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However, after chronic liver injury, injured hepatocytes release several proinflammatory mediators, reactive oxygen species, and damage\u2010associated molecular patterns into the perisinusoidal space. Consequently, such alteration activates quiescent HSCs to acquire a myofibroblast\u2010like phenotype and express high amounts of transforming growth factor\u2010\u03b21, angiopoietins, vascular endothelial growth factors, interleukins 6 and 8, fibril forming collagens, laminin, and E\u2010cadherin. These phenotypic and functional transdifferentiation lead to hepatic fibrosis with a typical abnormal extracellular matrix\u00a0synthesis and disorganization of the perisinusoidal space of the injured liver. Those changes provide a favorable environment that regulates tumor cell proliferation, migration, adhesion, and survival in the perisinusoidal space. Such tumor cells by releasing transforming growth factor\u2010\u03b21 and other cytokines, will, in turn, activate and deeply interact with HSCs via a bidirectional loop. Furthermore, hepatocellular carcinoma\u2010derived mediators convert HSCs and macrophages into protumorigenic cell populations. Thus, the perisinusoidal space serves as a critical hub for activating HSCs and their interactions with other cell types, which cause a variety of liver diseases such as hepatic inflammation, fibrosis, cirrhosis, and their complications, such as portal hypertension and hepatocellular carcinoma. Therefore, targeting the crosstalk between activated HSCs and tumor cells\/immune cells in the tumor microenvironment may also support a promising therapeutic strategy.<\/jats:p>","DOI":"10.1002\/jcp.30915","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T13:38:25Z","timestamp":1669037905000},"page":"70-81","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Intercellular communication among liver cells in the perisinusoidal space of the injured liver: Pathophysiology and therapeutic directions"],"prefix":"10.1002","volume":"238","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2383","authenticated-orcid":false,"given":"Devaraj","family":"Ezhilarasan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College Saveetha Institute of Medical and Technical Sciences (SIMATS)  Chennai Tamil Nadu 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