Locating the stem cell niche and tracing hepatocyte lineages in human liver.
We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase-deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic.


CONCLUSIONS
These data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins.
Fellous
Tariq G
TG
Centre for Diabetes and Metabolic Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Islam
Shahriar
S
Tadrous
Paul J
PJ
Elia
George
G
Kocher
Hemant M
HM
Bhattacharya
Satyajit
S
Mears
Lisa
L
Turnbull
Douglas M
DM
Taylor
Robert W
RW
Greaves
Laura C
LC
Chinnery
Patrick F
PF
Taylor
Geoffery
G
McDonald
Stuart A C
SA
Wright
Nicholas A
NA
Alison
Malcolm R
MR
D019070:Cell Lineage; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology*; D055153:Stem Cell Niche / Q000166:cytology*
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV