The Bone Marrow Functionally Contributes to Liver Fibrosis

Russo, Francesco Paolo; Alison, Malcolm R.; Bigger, Brian; Amofah, Eunice; Florou, Aikaterini; Amin, Farhana; Bou‐Gharios, George; Jeffery, Rosemary; Iredale, John P.; Forbes, Stuart J.

doi:10.1053/j.gastro.2006.01.036

Cited by 446 publications

(380 citation statements)

References 40 publications

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“…Furthermore, a growing body of evidence indicates that bone marrow cells can contribute to the fibrogenic population (Table 3a). For example, female mice, having had a male bone marrow transplant, were chronically poisoned with CCl 4 and, up to 70% of HpSCs and myofibroblasts associated with septal scars were bone marrow-derived, most likely from MSCs [7]. A bone marrow contribution to hepatic fibrogenesis has also been shown in the bile duct-ligated mouse, a model of cholestatic liver disease [116].…”

Section: Liver Fibrosismentioning

confidence: 99%

“…In the context of disease, the bone marrow may also harbour cells with fibrogenic potential, contributing significantly to end-stage liver fibrosis [6,7]; conversely, autologous bone marrow cell therapies may ameliorate this condition and a small number of clinical trials are providing some evidence of this. In common with other tissues, there is persuasive evidence that in the liver, stem cells can be the founder cells of primary hepatic malignancies, such as hepatocellular carcinoma (HCC).…”

Section: Introductionmentioning

confidence: 99%

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Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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Section: Liver Fibrosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

View full text Add to dashboard Cite

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“…HMs may also be recruited to injured tissue from bone marrow-derived stem cells. 38 Irrespective of their cellular origin, and despite a high degree of plasticity that complicates their phenotypic characterization, HMs display many properties compatible with a tumor-promoting cell. HMs are highly proinflammatory and secrete a plethora of cytokines and growth factors, including hepatomitogens directly implicated in HCC growth, such as IL-6 and hepatocyte growth factor.…”

Section: Nf-b As a Tumor Suppressor In Hepatocytesmentioning

confidence: 99%

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

2007

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Nuclear factor-B (NF-B) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-B in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-B activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma-a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-B signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590-597.)

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“…Although in chronic liver injury hepatic stellate cells (HSCs) differentiate into myofibroblasts (also termed activation) and produce ECM, 2 the myofibroblast population of the diseased liver is heterogeneous, and fibrogenic myofibroblasts also arise from other cells, including portal fibroblasts (PFs). [3][4][5][6][7][8][9][10] PFs are fibroblasts surrounding the biliary tree; their differentiation into myofibroblasts in bile duct ligation (BDL) models of fibrosis precedes HSC activation, and they may function as first responders after biliary injury. [11][12][13][14] Isolation of rat liver myofibroblast precursor cells distinct from HSCs was first reported in 1984.…”

mentioning

confidence: 99%

Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture

et al. 2007

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Myofibroblasts derived from portal fibroblasts are important fibrogenic cells in the early stages of biliary fibrosis. In contrast to hepatic stellate cells, portal fibroblasts have not been well studied in vitro, and little is known about their myofibroblastic differentiation. In this article we report the isolation and characterization of rat portal fibroblasts in culture. We demonstrate that primary portal fibroblasts undergo differentiation to ␣-smooth muscle actin-expressing myofibroblasts over 10 -14 days. Marker analysis comparing portal fibroblasts to hepatic stellate cells demonstrated that these are distinct populations and that staining with elastin and desmin can differentiate between them. Portal fibroblasts expressed elastin at all stages in culture but never expressed desmin, whereas hepatic stellate cells consistently expressed desmin but never elastin. Immunostaining of rat liver tissue confirmed these results in vivo. Characterization of portal fibroblast differentiation in culture demonstrated that these cells required transforming growth factor-␤ (TGF-␤): cells remained quiescent in the presence of a TGF-␤ receptor kinase inhibitor, whereas exogenous TGF-␤1 enhanced portal fibroblast ␣-smooth muscle actin expression and stress fiber formation. In contrast, platelet-derived growth factor inhibited myofibroblastic differentiation. Portal fibroblasts were also dependent on mechanical tension for myofibroblastic differentiation, and cells cultured on polyacrylamide supports of variable stiffness demonstrated an increasingly myofibroblastic phenotype as stiffness increased. Conclusion: Portal fibroblasts are morphologically and functionally distinct from hepatic stellate cells. Portal fibroblast myofibroblastic differentiation can be modeled in culture and requires both TGF-␤ and mechanical tension. (HEPATOLOGY 2007;46:1246-1256

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The Bone Marrow Functionally Contributes to Liver Fibrosis

Cited by 446 publications

References 40 publications

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Nuclear factor‐κB and the hepatic inflammation‐fibrosis‐cancer axis†

Transforming growth factor-β and substrate stiffness regulate portal fibroblast activation in culture

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