静脉注射间充质基质细胞会导致剂量依赖性的凝血功能障碍，并且不能减轻大鼠的急性创伤性凝血病。

Intravenous administration of mesenchymal stromal cells leads to a dose-dependent coagulopathy and is unable to attenuate acute traumatic coagulopathy in rats.

机构信息

From the Blood and Shock Resuscitation, United States Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas.

出版信息

J Trauma Acute Care Surg. 2022 Mar 1;92(3):542-552. doi: 10.1097/TA.0000000000003476.

DOI:10.1097/TA.0000000000003476

PMID:34797814

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8860226/

Abstract

BACKGROUND

Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats.

METHODS

Tissue factor expression of rat bone marrow-derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma.

RESULTS

Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow-derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe.

CONCLUSION

Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock.

摘要

背景

间充质基质细胞（MSCs）表达表面组织因子（TF），如果静脉内给药，可能会影响止血并影响 MSCs 的治疗效果。在这项研究中，我们确定了静脉内（IV）给药的 MSC 安全剂量，并进一步证明了 IV-MSC 对大鼠急性创伤性凝血病（ATC）的影响。

方法

通过免疫组织化学和酶联免疫吸附试验检测大鼠骨髓间充质基质细胞（BMSC）或脂肪间充质基质细胞（AMSC）的 TF 表达。在 MSC 处理的大鼠全血中测量凝血特性，并在静脉内给予 MSCs 后从大鼠采集血液样本。急性创伤性凝血病大鼠接受多发伤和 40%出血，然后在创伤后 1 小时静脉内给予 5 或 1000 万/kg BMSC（BMSC-5，BMSC-10）或载体。

结果

大鼠 MSCs 表达 TF，并且在体外与全血孵育的大鼠 BMSC 或 AMSC 导致凝血时间明显缩短。然而，在健康大鼠中，静脉内给予 IV-MSCs 会导致剂量依赖性的凝血酶原时间延长，血小板计数和纤维蛋白原减少。静脉内给予 500 万/kg 或更少的 BMSC 导致对止血的影响最小。无论剂量如何，静脉内给予后，MSCs 都不会在循环中发现，而是在肺部发现。急性创伤性凝血病伴凝血酶原时间延长，5 或 1000 万/kg BMSC 无明显影响。与 BMSC-5 或载体相比，静脉内给予 1000 万/kg BMSC 导致纤维蛋白原和血小板计数明显降低，而肺中的乳酸水平、湿/干重比和白细胞浸润明显升高。在 ATC 大鼠中，至少在急性时间范围内，BMSC 治疗与免疫或炎症特征无差异。