Progranulin A Promotes Compensatory Hepatocyte Proliferation via HGF/c-Met Signaling after Partial Hepatectomy in Zebrafish

• Published in: International journal of molecular sciences Vol. 22; no. 20; p. 11217
• Main Authors: Chiang, Keng-Yu, Li, Ya-Wen, Li, Yen-Hsing, Huang, Shin-Jie, Wu, Chih-Lu, Gong, Hong-Yi, Wu, Jen-Leih
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.10.2021; MDPI
• Subjects: Animals; c-met; c-Met protein; Cell cycle; Cell growth; Cell Proliferation; Cholangiocarcinoma; Cytokines; Danio rerio; Embryogenesis; Fluorescence; Gene expression; gRNA; Growth factors; Hepatectomy; Hepatectomy - methods; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Hepatocytes - cytology; Hepatocytes - metabolism; HGF; Kinases; Liver; Liver cancer; Liver Regeneration; Mammals; Organogenesis; partial hepatectomy; progranulin; Progranulins - genetics; Progranulins - metabolism; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Signal Transduction; Transcriptomes; Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Vivo-Morpholino; partial hepatectomy; intraperitoneal injection; cell proliferation; cell cycle; HGF; progranulin; c-met; zebrafish; liver regeneration
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222011217

Compensatory hepatocyte proliferation and other liver regenerative processes are activated to sustain normal physiological function after liver injury. A major mitogen for liver regeneration is hepatocyte growth factor (HGF), and a previous study indicated that progranulin could modulate c-met, the receptor for HGF, to initiate hepatic outgrowth from hepatoblasts during embryonic development. However, a role for progranulin in compensatory hepatocyte proliferation has not been shown previously. Therefore, this study was undertaken to clarify whether progranulin plays a regulatory role during liver regeneration. To this end, we established a partial hepatectomy regeneration model in adult zebrafish that express a liver-specific fluorescent reporter. Using this model, we found that loss of progranulin A (GrnA) function by intraperitoneal-injection of a Vivo-Morpholino impaired and delayed liver regeneration after partial hepatectomy. Furthermore, transcriptome analysis and confirmatory quantitative real-time PCR suggested that cell cycle progression and cell proliferation was not as active in the morphants as controls, which may have been the result of comparative downregulation of the HGF/c-met axis by 36 h after partial hepatectomy. Finally, liver-specific overexpression of GrnA in transgenic zebrafish caused more abundant cell proliferation after partial hepatectomy compared to wild types. Thus, we conclude that GrnA positively regulates HGF/c-met signaling to promote hepatocyte proliferation during liver regeneration.