School of Pharmacy, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Int J Mol Sci. 2022 Apr 28;23(9):4900. doi: 10.3390/ijms23094900.
Genetic mutations of cause intellectual disability with the atrophy of brain structures and variable obesity by poorly understood mechanisms. Trappc9-deficient mice develop phenotypes resembling pathological changes in humans and appear overweight shortly after weaning, and thus are useful for studying the pathogenesis of obesity. Here, we investigated the effects of trappc9 deficiency on the proliferation and differentiation capacity of adipose-derived stem cells (ASCs). We isolated ASCs from mice before overweight was developed and found that trappc9-null ASCs exhibited signs of premature senescence and cell death. While the lineage commitment was retained, trappc9-null ASCs preferred adipogenic differentiation. We observed a profound accumulation of lipid droplets in adipogenic cells derived from trappc9-deficient ASCs and marked differences in the distribution patterns and levels of calcium deposited in osteoblasts obtained from trappc9-null ASCs. Biochemical studies revealed that trappc9 deficiency resulted in an upregulated expression of rab1, rab11, and rab18, and agitated autophagy in ASCs. Moreover, we found that the content of neural stem cells in both the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus vastly declined in trappc9-null mice. Collectively, our results suggest that obesity, as well as brain structure hypoplasia induced by the deficiency of trappc9, involves an impairment in the plasticity of stem cells.
遗传突变导致智力障碍，其脑结构萎缩和肥胖程度不同，其机制尚不清楚。Trappc9 缺陷型小鼠表现出类似于人类病理变化的表型，并在断奶后不久就出现超重，因此可用于研究肥胖症的发病机制。在这里，我们研究了 trappc9 缺乏对脂肪干细胞（ASCs）增殖和分化能力的影响。我们在超重发生之前从小鼠中分离出 ASCs，发现 trappc9 缺失的 ASC 表现出衰老和细胞死亡的早期迹象。虽然谱系定向得以保留，但 trappc9 缺失的 ASC 更喜欢脂肪生成分化。我们观察到源自 trappc9 缺失 ASC 的脂肪细胞中脂质滴的大量积累，以及源自 trappc9 缺失 ASC 的成骨细胞中钙沉积的分布模式和水平存在明显差异。生化研究表明，trappc9 缺乏导致 rab1、rab11 和 rab18 的表达上调，并激活了 ASC 中的自噬。此外，我们发现 trappc9 缺失小鼠的侧脑室室下区和齿状回颗粒下层的神经干细胞含量大量减少。总之，我们的结果表明，肥胖以及 trappc9 缺乏引起的脑结构发育不良涉及干细胞可塑性的损伤。
