In vivo screening identifies SPP2, a secreted factor that negatively regulates liver regeneration

肝再生 再生(生物学) 体内 生物 细胞生物学 骨形态发生蛋白 生长因子 骨形态发生蛋白7 癌症研究 受体 生物化学 遗传学 基因
作者
Yu-Hsuan Lin,Qi‐Yu Zeng,Yuemeng Jia,Zixi Wang,Lin Li,Meng-Hsiung Hsieh,Qiang Cheng,Chase A. Pagani,Nicholas Livingston,Jeon Lee,Yu Zhang,Tripti Sharma,Daniel J. Siegwart,Dean Yimlamai,Benjamin Levi,Hao Zhu
出处
期刊:Hepatology [Wiley]
卷期号:78 (4): 1133-1148 被引量:2
标识
DOI:10.1097/hep.0000000000000402
摘要

Background and Aims: The liver is remarkably regenerative and can completely recover even when 80% of its mass is surgically removed. Identification of secreted factors that regulate liver growth would help us understand how organ size and regeneration are controlled but also provide candidate targets to promote regeneration or impair cancer growth. Approach and Results: To enrich for secreted factors that regulate growth control, we induced massive liver overgrowth with either YAP or MYC . Differentially expressed secreted factors were identified in these livers using transcriptomic analysis. To rank candidates by functionality, we performed in vivo CRISPR screening using the Fah knockout model of tyrosinemia. We identified secreted phosphoprotein-2 (SPP2) as a secreted factor that negatively regulates regeneration. Spp2 -deficient mice showed increased survival after acetaminophen poisoning and reduced fibrosis after repeated carbon tetrachloride injections. We examined the impact of SPP2 on bone morphogenetic protein signaling in liver cells and found that SPP2 antagonized bone morphogenetic protein signaling in vitro and in vivo. We also identified cell-surface receptors that interact with SPP2 using a proximity biotinylation assay coupled with mass spectrometry. We showed that SPP2’s interactions with integrin family members are in part responsible for some of the regeneration phenotypes. Conclusions: Using an in vivo CRISPR screening system, we identified SPP2 as a secreted factor that negatively regulates liver regeneration. This study provides ways to identify, validate, and characterize secreted factors in vivo.
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