Expression of transforming growth factor‐alpha in regenerating liver and during hepatic differentiation

Evarts, Ritva P.; Nakatsukasa, Harushige; Marsden, Elizabeth R.; Hu, Zongyi; Thorgeirsson, Snorri S.

doi:10.1002/mc.2940050107

Cited by 104 publications

(66 citation statements)

References 22 publications

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“…In both the intact adult and weanling livers, as well as in freshly isolated cell subpopulations, the principal concentration of ALR peptide and essentially all of the mRNA transcripts were in hepatocytes, similar to TGF-␣ 34,35 but unlike the hepatotrophic HGF 37 and antihepatotrophic TGF-␤ 46,47 that are synthesized by NPCs (Table 1). ALR also was found by immunolabeling in the NPCs of the intact livers, but the peptide was irregularly distributed and of lower concentration than in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

A Fresh Look At Augmenter of Liver Regeneration in Rats

et al. 1999

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Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reversetranscriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a timedependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration. (HEPATOLOGY 1999;29:1435-1445.)The control of hepatic growth and regeneration has interested experimentalists for much of the 20th century. 1 Soon after the classical description in 1931 by Higgins and Anderson 2 of liver regeneration in rats following 70% hepatectomy, a search began for growth factors within the liver itself. McJunkin and Breuhaus 3 observed that the modest mitotic response to a 30% to 40% hepatectomy in rats was enhanced with an intraperitoneal injection 2 days postoperatively of homogenized homologous rat liver. Two decades later, Teir and Ravanti 4 and Blomquist 5 noted that this ''augmentation'' effect was demonstrable only when the injected homogenates were prepared from regenerating liver fragments following hepatectomy or from weanling rat livers that have a naturally heightened mitotic index. Subsequently, LaBrecque and Pesch 6 reported the same prerequisite of a hyperplastic liver source for cytosol extracts containing a putative ''hepatic stimulatory substance'' (HSS).Importantly, however, a cocondition for demonstrating a mitosis-augmenting a...

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Section: Discussionmentioning

confidence: 99%

A Fresh Look At Augmenter of Liver Regeneration in Rats

et al. 1999

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“…60 A marked increase in hepatic aFGF levels has been reported at the peak of oval cell proliferation in the 2-AAF/PH model, and levels greatly exceeded those observed after PH alone, suggesting a more prominent role for aFGF in oval cellmediated regeneration. 54 High levels of TGF-a expression are observed not only in hepatic stellate cells, but also in oval cells in the 2-AAF/PH model, 50,61 and TGFa expression is detected in foci of hepatocytes that appear to be oval cell-derived. Similar results have been observed in human hepatitis B-associated HCC, where TGF-a is localized to oval cells.…”

Section: Role Of Hepatic Stellate Cellsmentioning

confidence: 99%

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

Lowes

Croager

Olynyk

et al. 2002

J of Gastro and Hepatol

154

123

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In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.

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“…The fact that infusion of TGF-α increases oval cell proliferation after 2-AAF/PH protocol [15] suggested that EGFR signalling is also an important regulator of liver progenitor cells proliferation in a regenerative context, but for now, the impact of deleting EGFR signalling in liver regeneration from oval progenitor cells remains undefined. Interestingly, TGF-α transcripts are undetectable or very low in normal liver or non-replicating hepatocytes, but are up-regulated in hepatocytes during partial hepatectomy and toxic injury [32,33] as well as in proliferating oval cells and basophilic foci of hepatocytes in regenerating liver induced by a modified Solt-Farber protocol [12], providing indirect evidence for the implication of an autocrine mechanism. Here, using in vitro approaches we present the first direct evidence of the autocrine action of EGFR ligands in non-tumorigenic oval cells.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, both TGF-α and HGF, as well as their respective receptors, ErbB1 and c-Met, are transcriptionally up-regulated during the period of active proliferation and differentiation of progenitor cells in the rat liver subjected to the 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) protocol [12][13][14]. Furthermore, in vivo infusion with either EGF or HGF amplifies liver progenitor expansion following liver injury and decreases cell apoptosis [15].…”

Section: Introductionmentioning

confidence: 99%