Dept. of Anatomy and Cell Biology, The Univ. of Iowa, Iowa City, IA, USA; Dept. Biomedical Engineering, The Univ. of Iowa, Iowa City, IA, USA.
Dept. of Anatomy and Cell Biology, The Univ. of Iowa, Iowa City, IA, USA.
J Cyst Fibros. 2022 Jan;21(1):172-180. doi: 10.1016/j.jcf.2021.04.010. Epub 2021 May 17.
Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals.
We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion.
The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFβ, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFβ, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126.
These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.
囊性纤维化（CF）相关糖尿病是 CF 患者最常见的合并症，与胰岛功能障碍有关。CF 中外分泌胰腺的重塑改变了胰岛所处的微环境。由于 CFTR 主要在胰腺导管上皮中表达，我们假设改变的 CF 导管分泌物可以通过旁分泌信号影响胰岛功能。
我们使用定量比率质谱法评估了极化 WT 和 CF 雪貂导管上皮的分泌组和细胞蛋白质组。差异分泌蛋白（DSP）或表达的细胞蛋白被用于挖掘途径、上游调节剂和 CFTR 相互作用组，以绘制候选 CF 相关的导管信号和表型改变。候选 DSP 用于评估其在体内胰腺的表达模式及其对胰岛激素分泌的功能影响。
CF 导管上皮的分泌组和细胞蛋白质组与 WT 相比发生了显著改变，并暗示了失调的 TGFβ、WNT 和 BMP 信号通路。CF 上皮 DSP 的同源受体均匀分布于内分泌、外分泌和基质胰腺细胞类型中。IGFBP7 是 CF 导管上皮中下调的 DSP，在体内 CF 导管中表达减少。IGFBP7 也改变了 WT 胰岛对葡萄糖的胰岛素分泌。许多 CFTR 相关蛋白，包括 SLC9A3R1，在 CF 细胞蛋白质组中表达不同。差异 CF 导管蛋白质组的上游调节剂包括 TGFβ、PDX1、AKT/PTEN 和 INSR 信号。数据可通过 ProteomeXchange 以标识符 PXD025126 获得。
这些发现为阐明 CF 胰腺导管中自分泌和旁分泌信号的紊乱及其如何改变胰岛功能和维持提供了蛋白质组学路线图。
