Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children's Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No.56 Nan-Li-Shi Road, Beijing, 100045, China.
Department of Stem Cell & Regeneration Medicine, Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, No.27 Tai-Ping Road, Beijing, 100091, China.
Stem Cell Res Ther. 2024 Aug 13;15(1):252. doi: 10.1186/s13287-024-03860-8.
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.
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.
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).
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.
肥胖的特征是脂肪过度积累，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）摄入不足是导致后代长期健康不良的一个众所周知的危险因素。然而，对于其对 MSCs 不同分化潜能的影响及其潜在机制，人们知之甚少。
4 周龄雌性 C57BL/6J 小鼠在整个妊娠和哺乳期通过不同的 VD 生殖饮食喂养。通过流式细胞术、RT-PCR 和免疫荧光证实了来自其 7 天大雄性后代的 BMSCs、HuMSCs 的 VDR 敲低建立以及体外不同 VD 干预下 HuMSCs 的特征。还研究了 VD 对其线粒体功能障碍和分化潜能的作用。然后，通过给予高脂肪饮食（HFD）16 周诱导其余断奶雄性幼崽，同时作为对照给予正常脂肪饮食。通过组织学染色和相关基因表达来确定脂肪积累和脂肪细胞肥大。
在此证明，早期生命 VD 摄入失衡可通过影响 VD 代谢和相关代谢物，显著加重肥胖的发生，从而诱导脂肪生成（P < 0.05）。此外，异常的母体 VD 摄入可能参与了分化潜能的紊乱，通过增加 ROS 的产生，抑制 MSCs 干性的维持，这伴随着与脂肪-成骨分化相关的基因表达受损（P < 0.05）。此外，随着 VD 缺乏状态下 MSC 脂肪生成分化潜能的增加，ROS 水平升高，而过量的母体 VD 状态则可通过轻度降低 ROS 水平来增强成骨分化（P < 0.05）。此外，通过体内和体外研究，涉及线粒体功能障碍，特别是自噬，通过激活 LC3b、P62 等，可能是潜在的机制（P < 0.05）。
这些发现表明，早期生命 VD 摄入失衡可靶向 ROS 介导的线粒体功能障碍与 MSCs 分化潜能之间的串扰，这与肥胖症密切相关。显然，我们的研究结果为妊娠和哺乳期适当摄入 VD 带来的益处开辟了一种有吸引力的模式。
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