Mesenchymal Stem Cell Secretome Mitigates Inflammatory Endothelial Dysfunction.

IF 2.7 3区医学 Q2 CRITICAL CARE MEDICINE

SHOCK Pub Date : 2026-08-24 DOI:10.1097/SHK.0000000000002928

Marissa D Pokharel, Baron K Osborn, Anthony J Saviola, Sean P Maroney, Alyssa Caldwell-McGee, Jillian R Richter, Todd Getz, Mitchell J Cohen, Jessica C Cardenas

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引用次数: 0

Abstract

Background: Endothelial cells (EC) dysfunction and barrier disruption are central drivers of inflammatory lung injury and adverse outcomes, yet targeted therapies remain lacking. We tested the hypothesis that a mesenchymal stem cell (MSC)-derived secretome can directly preserve EC function under inflammatory stress. We evaluated AlloEx (Vitro Biopharma), a Wharton's Jelly MSC-derived secretome enriched in bioactive RNAs, proteins, lipids, and extracellular vesicles with pro-reparative and immunomodulatory activity.

Methods: Human lung microvascular endothelial cells (HLMVEC) were exposed to TNFα (4 h) with AlloEx administered 30 min before or after TNFα stimulation. EC thromboinflammatory gene expression was quantified by qPCR. Barrier integrity was assessed by transendothelial resistance (TEER) and VE-cadherin immunofluorescence. Mitochondrial function was evaluated using MitoSOX, TMRM, and mitochondrial fission imaging. Proteomic profiling was performed using trauma patient plasma as a clinically relevant inflammatory stimulus.

Results: AlloEx potently suppressed TNFα-induced EC activation, markedly reducing ICAM1, SELE, IL6, NOS3, ANG2, TEK, VEGFA, and F3 expression. Functionally, AlloEx rescued EC barrier integrity, preserving VE-cadherin localization at endothelial junctions and restoring TEER by 79% with pretreatment and 65% with post-treatment. Mechanistically, AlloEx prevented mitochondrial dysfunction, limiting reactive oxygen species generation, preserving membrane potential, and reducing fission. Proteomic profiling demonstrated that AlloEx induced coordinated remodeling of metabolic, vesicular, and inflammatory signaling pathways while suppressing cellular stress and pro-inflammatory signaling.

Conclusion: These findings identify MSC-derived secretome therapy as a potent modulator of EC thromboinflammatory activation, barrier integrity, and mitochondrial function. AlloEx represents a promising, clinically translatable strategy to target EC dysfunction in inflammatory lung injury and trauma-associated endotheliopathy.

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间充质干细胞分泌组减轻炎性内皮功能障碍。

背景：内皮细胞（EC）功能障碍和屏障破坏是炎症性肺损伤和不良后果的主要驱动因素，但靶向治疗仍然缺乏。我们验证了间充质干细胞（MSC）衍生的分泌组可以在炎症应激下直接保持EC功能的假设。我们评估了AlloEx（体外生物制药），这是一种沃顿果冻msc衍生的分泌组，富含生物活性rna、蛋白质、脂质和具有促修复和免疫调节活性的细胞外囊泡。方法：将人肺微血管内皮细胞（HLMVEC）暴露于TNFα (4 h)，并在TNFα刺激前后30 min给予异氧异体酶（AlloEx）。采用qPCR定量检测EC血栓炎性基因表达。屏障的完整性通过跨内皮耐药（TEER）和ve -钙粘蛋白免疫荧光来评估。使用MitoSOX、TMRM和线粒体裂变成像评估线粒体功能。使用创伤患者血浆作为临床相关炎症刺激进行蛋白质组学分析。结果：同种异体酶能有效抑制tnf α诱导的EC活化，显著降低ICAM1、SELE、IL6、NOS3、ANG2、TEK、VEGFA和F3的表达。在功能上，AlloEx挽救了EC屏障的完整性，保留了内皮连接处VE-cadherin的定位，预处理后TEER恢复了79%，后处理后TEER恢复了65%。在机制上，同种异体酶防止线粒体功能障碍，限制活性氧的产生，保持膜电位，减少裂变。蛋白质组学分析表明，同种异体酶诱导代谢、囊泡和炎症信号通路的协调重塑，同时抑制细胞应激和促炎信号。结论：这些发现确定了间质干细胞衍生的分泌组疗法是EC血栓炎性激活、屏障完整性和线粒体功能的有效调节剂。异戊二烯代表了一个有前途的，临床可翻译的策略，针对炎性肺损伤和创伤相关内皮病变的EC功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

SHOCK 医学-外科

CiteScore

6.20

自引率

3.20%

发文量

199

审稿时长

1 months

期刊介绍： SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.