Diabetes impairs the angiogenic capacity of human adipose-derived stem cells by reducing the CD271+ subpopulation in adipose tissue
Diabetes impairs the angiogenic capacity of human adipose-derived stem cells by reducing the CD271+ subpopulation in adipose tissue
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DOI：
10.1016/j.bbrc.2019.07.081
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发表时间：
2019-09-17
影响因子：
3.1
通讯作者：
Takamura, Masayuki
中科院分区：
文献类型：
--
作者：
Inoue, Oto;Usui, Soichiro;Takamura, Masayuki
2型糖尿病是心血管疾病（CVD）的重要危险因素。利用脂肪干细胞（ADSC）进行血管生成治疗对于CVD治疗是有吸引力的。然而，尽管ADSC应用于CVD治疗至关重要，但糖尿病是否以及如何损害人类ADSC治疗潜力仍不确定。在这项研究中，我们的目的是研究糖尿病对血管性疾病患者ADSCs血管生成潜力的影响，特别关注ADSCs的干细胞相关基因和细胞改变。我们从患有CVD的糖尿病患者（DM-ADSCs）和非糖尿病患者（nonDM-ADSCs）中建立了培养的ADSCs。DM-ADSC表现出有限的增殖能力和VEGF的旁分泌能力降低，干性基因SOX 2的表达较低。在无胸腺裸鼠后肢缺血模型中使用异种移植实验评估血管生成能力和ADSC植入。与体外试验结果一致，DM-ADSC不能挽救肢体缺血。相比之下，非DM-ADSC诱导的新血管形成具有增强的植入。为了阐明这些ADSC变化的机制，我们通过流式细胞术比较了从糖尿病和非糖尿病患者中获得的新鲜分离的ADSC的表面标志物谱。在研究的亚群中，糖尿病患者脂肪组织中的CD 34（+）CD 31（-）CD 271（+）亚群减少。此外，在来源于间质血管组分（SVF）的非DM-ADSC中，随着CD 271（+）细胞的消耗，SOX 2表达和增殖能力显著降低（p < 0.01）。我们的观察阐明，减少CD 271（+）亚群是糖尿病患者ADSC受损的关键。对ADSC的CD 271（+）子集的进一步研究可能会为细胞治疗中糖尿病相关ADSC功能障碍的机制和解决方案提供新的见解。(C)2019爱思唯尔公司All rights reserved.
Type 2 diabetes mellitus is an important risk factor for cardiovascular diseases (CVDs). Therapeutic angiogenesis using adipose-derived stem cells (ADSCs) is attractive for CVD therapy. However, although it would be critical for ADSC application on CVD therapy, whether and how diabetes impairs human ADSC therapeutic potential is still uncertain. In this study, we aimed to investigate the impact of diabetes on the angiogenic potential of ADSCs in patients with CVDs, with special focus on stemness-related genes and cellular alteration of ADSCs. We established cultured ADSCs from diabetic (DM-ADSCs) and nondiabetic patients (nonDM-ADSCs) with CVDs. DM-ADSCs demonstrated limited proliferative capacity and reduced paracrine capacity of VEGF, with lower expression of the stemness gene SOX2. Angiogenic capacity and ADSC engraftment were assessed using xenograft experiments in a hindlimb ischemia model of athymic nude mice. Consistent with the results of in vitro assays, DM-ADSCs did not rescue limb ischemia. In contrast, nonDM-ADSCs induced neovascularization with enhanced engraftment. To elucidate the mechanism underlying these ADSC changes, we compared the surface marker profiles of freshly isolated ADSCs obtained from diabetic and non-diabetic patients by flow cytometry. Among studied subsets, the CD34(+)CD31(-)CD271(+) subpopulation was reduced in the adipose tissues of diabetic patients. In addition, SOX2 expression and proliferative capacity were considerably reduced in nonDM-ADSCs derived from the stromal vascular fraction (SVF) with depletion of CD271(+) cells (p < 0.01). Our observations elucidated that reduced CD271(+) subpopulation is critical for the impairment of ADSCs in diabetic patients. Further investigations on the CD271(+) subset of ADSCs might provide novel insights into the mechanisms and solutions for diabetes-related ADSC dysfunction in cell therapy. (C) 2019 Elsevier Inc. All rights reserved.