Abstract

Purpose

Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor β (PDGFRβ)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs.

Methods

Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRβ as biomarker for human aHSCs and determine the correlation of PDGFRβ with the severity of liver fibrosis. The high affinity affibody for PDGFRβ (Z_PDGFRβ) was labeled with gallium-68 (⁶⁸Ga) for PET imaging of mice with carbon tetrachloride (CCl₄)-induced liver fibrosis. Binding of the [⁶⁸Ga]Ga-labeled Z_PDGFRβ ([⁶⁸Ga]Ga-DOTA-Z_PDGFRβ) for aHSCs in human liver tissues was measured by autoradiography.

Results

PDGFRβ overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl₄-treated mice. The ⁶⁸Ga-labeled Z_PDGFRβ affibody ([⁶⁸Ga]Ga-DOTA-Z_PDGFRβ) showed PDGFRβ-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [⁶⁸Ga]Ga-DOTA-Z_PDGFRβ increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [⁶⁸Ga]Ga-DOTA-Z_PDGFRβ decreased with spontaneous recovery or treatment of liver fibrosis, indicating that the progression and therapeutic responses of liver fibrosis in mice could be visualized by PDGFRβ-targeted PET imaging. [⁶⁸Ga]Ga-DOTA-Z_PDGFRβ also bound human aHSCs and visualized fibrosis in patient-derived liver tissues.

Conclusions

PDGFRβ is a reliable biomarker for both human and mouse aHSCs. PDGFRβ-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.

中文翻译：

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血小板源性生长因子受体β靶向正电子发射断层扫描成像用于肝纤维化的无创监测

摘要

目的

通过分子成像无创量化活化的肝星状细胞（aHSC）有助于评估肝纤维化的疾病进展和治疗反应。我们的目的是开发血小板衍生生长因子受体 β (PDGFRβ) 靶向放射性示踪剂，通过 aHSC 的正电子发射断层扫描 (PET) 成像来评估肝纤维化。

方法

采用比较转录组学、免疫荧光染色和流式细胞术评估PDGFRβ作为人aHSCs的生物标志物，并确定PDGFRβ与肝纤维化严重程度的相关性。PDGFRβ 高亲和力亲和体 (Z _PDGFRβ ) 用镓 68 ( ⁶⁸ Ga) 标记，用于对四氯化碳 (CCl ₄ ) 诱导的肝纤维化小鼠进行 PET 成像。通过放射自显影测量[ ⁶⁸ Ga]Ga标记的Z _PDGFRβ（[ ⁶⁸ Ga]Ga-DOTA-Z _PDGFRβ）与人肝组织中aHSC的结合。

结果

_{aHSC 中过表达的 PDGFRβ 与患者和 CCl 4}治疗小鼠的肝纤维化严重程度高度相关。⁶⁸ Ga 标记的 Z _PDGFRβ亲和体 ([ ⁶⁸ Ga]Ga-DOTA-Z _PDGFRβ ) 显示出与 aHSC 的 PDGFRβ 依赖性结合。根据PET成像，随着小鼠纤维化肝脏中aHSC和胶原蛋白的积累， [ ⁶⁸ Ga]Ga-DOTA-Z _{PDGFRβ的肝脏摄取增加。}相反，随着肝纤维化的自发恢复或治疗，[ ⁶⁸ Ga]Ga-DOTA-Z _PDGFRβ的肝脏摄取减少，表明小鼠肝纤维化的进展和治疗反应可以通过PDGFRβ靶向PET成像可视化。[ ⁶⁸ Ga]Ga-DOTA-Z _PDGFRβ还结合人 aHSC，并在患者来源的肝组织中观察到纤维化。

结论

PDGFRβ 是人类和小鼠 aHSC 的可靠生物标志物。PDGFRβ靶向PET成像可用于无创监测小鼠肝纤维化，具有巨大的临床转化潜力。