Mitochondrial transfer from adipose-derived regenerative cells contributes therapeutic angiogenesis in a murine hindlimb ischemia model

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2025-09-10 DOI:10.1007/s10456-025-10001-z

Yiyang Che, Yuuki Shimizu, Takumi Hayashi, Junya Suzuki, Zhongyue Pu, Kazuhito Tsuzuki, Shingo Narita, Yoshimitsu Yura, Rei Shibata, Toyoaki Murohara

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引用次数: 0

Abstract

Objective

Adipose-derived regenerative cells (ADRCs) are promising cell sources for damaged tissue regeneration. The efficacy of therapeutic angiogenesis with ADRC implantation in patients with critical limb ischemia has been demonstrated in clinical studies. There are several possible mechanisms in this process such as cytokines and microRNA. Recently, cell-to-cell transfer of mitochondria gains more attention in regenerative medicine. However, the role of the mitochondrial transfer mechanism in ADRCs in the regeneration of functional tissue perfusion following ischemic injury remains unclear. In this study, we aimed to investigate whether mitochondrial transfer is a potential mechanism of therapeutic angiogenesis in ADRCs using a murine hindlimb ischemia model.

Methods and results

In initial studies, the occurrence of mitochondrial transfer of ADRC to endothelial cells and macrophages in a series of pro-angiogenic effects of ADRC was demonstrated in a mouse model of hindlimb ischemia. Subsequently, we comprehensively elucidated the modes of mitochondrial transfer from ADRCs to HUVECs and macrophages mediated by Connexin43-based gap junctions and tunneling nanotubes using time-lapse confocal microscopy and cell sorting techniques. Furthermore, mitochondrial transfer from ADRCs enhanced mitochondrial biogenesis and angiogenesis in vascular endothelial cells and shifted macrophages toward the M2-phenotype. Notably, partially canceled mitochondrial transfer from ADRCs could impede the angiogenic ability of ADRCs in hind limb ischemia.

Conclusions

ADRCs can protect against ischemic limbs, at least in part by mitochondrial transfer via gap junctions and tunneling of nanotubes into injured endothelial cells and macrophages. Additionally, mitochondrial transfer is a potential mechanism for therapeutic angiogenesis with ADRCs in hindlimb ischemia.

Graphical abstract

Schematic illustration showing potential mechanisms of mitochondrial transfer from ADRCs in mouse hindlimb ischemia model. This figure was created with BioRender.

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在小鼠后肢缺血模型中，来自脂肪再生细胞的线粒体转移有助于治疗性血管生成

目的脂肪再生细胞（adrc）是一种很有前途的损伤组织再生细胞来源。临床研究已经证实了ADRC植入治疗性血管生成在重症肢体缺血患者中的疗效。在这一过程中有多种可能的机制，如细胞因子和microRNA。近年来，线粒体的细胞间转移在再生医学中受到越来越多的关注。然而，线粒体转移机制在缺血损伤后功能性组织灌注再生中的作用尚不清楚。在这项研究中，我们旨在通过小鼠后肢缺血模型研究线粒体转移是否是adrc治疗性血管生成的潜在机制。方法和结果在小鼠后肢缺血模型中，研究证实了ADRC线粒体向内皮细胞和巨噬细胞转移的一系列促血管生成作用。随后，我们利用延时共聚焦显微镜和细胞分选技术，全面阐明了基于connexin43的间隙连接和隧道纳米管介导的线粒体从adrc向HUVECs和巨噬细胞转移的模式。此外，来自adrc的线粒体转移增强了血管内皮细胞的线粒体生物发生和血管生成，并使巨噬细胞向m2表型转移。值得注意的是，部分取消的adrc线粒体转移可能会阻碍后肢缺血时adrc的血管生成能力。结论sadrcs对缺血肢体的保护作用，至少部分是通过间隙连接的线粒体转移和纳米管隧道进入损伤的内皮细胞和巨噬细胞。此外，线粒体转移是后肢缺血用adrc治疗血管生成的潜在机制。图示：小鼠后肢缺血模型中adrc线粒体转移的潜在机制。这个图是用BioRender创建的。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.