Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.

IF 9 2区 医学 Q1 CELL BIOLOGY Journal of Biomedical Science Pub Date : 2024-07-15 DOI:10.1186/s12929-024-01059-w
Marta Rojas-Torres, Lucía Beltrán-Camacho, Ana Martínez-Val, Ismael Sánchez-Gomar, Sara Eslava-Alcón, Antonio Rosal-Vela, Margarita Jiménez-Palomares, Esther Doiz-Artázcoz, Mario Martínez-Torija, Rafael Moreno-Luna, Jesper V Olsen, Ma Carmen Duran-Ruiz
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Abstract

Background: Critical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal "cellular-cocktail" prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties. Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.

Methods: Balb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.

Results: AT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.

Conclusions: The combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).

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在小鼠危重肢体缺血模型中,揭示来自脂肪组织或脐带的间充质干细胞和脐带细胞促进血管再通的不同机制。
背景:危重肢体缺血(CLTI)是外周动脉疾病最严重的表现,通常由动脉粥样硬化引起。CLTI患者下肢截肢的风险很高,死亡率也很高,而由于相关的并发症,他们选择手术血管重建的几率很低。另外,以细胞为基础的治疗策略是促进血管再通的一种有效而安全的方法。然而,细胞组合或应用剂量等几个因素的变化限制了它们在临床试验中的成功,因此有必要在进一步应用于临床之前就最佳 "细胞鸡尾酒 "达成共识。为此,了解这些细胞发挥再生特性的机制至关重要。在此,我们首次评估了从脂肪组织(AT)分离出来的内皮集落形成细胞(ECFCs)和间充质干细胞(MSCs)组合,与脐带血ECFCs(CB-ECFCs)和AT-间充质干细胞相比,在CLTI小鼠模型中的再生和血管生成潜力:将 Balb-c 裸鼠(n:32)分为四组(n:8/组):对照组和缺血小鼠(股骨结扎后),分别接受 50 µl 生理血清或 AT-MSCs 与 CB-ECFCs 或 AT-ECFCs 的细胞组合。对血流再灌注和缺血症状进行了 21 天的跟踪观察,然后将小鼠处死,以评估血管密度的形成。此外,还采用蛋白质组定量方法分析了CLTI和两种细胞组合的长期分子变化:结果:AT-间充质干细胞与 AT- 或 CB-ECFCs 可促进缺血 21 天后 CLTI 小鼠血流量的显著恢复。此外,它们还调节了炎症和坏死相关过程,尽管 CB 组的缺血进展最慢。此外,还发现了许多参与细胞治疗所促进的修复机制的蛋白质:结论:AT-间充质干细胞与AT-ECFCs或CB-ECFCs的结合通过恢复血流水平、调节炎症和坏死过程以及减少肌肉损伤,促进了CLTI小鼠类似的血管再通。所发现的蛋白质变化代表了参与 ECFCs 和间充质干细胞诱导血管再通的分子机制(免疫反应、血管修复、肌肉再生等)。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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