Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair

Knittel, Thomas; Kobold, Dominik; Piscaglia, Fabio; Saile, Bernhard; Neubauer, Katrin; Mehde, Mirko; Timpl, Rupert; Ramadori, Giuliano

doi:10.1007/s004180050421

Cited by 164 publications

(157 citation statements)

References 29 publications

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“…MFs are the principal cells located within the scar tissue (Knittel et al 1999b). Thy-1 expression has the potential to distinguish between aHSC and rMF in vitro Dudas et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury

Dudás

Mansuroglu

Batusic

et al. 2008

Histochem Cell Biol

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Thy-1 (CD90) is an adhesion molecule induced in Wbroblast populations associated with wound healing and Wbrosis. In this study the question whether Thy-1-geneexpression can be induced in hepatic stellate cells (HSC) in vivo, under conditions of liver injury or liver regeneration was addressed. Acute and chronic rat liver injury was induced by the administration of CCl 4 . For comparison, cirrhotic human liver, and rat 67% partial hepatectomy (PH) was studied as well. Thy-1-gene-expression was examined also in isolated human liver myoWbroblasts. Thy-1-mRNA expression was signiWcantly upregulated in chronic liver injury. Thy-1 + cells were detected in the periportal area of rat liver specimens in normal-, injured-and regenerativeconditions. In chronic human and rat liver injury, Thy-1 + cells were located predominantly in scar tissue. In the pericentral necrotic zone after CCl 4 -treatment, no induction of Thy-1 was found. Gremlin and Thy-1 showed comparable localization in the periportal areas. Thy-1 was not detected in either normal or capillarized sinusoids, in isolated rat HSC, and was neither inducible by inXammatory cytokines in isolated HSC, nor upregulated in treated myoWbroblasts. Based upon these data Thy-1 is not a marker of "activated" sinusoidal HSC, but it is a marker of "activated" (myo)Wbroblasts found in portal areas and in scar tissue.

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“…MFs are the principal cells located within the scar tissue (Knittel et al 1999b). Thy-1 expression has the potential to distinguish between aHSC and rMF in vitro Dudas et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury

Dudás

Mansuroglu

Batusic

et al. 2008

Histochem Cell Biol

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“…At one time the origin of the myofibroblasts in liver injury was obscure, because "fibroblasts" are rare in normal liver, consisting only of a few that reside in the periportal stroma (Knittel et al, 1999). Initial clues derived from histological studies that found "fat-storing cells" (now termed hepatic stellate cells, HSC) in the vicinity of injury and fibrosis (Kent et al, 1976).…”

Section: Hepatic Stellate Cell (Hsc) Activationmentioning

confidence: 99%

Chronic liver injury, TGF-β, and cancer

Bissell

2001

Exp Mol Med

156

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Cells termed myofibroblasts are prominent in the injury response of all epithelial tissues. They exhibit proliferation, migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction, all for containing the injury and closing the wound. When the injury is limited in time, the final stage of the repair involves a dismantling of the cellular apparatus and restoration of normal tissue structure. With multiple cycles of repair, however, there is net accumulation of ECM, to the detriment of tissue structure and function. Repair-related ECM coalesces into fibrous bundles and, over time, undergoes changes that render it resistant to degradation. The result is a scar. In the skin, a scar may have cosmetic importance only. In the liver, however, extensive scarring is the setting for unregulated growth and neoplasia; also, fibrous bands disrupt normal blood flow, leading to portal hypertension and its complications. With regard to therapy for fibrosis, the first consideration is elimination of the injury factor. However, given that many liver diseases do not have effective therapies at present, strategies targeting fibrogenesis per se are under development. The main source of myofibroblast-like cells and ECM production in the liver is the perisinusoidal stellate cell, which responds to injury with a pleiotypic change termed activation. Activation is orchestrated by cytokines and the ECM itself. Among the cytokines involved in this process, transforming growth factor-beta (TGF-β) is particularly prominent. The early changes in ECM include de novo production of a specific "fetal" isoform of fibronectin, which arises from sinusoidal endothelial cells. It is stimulated by TGF-β and acts directly on stellate cells to promote their activation. Based on these and other advances in understanding the fundamentals of the injury response, several strategies now exist for altering fibrogenesis, ranging from agents that block TGF-β to traditional Chinese herbal extracts. Arrest of fibrogenesis, even with underlying cirrhosis, is likely to extend life or prolong the time to transplant. Whether it reduces the risk of hepatocellular carcinoma remains to be proven. Although TGF-β antagonists are effective anti-fibrogenic agents, they will require detailed safety testing because of the finding that several forms of epithelial neoplasia are associated with altered regulation of TGF-β.

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“…To date, there are no FDA approved antifibrotic drugs (2). Fibrosis is characterized by excessive production of extracellular matrix (ECM) components, especially type I and III fibrillar collagens within the perivascular and interstitial space of tissues (3,4). † This work was supported by a grant RO1 DK064633 from the NIH and USPHS grant 47379.…”

Section: Introductionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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Excessive production of extracellular matrix, predominantly type I collagen results in liver fibrosis. Earlier we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) and conjugated to the type I collagen specific triplex forming oligonucleotide (TFO) for its enhanced delivery to hepatic stellate cells (HSCs), which is the principle liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-33 P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-33 P-TFO were significantly higher than those of 33 P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-33 P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33 P-TFO, there was no significant decrease in the hepatic uptake of (M6P) 20 -BSA-33 P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P) 20 -BSA-33 P-TFO from 66% to 40% in normal rats, and from 60% to 15% in fibrotic rats, suggesting M6P/insulin-like growth factor II (M6P/IGF-II) receptor-mediated endocytosis of M6P-BSA-33 P-TFO by HSCs. Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis.

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Localization of liver myofibroblasts and hepatic stellate cells in normal and diseased rat livers: distinct roles of (myo-)fibroblast subpopulations in hepatic tissue repair

Cited by 164 publications

References 29 publications

Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury

Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury

Chronic liver injury, TGF-β, and cancer

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

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