[2] Liver transplantation CFTR activator is the only effective therapeutic option for these patients.[3] Because of a shortage of donor organs[4] and a dramatic increase in the mortality rate of patients on the liver transplant waiting list during the past decade,[5] an alternative strategy to restore liver mass before the endstage would represent a major clinical advance. Progressive hepatic fibrosis as a wound-healing
response to chronic liver injury leads to accumulation of collagen surrounding liver nodules and further replacement of injured parenchyma by scar tissue, resulting in impaired hepatocyte function.[2, 6] Hepatic stellate cells are the main contributors to the pathogenesis of liver fibrosis.[7, 8] Therefore, these cells have represented the primary target to reduce or reverse fibrosis by
developing specific antifibrotic strategies.[9, 10] At present, however, therapeutic options in humans are quite limited.[7, 11] Hepatic cell therapy could be an alternative strategy to generate new functional liver parenchyma in the cirrhotic liver. Stem/progenitor cells—characterized by their high proliferative capacity, ability to differentiate into different lineages, and ability to reconstitute tissue mass[12]—can be isolated from developing or adult liver, as well as from extrahepatic tissues, and can be transplanted into normal or preconditioned BAY 80-6946 recipient liver.[13-17] To date, rat fetal liver stem/progenitor cells (FLSPCs) exhibit the most favorable characteristics for effective liver repopulation by cells transplanted into the (near-)normal liver.[13, 17-21] Liver
repopulation by FLSPCs under nonselective conditions requires only partial hepatectomy (PH).[13, 19] This cell type, therefore, may represent an excellent resource for restoring hepatocyte mass in a diseased liver environment. In the present study, tetracosactide we transplanted FLSPCs and demonstrated that epithelial stem/progenitor cells can engraft, proliferate, and differentiate into hepatocytes in the recipient liver with advanced fibrosis/cirrhosis. Surprisingly, transplantation of FLSPCs leads to considerable liver repopulation without the need for PH and reduces active fibrogenesis and net fibrosis. In comparison, mature hepatocytes also repopulate the thioacetamide (TAA)-induced fibrotic liver, but to a lesser extent than FLSPCs. Our model system, therefore, represents an excellent tool to study novel cell transplantation strategies and to elucidate basic mechanisms necessary for successful tissue replacement, critical for development of useful protocols to treat patients with advanced liver diseases. Pregnant DPPIV+ F344 rats were purchased from Charles River. F344-Tg(EGFP) F455/Rrrc rats were obtained from the Rat Resource and Research Center of the University of Missouri-Columbia and used to provide time pregnant EGFP+ F344 rats.
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