Che Yiyang, Shimizu Yuuki, Hayashi Takumi, Suzuki Junya, Pu Zhongyue, Tsuzuki Kazuhito, Narita Shingo, Yura Yoshimitsu, Shibata Rei, Murohara Toyoaki
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan.
Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Angiogenesis. 2025 Sep 10;28(4):49. doi: 10.1007/s10456-025-10001-z.
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.
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.
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.
脂肪来源的再生细胞（ADRCs）是用于受损组织再生的有前景的细胞来源。临床研究已证实ADRCs植入治疗严重肢体缺血患者的治疗性血管生成疗效。此过程中有几种可能的机制，如细胞因子和微小RNA。最近，线粒体的细胞间转移在再生医学中受到更多关注。然而，线粒体转移机制在ADRCs对缺血性损伤后功能性组织灌注再生中的作用仍不清楚。在本研究中，我们旨在使用小鼠后肢缺血模型研究线粒体转移是否是ADRCs治疗性血管生成的潜在机制。
在初步研究中，在小鼠后肢缺血模型中证实了在ADRCs一系列促血管生成作用中ADRCs的线粒体转移至内皮细胞和巨噬细胞的发生。随后，我们使用延时共聚焦显微镜和细胞分选技术全面阐明了基于连接蛋白43的间隙连接和隧道纳米管介导的ADRCs线粒体转移至人脐静脉内皮细胞（HUVECs）和巨噬细胞的模式。此外，ADRCs的线粒体转移增强了血管内皮细胞的线粒体生物合成和血管生成，并使巨噬细胞向M2表型转变。值得注意的是，部分消除ADRCs的线粒体转移会阻碍后肢缺血中ADRCs的血管生成能力。
ADRCs可保护缺血肢体，至少部分是通过间隙连接和纳米管隧道将线粒体转移至受损内皮细胞和巨噬细胞来实现的。此外，线粒体转移是ADRCs治疗后肢缺血性血管生成的潜在机制。
