c-Casitas b-Lineage Lymphoma Downregulation Improves the Ability of Long-term Cultured Mesenchymal Stem Cells for Promoting Angiogenesis and Diabetic Wound Healing.
c-Casitas b-Lineage Lymphoma Downregulation Improves the Ability of Long-term Cultured Mesenchymal Stem Cells for Promoting Angiogenesis and Diabetic Wound Healing.
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c-Casitas b-谱系淋巴瘤下调提高了长期培养的间充质干细胞促进血管生成和糖尿病伤口愈合的能力
DOI：
10.1177/0963689721989605
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发表时间：
2021-01
影响因子：
3.3
通讯作者：
Fan D
中科院分区：
文献类型：
--
作者：
Shen C;Lu Y;Zhang J;Li Y;Zhang Y;Fan D
糖尿病引起的慢性伤口疗效差，可能导致截肢。骨髓间充质干细胞（mesenchymal stem cells，MSCs）在体外长期培养后其修复功能受损。研究表明，原癌基因c-Cbl可以调节受体和非受体酪氨酸激酶，这也参与了血管生成过程。本研究旨在探讨c-Cbl对长期培养的骨髓间充质干细胞促血管生成功能的调节作用及其对糖尿病创面愈合的促进作用。在这项研究中，c-Cbl水平下调锁核酸修饰的反义寡核苷酸gapmers（LNA Gapmers）。我们检测了c-Cbl下调对长期体外培养的MSC的磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（Akt）信号、细胞增殖、衰老、迁移和血管生成因子旁分泌活性的影响。在体内，我们观察了长期培养的MSC的促愈合作用，有或没有c-Cbl下调，对糖尿病伤口。第10代（P10）MSCs与第3代（P3）MSCs相比，c-Cbl磷酸化水平升高，Akt磷酸化水平降低（P < 0.05）。P10细胞增殖、旁分泌和迁移能力明显下降，细胞衰老程度加重（P < 0.05）。下调c-Cbl表达后，P10 MSCs的PI 3 K/Akt活性明显增强（P < 0.05）。与P10 MSC治疗相比，用c-Cbl下调的P10 MSC治疗加速糖尿病伤口愈合，如在糖尿病大鼠模型中更快的伤口闭合（P <0.05）、更多的新血管形成（P < 0.05）和更高的伤口组织学评估评分（P < 0.05）所定义的。我们的研究结果表明，下调c-Cbl可以减轻长期培养诱导的骨髓间充质干细胞的促血管生成功能的损害，并提高长期培养的骨髓间充质干细胞促进糖尿病伤口愈合的效果。
The chronic wound induced by diabetes has poor efficacy and could lead to amputation. The repair function of mesenchymal stem cells (MSCs) impaired after long-term culture in vitro. Studies have shown that the proto-oncogene c-Casitas b-lineage lymphoma (c-Cbl) can regulate receptor- and non-receptor tyrosine kinase, which was also involved in the angiogenesis process. This study aimed to explore the regulative effect of c-Cbl on the proangiogenic functions of long-term cultured MSCs and evaluate its pro-healing effect on diabetic wounds. In this study, the c-Cbl level was downregulated by locked nucleic acid–modified antisense oligonucleotide gapmers (LNA Gapmers). We detected the effect of c-Cbl downregulation on long-term cultured MSCs in terms of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal, cellular proliferation, senescence, migration, and angiogenic factors paracrine activity in vitro. In vivo, we observed the pro-healing effect of long-term cultured MSCs, with or without c-Cbl downregulation, on the diabetic wound. We found that the phosphorylation level of c-Cbl increased and that of Akt decreased in passage 10 (P10) MSCs compared with passage 3 (P3) MSCs (P < 0.05). Additionally, the proliferation, paracrine, and migration capacity of P10 MSCs decreased significantly, accompanied by the increase of cellular senescence (P < 0.05). However, these functions, including PI3K/Akt activity of P10 MSCs, have been improved by c-Cbl downregulation (P < 0.05). Compared with P10 MSCs treatment, treatment with c-Cbl downregulated P10 MSCs accelerated diabetic wound healing, as defined by a more rapid wound closure (P < 0.05), more neovascularization (P < 0.05), and higher scores of wound histological assessment (P < 0.05) in a diabetic rat model. Our findings suggested that c-Cbl downregulation could attenuate the impairment of proangiogenic functions in MSCs induced by long-term culture in vitro and improve the effect of long-term cultured MSCs in promoting diabetic wound healing.
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3.3
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