Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine.
Genetically marked hepatocytes from dipeptidyl peptidase (DPP) IV+ Fischer 344 rats were transplanted into the liver of DPPIV- mutant Fischer 344 rats after a combined treatment with retrorsine, a pyrrolizidine alkaloid that blocks the hepatocyte cell cycle, and two-thirds partial hepatectomy. In female rats, clusters of proliferated DPPIV+ hepatocytes containing 20 to 50 cells/cluster, mostly derived from single transplanted cells, were evident at 2 weeks, increasing in size to hundreds of cells per cluster at 1 month and 1000 to several thousand cells per cluster at 2 months, representing 40 to 60% of total hepatocyte mass. This level of hepatocyte replacement remained constant for up to 1 year, the duration of experiments conducted. In male rats, liver replacement occurred more rapidly and was more extensive, with transplanted hepatocytes representing 10 to 15% of hepatocyte mass at 2 weeks, 40 to 50% at 1 month, 90 to 95% at 2 months, 98% at 4 months, and 99% at 9 months. Transplanted hepatocytes were integrated into the parenchymal plates, exhibited unique hepatic biochemical functions, and fully reconstituted a normal hepatic lobular structure. The extensive proliferation of transplanted cells in this setting of persistent inhibition of resident hepatocytes represents a new general model to study basic aspects of liver repopulation with potential applications in chronic liver disease and ex vivo gene therapy.
Laconi
E
E
Istituto di Patologia Sperimentale, Ospedale Oncologico A Businco, University of Cagliari, Italy.
Oren
R
R
Mukhopadhyay
D K
DK
Hurston
E
E
Laconi
S
S
Pani
P
P
Dabeva
M D
MD
Shafritz
D A
DA
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D017690:Cell Transplantation / Q000379:methods*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005260:Female; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006498:Hepatectomy; D007633:Keratins / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D012709:Serum Albumin / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
D011763:Pyrrolizidine Alkaloids; D012709:Serum Albumin; D019298:Glucose-6-Phosphate; D007633:Keratins; D006003:Glycogen; D018819:Dipeptidyl Peptidase 4; D000251:Adenosine Triphosphatases; C003300:retrorsine