背景:肥胖的特征是过度的脂肪积累,这与间充质干细胞(MSCs)的异常多能性有关。最近,越来越多的证据表明,母体维生素D(VD)摄入紊乱是导致后代长期不良健康结局的一个众所周知的危险因素.否则,其对MSCs不同分化潜能的影响和潜在机制知之甚少。
方法:在整个妊娠和哺乳期间,给四周龄雌性C57BL/6J小鼠饲喂不同的VD生殖饮食。7天雄性后代BMSCs的特征,流式细胞术证实了体外不同VD干预下HuMSCs和HuMSCs的VDR敲除建立,RT-PCR,和免疫荧光。还研究了VD在线粒体功能障碍和分化潜能中的作用。然后通过给予高脂饮食(HFD)16周来诱导其剩余的断奶雄性幼崽,同时以正常脂肪饮食为对照。通过组织学染色和相关基因表达来确定它们的脂质积累和脂肪细胞肥大。
结果:这里,研究证明,生命早期VD摄入失衡可通过影响VD代谢及相关代谢产物诱导脂肪形成,从而显著加重肥胖的发生(P<0.05)。此外,异常的母体VD摄入可能参与分化潜能的紊乱,通过增加ROS的产生来抑制MSCs的干性维持,伴随着脂肪成骨分化相关基因的表达受损(P<0.05)。此外,在VD缺乏状态下,随着MSCs成脂分化潜力的增加,ROS水平更高,而过度的母体VD状态可以相反地增强成骨分化,ROS略低(P<0.05)。此外,潜在的机制可能与线粒体功能失调有关,尤其是有丝分裂,通过激活LC3b,P62等。使用体内和体外研究(P<0.05)。
结论:这些研究结果表明,生命早期VD摄入的失衡可以靶向ROS介导的线粒体功能障碍与MSCs分化潜能之间的串扰,这与后来的肥胖显著相关。显然,我们的结果可能为在怀孕和哺乳期间适当摄入VD的益处开辟一种有吸引力的方式.
BACKGROUND: Obesity is characterized by excessive fat accumulation, which is related with abnormal pluripotency of mesenchymal stem cells (MSCs). Recently, there is growing evidence that the disorder of maternal vitamin D (VD) intake is a well-known risk factor for long-term adverse health outcomes to their offspring. Otherwise, less is known of its repercussion and underlying mechanisms on the different differentiation potential of MSCs.
METHODS: Four-week-old female C57BL/6J mice were fed with different VD reproductive diets throughout the whole pregnancy and lactation. The characteristics of BMSCs from their seven-day male offspring, VDR knockdown establishment of HuMSCs and HuMSCs under the different VD interventions in vitro were confirmed by flow cytometry, RT-PCR, and immunofluorescence. The roles of VD on their mitochondrial dysfunction and differentiation potential were also investigated. Then their remaining weaned male pups were induced by administrating high-fat-diet (HFD) for 16 weeks and normal fat diet was simultaneously as controls. Their lipid accumulation and adipocytes hypertrophy were determined by histological staining and related gene expressions.
RESULTS: Herein, it was proved that imbalance of early-life VD intake could significantly aggravate the occurrence of obesity by inducing the adipogenesis through affecting the VD metabolism and related metabolites (P < 0.05). Moreover, abnormally maternal VD intake might be involved on the disorders of differentiation potential to inhibit the maintenance of MSCs stemness through increasing the productions of ROS, which was accompanied by impairing the expression of related genes on the adipo-osteogenic differentiation (P < 0.05). Moreover, it was along with increasing potential of adipogenic differentiation of MSCs as higher ROS in the state of VD deficiency, while excessive maternal VD status could conversely enhance the osteogenic differentiation with slightly lower ROS (P < 0.05). Furthermore, the underlying mechanisms might be involved on the mitochondria dysfunctional, especially the mitophagy, by activating the LC3b, P62 and etc. using in vivo and in vitro studies (P < 0.05).
CONCLUSIONS: These findings demonstrated that imbalance of early-life VD intake could target ROS-mediated crosstalk between mitochondrial dysfunction and differentiation potential of MSCs, which was significantly associated with the later obesity. Obviously, our results could open up an attractive modality for the benefits of suitable VD intake during the pregnancy and lactation.