IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution.
IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution.
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DOI：
10.1002/stem.2645
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Phinney DG
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文献类型：
--
作者：
Boregowda SV;Ghoshal S;Booker CN;Krishnappa V;Chakraborty A;Phinney DG
间充质干/基质细胞（MSCs）是成年骨髓中骨和脂肪组织的主要来源，在骨骼内稳态中起关键作用。年龄诱导的骨髓变化有利于脂肪生成而非骨生成，导致骨骼退化和骨髓脂肪增多，因此预防MSC衰老的途径是治疗年龄相关骨病的潜在治疗靶点。在此，我们发现小鼠中肌醇六磷酸激酶1（Ip6k1）缺失会增加骨髓中MSC的产量，并提高细胞在体外的生长和存活能力。在适当刺激下，与Ip6k1+/+ MSCs相比，Ip6k1 -/ - MSCs还表现出更强的成骨和造血支持活性以及更低的成脂分化能力。基于机制的研究表明，与Ip6k1+/+ MSCs相比，Ip6k1 -/ - MSCs表达更高的MDM2和更低的p53蛋白水平，导致内在线粒体活性氧（ROS）水平更低，但在氧诱导应激时，两种细胞群线粒体ROS上调程度相似。最后，我们发现喂食高脂肪饮食的小鼠表现出骨小梁体积减少，并且使用一种泛IP6K抑制剂对IP6K1进行药理抑制在很大程度上逆转了这种表型，同时增加了骨髓中MSC的产量。总之，这些发现揭示了IP6K1在调节MSC适应性和分化命运方面的重要作用。与针对过氧化物酶体增殖物激活受体γ和瘦素受体活性的治疗干预不同（分别会产生包括骨折风险增加和进食行为改变等有害副作用），抑制IP6K1可维持胰岛素敏感性，预防肥胖，同时保持骨骼完整性。因此，由于其保护骨骼的特性，IP6K1抑制剂可能是更有效的胰岛素增敏剂。《干细胞》2017年；35卷：1973 - 1983页
Mesenchymal stem/stromal cells (MSCs) are the predominant source of bone and adipose tissue in adult bone marrow and play a critical role in skeletal homeostasis. Age‐induced changes in bone marrow favor adipogenesis over osteogenesis leading to skeletal involution and increased marrow adiposity so pathways that prevent MSC aging are potential therapeutic targets for treating age‐related bone diseases. Here, we show that inositol hexakisphosphate kinase 1 (Ip6k1) deletion in mice increases MSC yields from marrow and enhances cell growth and survival ex vivo. In response to the appropriate stimuli, Ip6k1 −/− versus Ip6k1+/+ MSCs also exhibit enhanced osteogenesis and hematopoiesis‐supporting activity and reduced adipogenic differentiation. Mechanistic‐based studies revealed that Ip6k1 −/− MSCs express higher MDM2 and lower p53 protein levels resulting in lower intrinsic mitochondrial reactive oxygen species (ROS) levels as compared to Ip6k1+/+ MSCs, but both populations upregulate mitochondrial ROS to similar extents in response to oxygen‐induced stress. Finally, we show that mice fed a high fat diet exhibit reduced trabecular bone volume, and that pharmacological inhibition of IP6K1 using a pan‐IP6K inhibitor largely reversed this phenotype while increasing MSC yields from bone marrow. Together, these findings reveal an important role for IP6K1 in regulating MSC fitness and differentiation fate. Unlike therapeutic interventions that target peroxisome proliferator‐activated receptor gamma and leptin receptor activity, which yield detrimental side effects including increased fracture risk and altered feeding behavior, respectively, inhibition of IP6K1 maintains insulin sensitivity and prevents obesity while preserving bone integrity. Therefore, IP6K1 inhibitors may represent more effective insulin sensitizers due to their bone sparing properties. Stem Cells 2017;35:1973–1983
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作者：
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