Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia.
Exosomes derived from adipose-derived stem cells overexpressing glyoxalase-1 protect endothelial cells and enhance angiogenesis in type 2 diabetic mice with limb ischemia.
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来自过度表达乙二醛酶-1的脂肪干细胞的外泌体可保护肢体缺血的2型糖尿病小鼠的内皮细胞并增强血管生成
DOI：
10.1186/s13287-021-02475-7
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发表时间：
2021-07-15
影响因子：
7.5
通讯作者：
Peng Z
中科院分区：
文献类型：
--
作者：
Zhang X;Jiang Y;Huang Q;Wu Z;Pu H;Xu Z;Li B;Lu X;Yang X;Qin J;Peng Z
糖尿病肢体缺血是一种临床综合征，治疗困难。我们前期的研究表明，过表达glycoproteinase-1（GLO-1）的脂肪干细胞（ADSCs）可促进糖尿病小鼠缺血下肢的再生，但移植细胞存活率低、分化困难、致瘤性等问题限制了其应用。最近的研究发现，由ADSC分泌的exosomes具有包含亲本有益因子并且表现出非免疫原性、非致瘤性和强稳定性的特性的优点。使用慢病毒转染建立过表达GLO-1的ADSC（G-ADSC），并分离从ADSC分泌的外泌体（G-ADSC-Exos），并表征其与人脐静脉内皮细胞（HUVECs）共培养。在高糖条件下检测HUVECs的增殖、凋亡、迁移和管腔形成。将G-ADSC-Exos注射到2型糖尿病（T2 DM）小鼠缺血后肢肌肉中，通过激光多普勒血流灌注指数、Masson染色、免疫荧光和免疫组化检测来评估治疗效果。此外，探讨了G-ADSC-Exos对HUVECs增殖、迁移、血管生成和凋亡的潜在调节机制。在高糖条件下，G-ADSC-Exos增强体外HUVECs的增殖、迁移、管形成和抗凋亡。在体内移植后，G-ADSC-Exo组显示出更高的激光多普勒血流灌注指数，更好的肌肉结构完整性和更高的微血管密度比ADSC-Exo和对照组通过Masson染色和免疫荧光检测。G-ADSC-Exos在体内外保护内皮细胞的潜在机制可能是通过激活eNOS/AKT/ERK/P-38信号通路，抑制AP-1/ROS/NLRP 3/ASC/Caspase-1/IL-1β，以及增加VEGF、IGF-1和FGF的分泌。过表达GLO-1的脂肪干细胞来源的Exosomes可保护2型糖尿病小鼠下肢缺血的内皮细胞，促进血管新生，有望成为糖尿病下肢缺血的临床治疗方法。在线版本包含补充材料，可通过10.1186/s13287-021-02475-7获得。
Diabetic limb ischemia is a clinical syndrome and refractory to therapy. Our previous study demonstrated that adipose-derived stem cells (ADSCs) overexpressing glyoxalase-1 (GLO-1) promoted the regeneration of ischemic lower limbs in diabetic mice, but low survival rate, difficulty in differentiation, and tumorigenicity of the transplanted cells restricted its application. Recent studies have found that exosomes secreted by the ADSCs have the advantages of containing parental beneficial factors and exhibiting non-immunogenic, non-tumorigenic, and strong stable characteristics. ADSCs overexpressing GLO-1 (G-ADSCs) were established using lentivirus transfection, and exosomes secreted from ADSCs (G-ADSC-Exos) were isolated and characterized to coculture with human umbilical vein endothelial cells (HUVECs). Proliferation, apoptosis, migration, and tube formation of the HUVECs were detected under high-glucose conditions. The G-ADSC-Exos were injected into ischemic hindlimb muscles of type 2 diabetes mellitus (T2DM) mice, and the laser Doppler perfusion index, Masson’s staining, immunofluorescence, and immunohistochemistry assays were adopted to assess the treatment efficiency. Moreover, the underlying regulatory mechanisms of the G-ADSC-Exos on the proliferation, migration, angiogenesis, and apoptosis of the HUVECs were explored. The G-ADSC-Exos enhanced the proliferation, migration, tube formation, and anti-apoptosis of the HUVECs in vitro under high-glucose conditions. After in vivo transplantation, the G-ADSC-Exo group showed significantly higher laser Doppler perfusion index, better muscle structural integrity, and higher microvessel’s density than the ADSC-Exo and control groups by Masson’s staining and immunofluorescence assays. The underlying mechanisms by which the G-ADSC-Exos protected endothelial cells both in vitro and in vivo might be via the activation of eNOS/AKT/ERK/P-38 signaling pathways, inhibition of AP-1/ROS/NLRP3/ASC/Caspase-1/IL-1β, as well as the increased secretion of VEGF, IGF-1, and FGF. Exosomes derived from adipose-derived stem cells overexpressing GLO-1 protected the endothelial cells and promoted the angiogenesis in type 2 diabetic mice with limb ischemia, which will be a promising clinical treatment in diabetic lower limb ischemia. The online version contains supplementary material available at 10.1186/s13287-021-02475-7.
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影响因子：
7.4
作者：
Dzhoyashvili NA;Efimenko AY;Kochegura TN;Kalinina NI;Koptelova NV;Sukhareva OY;Shestakova MV;Akchurin RS;Tkachuk VA;Parfyonova YV
通讯作者：
Parfyonova YV
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
4
作者：
Lane T;Flam B;Lockey R;Kolliputi N
通讯作者：
Kolliputi N
影响因子：
39.3
作者：
Hanssen, Nordin M. J.;Wouters, Kristiaan;Schalkwijk, Casper G.
通讯作者：
Schalkwijk, Casper G.