Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response

Kallis, Yiannis; Robson, Andrew; Fallowfield, Jonathan; Thomas, Howard; Alison, Malcolm R.; Wright, Nicholas; Goldin, Robert; Iredale, John P.; Forbes, Stuart J.

doi:10.1136/gut.2010.224436

Cited by 90 publications

(77 citation statements)

References 56 publications

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“…Although paracrine signaling from the BMCs to the target organ has been suggested to underlie this phenomenon, such signaling has not been well characterized. Furthermore in the damaged liver any improvement in regeneration seen following BM injection may be an indirect phenomena secondary to the effects upon the surrounding matrix (23). Here we have demonstrated that a single infusion of unfractionated BMCs results in direct activation of a DR response in the undamaged liver.…”

Section: Discussionmentioning

confidence: 63%

“…However, a direct effect of macrophages upon the DRs or HPCs themselves has not been shown. The reduction of liver fibrosis itself is associated with improved hepatic regeneration (25) and the degree of matrix remodeling correlates to the magnitude of the DR response (23). Furthermore macrophages themselves are critical for the reduction in fibrosis (21).…”

mentioning

confidence: 99%

“…Nonetheless, interpretation of a direct paracrine pathway from BM-derived cells to tissue progenitor cells is complicated during tissue injury by the association of local inflammation and tissue remodeling, processes that are affected by BM-derived cells (21,22) and that also indirectly influence tissue progenitor cell activation (23).…”

mentioning

confidence: 99%

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Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

Bird

Boulter

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

146

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Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury. We therefore examined a model without injury; a single i.v. injection of unfractionated BMCs in healthy mice. This induced ductular reactions (DRs) in healthy mice. We demonstrate that macrophages within the unfractionated BMCs are responsible for the production of DRs, engrafting in the recipient liver and localizing to the DRs. Engrafted macrophages produce the cytokine TWEAK (TNF-like weak inducer of apoptosis) in situ. We go on to show that recombinant TWEAK activates DRs and that BMC mediated DRs are TWEAK dependent. DRs are accompanied by liver growth, occur in the absence of liver tissue injury and hepatic progenitor cells can be isolated from the livers of mice with DRs. Overall these results reveal a hitherto undescribed mechanism linking macrophage infiltration to DRs in the liver and highlight a rationale for macrophage derived cell therapy in regenerative medicine.liver regeneration | adult stem cell

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 99%

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Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

Bird

Boulter

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

146

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“…Type IV collagen is also subject to extensive remodeling during fibrosis, and its quantity has been found to increase more than 10-fold during liver fibrogenesis (116,289). Variants of type IV collagen together with isoforms of laminin, nidogen, and perlecan are the main components of all basement membranes and form a sheet-like scaffold at the basal site of epithelia and endothelia and around interstitial cells (135,289) that maintain viability and differentiation of these cells (157,231). Other functions of this network are the provision of interaction sites for other ECM components, inflammatory cells, chemokines, cytokines, and important functions in cellular signaling (394).…”

Section: Fibrosis and The Ecmmentioning

confidence: 99%

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

Karsdal

Manon‐Jensen

Genovese

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

216

176

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Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases.collagen; cytokine; extracellular fibrogenesis; integrin; laminin; matrix metalloproteinase; posttranslational modification; proteoglycan; endocrine 45% OF ALL DEATHS IN THE DEVELOPED WORLD are associated with chronic fibroproliferative diseases (256, 378). Thus there is an increasing need to address fibroproliferative diseases because of their strong impact on the quality of life and health costs consequent to pain and organ failure, with an increased need for organ transplants despite dwindling availability, often followed by death. Moreover, their severity and perceived irreversibility in view of a current paucity of treatment options, coupled with a high prevalence in most and an orphan status in some fibrotic diseases, have just begun to attract biotechnology and big pharmaceutical companies to the field.The common denominator of fibroproliferative diseases is a dysregulated tissue remodeling leading to the excessive and abnormal accumulation of extracellular matrix (ECM) components, thereby generating an ECM with different structural and signaling properties in the affected tissues (285, 287, 289, 378 -380). Fibrosis can affect almost any organ or tissue and is therefore associated with a wide variety of diseases and injuries (287). Figure 1 illustrates the major fibroproliferative diseases with a significant impact on human health (20, ...

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“…A recent report has shown that activation of HPC might be linked up with ECM remodelling. Degradation of collagen I and subsequent laminin deposition seem to be important prerequisites for HPC activation and expansion [10]. Based upon these results it appears that a better understanding of the factors that govern HPC proliferation and the resultant ECM changes would provide clues to improve regeneration of liver cells in chronic liver disease.…”

Section: Activation Of Resident Regenerative Cells In the Liver By Inmentioning

confidence: 97%

Cell Based Therapy for Chronic Liver Disease: Role of Fetal Liver Cells in Restoration of the Liver Cell Functions

Tripura¹,

Khan²,

Pande³

2012

Liver Regeneration

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Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response

Abstract: Failure of ECM remodelling after chronic fibrotic liver injury hinders the ability of the liver to activate HPCs. Laminin-progenitor cell interactions within the HPC niche are a critical for HPC mediated regeneration.

Cited by 90 publications

References 56 publications

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

Cell Based Therapy for Chronic Liver Disease: Role of Fetal Liver Cells in Restoration of the Liver Cell Functions

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