Khan Mohsin, Ali Fatima, Mohsin Sadia, Akhtar Shoaib, Mehmood Azra, Choudhery Mahmood S, Khan Shaheen N, Riazuddin Sheikh
Stem Cell Res Ther. 2013 May 24;4(3):58. doi: 10.1186/scrt207.
Mesenchymal stem cells (MSCs) have the potential for treatment of diabetic cardiomyopathy; however, the repair capability of MSCs declines with age and disease. MSCs from diabetic animals exhibit impaired survival, proliferation, and differentiation and therefore require a strategy to improve their function. The aim of the study was to develop a preconditioning strategy to augment the ability of MSCs from diabetes patients to repair the diabetic heart.
Diabetes was induced in C57BL/6 mice (6 to 8 weeks) with streptozotocin injections (55 mg/kg) for 5 consecutive days. MSCs isolated from diabetic animals were preconditioned with medium from cardiomyocytes exposed to oxidative stress and high glucose (HG/H-CCM).
Gene expression of VEGF, ANG-1, GATA-4, NKx2.5 MEF2c, PCNA, and eNOS was upregulated after preconditioning with HG/H-CCM, as evidenced by reverse transcriptase/polymerase chain reaction (RT-PCR). Concurrently, increased AKT phosphorylation, proliferation, angiogenic ability, and reduced levels of apoptosis were observed in HG/H-CCM-preconditioned diabetic MSCs compared with nontreated controls. HG/H-CCM-preconditioned diabetic-mouse-derived MSCs (dmMSCs) were transplanted in diabetic animals and demonstrated increased homing concomitant with augmented heart function. Gene expression of angiogenic and cardiac markers was significantly upregulated in conjunction with paracrine factors (IGF-1, HGF, SDF-1, FGF-2) and, in addition, reduced fibrosis, apoptosis, and increased angiogenesis was observed in diabetic hearts 4 weeks after transplantation of preconditioned dmMSCs compared with hearts with nontreated diabetic MSCs.
Preconditioning with HG/H-CCM enhances survival, proliferation, and the angiogenic ability of dmMSCs, augmenting their ability to improve function in a diabetic heart.
间充质干细胞（MSCs）具有治疗糖尿病性心肌病的潜力；然而，MSCs的修复能力会随着年龄和疾病而下降。来自糖尿病动物的MSCs在存活、增殖和分化方面表现受损，因此需要一种策略来改善其功能。本研究的目的是开发一种预处理策略，以增强糖尿病患者来源的MSCs修复糖尿病心脏的能力。
通过连续5天注射链脲佐菌素（55mg/kg）诱导6至8周龄的C57BL/6小鼠患糖尿病。从糖尿病动物分离的MSCs用暴露于氧化应激和高糖环境的心肌细胞培养基（HG/H-CCM）进行预处理。
经HG/H-CCM预处理后，通过逆转录酶/聚合酶链反应（RT-PCR）证明，血管内皮生长因子（VEGF）、血管生成素-1（ANG-1）、GATA-4、NKx2.5、心肌增强因子2c（MEF2c）、增殖细胞核抗原（PCNA）和内皮型一氧化氮合酶（eNOS）的基因表达上调。同时，与未处理的对照组相比，经HG/H-CCM预处理的糖尿病MSCs中AKT磷酸化增加、增殖、血管生成能力增强且凋亡水平降低。将经HG/H-CCM预处理的糖尿病小鼠来源的MSCs（dmMSCs）移植到糖尿病动物体内，结果显示归巢增加，同时心脏功能增强。血管生成和心脏标志物的基因表达与旁分泌因子（胰岛素样生长因子-1、肝细胞生长因子、基质细胞衍生因子-1、成纤维细胞生长因子-2）一起显著上调，此外，与移植未处理的糖尿病MSCs的心脏相比，移植经预处理的dmMSCs 4周后的糖尿病心脏中纤维化减少、凋亡减少且血管生成增加。
用HG/H-CCM进行预处理可增强dmMSCs的存活、增殖和血管生成能力，并增强其改善糖尿病心脏功能的能力。
