Transcriptional profiling of circulating mononuclear cells from patients with chronic obstructive pulmonary disease receiving mesenchymal stromal cell infusions,STEM CELLS Translational Medicine

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Transcriptional profiling of circulating mononuclear cells from patients with chronic obstructive pulmonary disease receiving mesenchymal stromal cell infusions
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2021-08-18 , DOI: 10.1002/sctm.21-0024
Jesse D Armitage _{1,

2} , Dino B A Tan _{1,

2,

3} , Marian Sturm _{3,

4} , Yuben P Moodley _{1,

2,

5}

Affiliation

Chronic obstructive pulmonary disease (COPD) is an inflammatory airways disease with limited therapeutic options. We have previously shown that mesenchymal stromal cell (MSC) infusions are well tolerated in patients with COPD and reduce circulatory biomarkers associated with systemic inflammation and oxidative stress. This study aimed to delineate the underlying mechanisms further by characterizing the transcriptional networks in these patients and to explore the role of MSC-derived paracrine factors in regulating these pathways. Allogeneic, bone marrow-derived MSCs were systemically administered into patients with stable COPD (n = 9). Gene expression profiles from peripheral blood mononuclear cells (PBMCs) were analyzed across the first week after infusion. Paracrine mechanisms associated with these transcriptional changes were explored further by culturing patient PBMCs with MSC-conditioned medium (MSC-CM) or post-MSC infusion (PI) plasma to measure the regulatory effects of soluble factors that may be derived from MSCs. MSC-CM and PI-plasma were characterized further to identify potential immunoregulatory candidates. MSC infusion elicited a strong but transient transcriptional response in patient PBMCs that was sustained up to 7 days. MSC infusion strongly downregulated transcriptional pathways related to interleukin (IL)-8 and IL-1β, which were also significantly inhibited in vitro following co-culture of PBMCs with MSC-CM and PI-plasma. MSC-derived soluble tumor necrosis factor receptor-1, transforming growth factor-β1, and extracellular vesicle-associated microRNAs were identified as potential mechanisms promoting these changes, but depletion of these individual candidates revealed inconsistent results. MSC-derived paracrine factors modulate important inflammatory pathways that are relevant to COPD pathogenesis. These data strengthen the hypothesis that therapies using MSCs and their secreted products may be beneficial to patients with COPD.

中文翻译：

来自接受间充质基质细胞输注的慢性阻塞性肺病患者的循环单核细胞的转录谱

慢性阻塞性肺病 (COPD) 是一种炎症性气道疾病，治疗选择有限。我们之前已经表明，间充质基质细胞 (MSC) 输注在 COPD 患者中具有良好的耐受性，并且可以减少与全身炎症和氧化应激相关的循环生物标志物。本研究旨在通过表征这些患者的转录网络进一步描述潜在机制，并探索 MSC 衍生的旁分泌因子在调节这些途径中的作用。将异基因的骨髓来源的 MSC 系统性地施用于患有稳定期 COPD 的患者（n = 9）。在输注后的第一周内分析来自外周血单个核细胞 (PBMC) 的基因表达谱。通过用 MSC 条件培养基 (MSC-CM) 或 MSC 输注后 (PI) 血浆培养患者 PBMC，进一步探索与这些转录变化相关的旁分泌机制，以测量可能源自 MSC 的可溶性因子的调节作用。MSC-CM 和 PI-血浆被进一步表征以鉴定潜在的免疫调节候选物。MSC 输注在患者 PBMC 中引发了持续长达 7 天的强烈但短暂的转录反应。MSC 输注强烈下调与白细胞介素 (IL)-8 和 IL-1β 相关的转录途径，在 PBMC 与 MSC-CM 和 PI-血浆共培养后，这些转录途径在体外也受到显着抑制。MSC衍生的可溶性肿瘤坏死因子受体-1、转化生长因子-β1、和细胞外囊泡相关的 microRNA 被确定为促进这些变化的潜在机制，但这些个体候选者的消耗显示出不一致的结果。MSC 衍生的旁分泌因子调节与 COPD 发病机制相关的重要炎症通路。这些数据强化了使用 MSC 及其分泌产物进行治疗可能对 COPD 患者有益的假设。

更新日期：2021-08-18

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