Dept of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Dept of Experimental Medical Science, Lung Biology Unit, Lund University, Lund, Sweden.
Eur Respir J. 2021 Oct 14;58(4). doi: 10.1183/13993003.04149-2020. Print 2021 Oct.
Despite increased interest in mesenchymal stromal cell (MSC)-based cell therapies for acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and our understanding of the potential mechanisms of MSC actions in ARDS remains limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined.
The aim of this study was to comparatively assess how the inflammatory environment present in ARDS lungs the lung environment present in healthy volunteers alters MSC behaviour.
Clinical-grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties, including viability, levels of expression of inflammatory cytokines, gene expression, cell surface human leukocyte antigen expression, and activation of coagulation and complement pathways.
Pro-inflammatory, pro-coagulant and major histocompatibility complex (self-recognition) related gene expression was markedly upregulated in hMSCs exposed to BALF obtained from healthy volunteers. These changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples.
These data provide new insights into how hMSCs behave in healthy inflamed lung environments, and strongly suggest that the inflamed environment in ARDS induces hMSC responses that are potentially beneficial for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
尽管人们对间充质基质细胞（MSC）为基础的细胞疗法治疗急性呼吸窘迫综合征（ARDS）越来越感兴趣，但临床研究尚未成功，我们对 MSC 在 ARDS 中作用的潜在机制的理解仍然有限。ARDS 是由急性严重的先天免疫失调驱动的，通常以炎症、凝血和细胞损伤为特征。这种炎症微环境如何影响 MSC 的功能仍有待确定。
本研究旨在比较评估 ARDS 肺部存在的炎症环境——健康志愿者肺部的环境如何改变 MSC 的行为。
临床级人骨髓源性 MSC（hMSC）暴露于从 ARDS 患者或健康志愿者获得的支气管肺泡灌洗液（BALF）样本中。暴露后，评估 hMSC 及其条件培养基的一系列相关特性，包括活力、炎症细胞因子表达水平、基因表达、细胞表面人白细胞抗原表达以及凝血和补体途径的激活。
暴露于来自健康志愿者的 BALF 的 hMSC 中，促炎、促凝和主要组织相容性复合体（自我识别）相关基因表达明显上调。在暴露于 ARDS BALF 样本的 hMSC 中，这些变化不太明显，且往往相反。
这些数据提供了关于 hMSC 在健康炎症肺环境中行为的新见解，并强烈表明 ARDS 中的炎症环境诱导 hMSC 反应，这些反应可能有利于细胞存活和作用。这进一步强调了需要了解不同疾病环境如何影响 hMSC 的功能。
