF-kappa B; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors
ALCOHOLIC LIVER DISEASE; CYTOKERATINS; EXTRACELLULAR MATRIX; HEPATOCYTE; LIVER REGENERATION