Evaluating the antifibrotic potency of galunisertib in a human <i>ex vivo</i> model of liver fibrosis

Luangmonkong, Theerut; Suriguga, Su; Bigaeva, Emilia; Boersema, Miriam; Oosterhuis, Dorenda; Jong, Koert P. de; Schuppan, Detlef; Mutsaers, Henricus A M; Olinga, Peter

doi:10.1111/bph.13945

Cited by 76 publications

(89 citation statements)

References 45 publications

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“…Due to the cooling, the agarose solidified and a solid‐like structure was created, suited for slicing. Simultaneously, Krebs‐Henseleit buffer (KHB) solution was prepared and kept at 0‐4°C on melting ice . The KHB solution was oxygenated with 95% O 2 /5% CO 2 for 30 minutes and adjusted to a pH of 7.4.…”

Section: Methodsmentioning

confidence: 99%

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

et al. 2019

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Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We therefore developed an ex vivo model using precision‐cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Postischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation, and maturation. Proliferation of PBG cells increased after 24 hours of oxygenated incubation, reaching a peak after 72 hours. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (homeobox protein Nanog+/ sex‐determining region Y‐box 9+) to a mature (cystic fibrosis transmembrane conductance regulator+/secretin receptor+) and activated phenotype (increased expression of hypoxia‐inducible factor 1 alpha, glucose transporter 1, and vascular endothelial growth factor A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. Conclusion: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behavior of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury.

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Section: Methodsmentioning

confidence: 99%

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

et al. 2019

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“…This strategy needs prospective evaluation in clinical trials. The transforming growth factor (TGF)‐β inhibitor galunisertib, that also has antifibrotic potency, is currently being tested in combination with nivolumab in HCC (NCT02423343). Notably, TGF‐β also promotes immunosuppression by inhibiting T‐cell responses, which makes this combination particularly attractive.…”

Section: Immunotherapymentioning

confidence: 99%

Review article: systemic treatment of hepatocellular carcinoma

Pinter

Peck‐Radosavljevic

2018

Aliment Pharmacol Ther

142

122

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SummaryBackgroundThe approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first‐ and second‐line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.AimTo summarise the evolving field of systemic therapy of hepatocellular carcinoma.MethodsWe reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.ResultsWe discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.ConclusionsThe tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib‐experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib‐experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

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“…Using human precision‐cut liver slices, it has been demonstrated that galunisertib attenuates SMAD2 phosphorylation in healthy and cirrhotic liver tissue and reduces the expression of several collagen subtypes (collagen types I, III, IV, V and VI). In addition, it reduces the expression of numerous genes associated with collagen maturation and homeostasis . Interestingly, there is also evidence suggesting that galunisertib can inhibit TGF‐β signaling in human oral keratinocytes …”

Section: Regenerative Medicine To Attenuate Scarring and Muscle Fibrosismentioning

confidence: 99%

“…In addition, it reduces the expression of numerous genes associated with collagen maturation and homeostasis. 124 Interestingly, there is also evidence suggesting that galunisertib can inhibit TGF-β signaling in human oral keratinocytes. 125 Overall, there are three distinct routes to target profibrotic signaling: (a) inhibiting transcription or translation of profibrotic factors, (b) blocking interleukin receptor binding and activation, and (c) interfering with down-stream signaling events.…”

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confidence: 99%

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

Schreurs

Suttorp

Mutsaers

et al. 2019

Medicinal Research Reviews

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Cleft lip with or without cleft palate is a congenital deformity that occurs in about 1 of 700 newborns, affecting the dentition, bone, skin, muscles and mucosa in the orofacial region. A cleft can give rise to problems with maxillofacial growth, dental development, speech, and eating, and can also cause hearing impairment. Surgical repair of the lip may lead to impaired regeneration of muscle and skin, fibrosis, and scar formation. This may result in hampered facial growth and dental development affecting oral function and lip and nose esthetics. Therefore, secondary surgery to correct the scar is often indicated. We will discuss the molecular and cellular pathways involved in facial and lip myogenesis, muscle anatomy in the normal and cleft lip, and complications following surgery. The aim of this review is to outline a novel molecular and cellular strategy to improve musculature and skin regeneration and to reduce scar formation following cleft repair. Orofacial clefting can be diagnosed in the fetus through prenatal ultrasound screening and allows planning for the harvesting of umbilical cord blood stem cells upon birth. Tissue engineering techniques using these cord blood stem cells and molecular targeting of inflammation and fibrosis during surgery may promote tissue regeneration. We expect that this novel strategy improves both muscle and skin regeneration, resulting in better function and esthetics after cleft repair.

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Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis

Cited by 76 publications

References 45 publications

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury

Review article: systemic treatment of hepatocellular carcinoma

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

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