骨髓间充质干细胞与支气管细支气管炎闭塞性模型中的慢性移植物病。

Bone Marrow-derived Mesenchymal Stem Cells and Chronic Allograft Disease in a Bronchiolitis Obliterans Animal Model.

机构信息

Thoracic Surgery Department, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.

出版信息

Arch Bronconeumol (Engl Ed). 2020 Mar;56(3):149-156. doi: 10.1016/j.arbres.2019.05.016. Epub 2019 Jul 8.

DOI:10.1016/j.arbres.2019.05.016

PMID:31296434

Abstract

INTRODUCTION

Bronchiolitis obliterans (BO) is the most common expression of chronic allograft dysfunction in lung transplantation. Moreover, BO represents the major cause of death in the long-term after this procedure. On the other hand, mesenchymal stem cells have been tested in animal models of BO aiming to interfere in its development. The aim of this experimental study is to explore the role of bone-marrow derived stem cells (BMSCs) as a preventive intervention of BO occurrence.

MATERIALS AND METHODS

This an experimental randomized study. A bronchiolitis obliterans animal model in rats was reproduced: heterotopical tracheal transplant model in lung parenchyma. Five of these animals were used as control group. After setting up the model, individuals were divided in 3 groups of treatment (n=15), in which BMSCs were administered in 3 different time points after the tracheal transplant (tracheal transplantation and BMSCs administration occurred the same day, group G0; after 7 days, group G7; after 14 days, group G14. In addition, within each group, BMSCs were administered through 3 different routes: endotracheally, endovascular and topically in the lung parenchyma). Animals were sacrificed at 21 days. Histology, fluorescence in situ hybridization and immunohistochemistry techniques were performed for identifying stem cells.

RESULTS

Compared to control group, animals receiving BMSCs showed large neovessels in a loose fibrous matrix. Group G7 showed less fibrosis (p<0.033) and edema (p<0.028). Moreover, G7 animals receiving stem cells endotracheally showed no fibrosis (p<0.008). Alveolar-like patches of tissue were observed among all groups (53.4%, 46.7% and 40% in G0, G7 and G14 respectively), consisting of cells expressing both stem and alveolar cells biomarkers.

CONCLUSION

BMSCs modify the course of bronchiolitis obliterans and differentiate into alveolar cells. Endotracheal administration of BMSCs 7 days after the heterotopical tracheal transplant might be considered an effective way to prevent BO in this animal model.

摘要

介绍

闭塞性细支气管炎（BO）是肺移植后慢性移植物功能障碍的最常见表现。此外，BO 是该手术长期后死亡的主要原因。另一方面，间充质干细胞已在 BO 动物模型中进行了测试，旨在干扰其发展。本实验研究旨在探讨骨髓源性干细胞（BMSCs）作为 BO 发生预防干预的作用。

材料与方法

这是一项实验性随机研究。在大鼠中复制闭塞性细支气管炎动物模型：肺实质内异位气管移植模型。其中 5 只作为对照组。建立模型后，将个体分为 3 个治疗组（n=15），在气管移植后 3 个不同时间点给予 BMSCs（气管移植和 BMSCs 给药在同一天进行，设为 G0 组；第 7 天，设为 G7 组；第 14 天，设为 G14 组。此外，在每组内，BMSCs 通过 3 种不同途径给药：气管内、血管内和肺实质内局部）。动物在 21 天处死。进行组织学、荧光原位杂交和免疫组织化学技术以鉴定干细胞。

结果

与对照组相比，给予 BMSCs 的动物在疏松纤维基质中显示出较大的新生血管。G7 组纤维化程度较低（p<0.033）和水肿程度较低（p<0.028）。此外，G7 组经气管内给予干细胞的动物无纤维化（p<0.008）。在所有组中均观察到肺泡样组织斑块（G0、G7 和 G14 组分别为 53.4%、46.7%和 40%），由表达干细胞和肺泡细胞生物标志物的细胞组成。