Gasanov Vagif Ali Oglu, Kashirskikh Dmitry Alexandrovich, Khotina Victoria Alexandrovna, Kuzmina Daria Mikhailovna, Nikitochkina Sofya Yurievna, Mukhina Irina Vasilievna, Vorotelyak Ekaterina Andreevna, Vasiliev Andrey Valentinovich
Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia.
Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia.
Cells. 2025 Feb 26;14(5):341. doi: 10.3390/cells14050341.
Mesenchymal stem/stromal cells (MSCs) offer promising therapeutic potential in cell-based therapies for various diseases. However, the safety of genetically modified MSCs remains poorly understood. This study aimed to evaluate the general toxicity and safety of Wharton's Jelly-Derived MSCs (WJ-MSCs) engineered to express the antimicrobial peptide SE-33 in an animal model. Genetically modified WJ-MSCs expressing SE-33 were administered to C57BL/6 mice at both therapeutic and excessive doses, either once or repeatedly. Animal monitoring included mortality, clinical signs, and behavioral observations. The toxicity assessment involved histopathological, hematological, and biochemical analyses of major organs and tissues, while immunotoxicity and immunogenicity were examined through humoral and cellular immune responses, macrophage phagocytic activity, and lymphocyte blast transformation. Antimicrobial efficacy was evaluated in a -induced pneumonia model by monitoring animal mortality and assessing bacterial load and inflammatory processes in the lungs. Mice receiving genetically modified WJ-MSCs exhibited no acute or chronic toxicity, behavioral abnormalities, or pathological changes, regardless of the dose or administration frequency. No significant immunotoxicity or alterations in immune responses were observed, and there were no notable changes in hematological or biochemical serum parameters. Infected animals treated with WJ-MSC-SE33 showed a significant reduction in bacterial load and lung inflammation and improved survival compared to control groups, demonstrating efficacy over native WJ-MSCs. Our findings suggest that WJ-MSCs expressing SE-33 are well tolerated, displaying a favorable safety profile comparable to native WJ-MSCs and potent antimicrobial activity, significantly reducing bacterial load, inflammation, and mortality in an pneumonia model. These data support the safety profile of WJ-MSCs expressing SE-33 as a promising candidate for cell-based therapies for bacterial infections, particularly those complicated by antibiotic resistance.
间充质干/基质细胞（MSCs）在针对各种疾病的细胞疗法中具有广阔的治疗潜力。然而，基因改造后的MSCs的安全性仍知之甚少。本研究旨在评估经基因工程改造以表达抗菌肽SE - 33的脐带来源间充质干细胞（WJ - MSCs）在动物模型中的一般毒性和安全性。将表达SE - 33的基因改造后的WJ - MSCs以治疗剂量和过量剂量给予C57BL / 6小鼠，给药一次或多次。动物监测包括死亡率、临床体征和行为观察。毒性评估涉及对主要器官和组织进行组织病理学、血液学和生化分析，同时通过体液和细胞免疫反应、巨噬细胞吞噬活性和淋巴细胞增殖转化来检测免疫毒性和免疫原性。在诱导性肺炎模型中，通过监测动物死亡率以及评估肺部细菌载量和炎症过程来评估抗菌效果。接受基因改造后的WJ - MSCs的小鼠无论剂量或给药频率如何，均未表现出急性或慢性毒性、行为异常或病理变化。未观察到明显的免疫毒性或免疫反应改变，血液学或生化血清参数也无显著变化。与对照组相比，用WJ - MSC - SE33治疗的感染动物的细菌载量和肺部炎症显著降低，存活率提高，表明其比天然WJ - MSCs更有效。我们的研究结果表明，表达SE - 33的WJ - MSCs耐受性良好，其安全性与天然WJ - MSCs相当且具有强大的抗菌活性，在肺炎模型中能显著降低细菌载量、炎症和死亡率。这些数据支持表达SE - 33的WJ - MSCs的安全性，使其成为治疗细菌感染，特别是那些伴有抗生素耐药性的细菌感染的基于细胞疗法的有前途的候选者。
