Basal p53 expression is indispensable for mesenchymal stem cell integrity.
Basal p53 expression is indispensable for mesenchymal stem cell integrity.
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DOI：
10.1038/s41418-017-0004-4
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发表时间：
2018-03
影响因子：
12.4
通讯作者：
Phinney DG
中科院分区：
文献类型：
--
作者：
Boregowda SV;Krishnappa V;Strivelli J;Haga CL;Booker CN;Phinney DG
骨髓间充质干细胞（MSC）作为血管周围生态位的功能成分，调节造血。它们也代表了成人骨髓中形成的骨的主要来源，并且它们分化成成骨细胞和脂肪细胞谱系在骨骼稳态和衰老中起关键作用。尽管肿瘤抑制因子p53在骨器官形成、体内平衡和肿瘤形成中也起作用，但其在MSC中的作用仍然很少被描述。在此，我们研究了在生理氧水平下培养的原代MSC中p53的正常生理作用。使用基因敲除小鼠和基因沉默，我们表明，p53失活下调TWIST 2的表达，TWIST 2通常抑制细胞分化，以维持野生型MSC在多能状态，消耗线粒体活性氧（ROS）水平，并抑制ROS生成和PPARG基因和蛋白诱导，以响应脂肪形成刺激。从机制上讲，这种成脂潜力的丧失使MSC偏向成骨命运，这通过TWIST 2下调进一步增强，导致高度增强的成骨分化。我们还表明，p53−/− MSC在支持造血方面存在缺陷，如标准集落测定所测量的，因为包括CXCL 12和CSF 1在内的各种细胞因子的分泌减少。最后，我们表明，野生型间充质干细胞瞬时暴露于21%的氧气上调p53蛋白的表达，导致增加线粒体ROS的生产和增强成脂分化的代价成骨，并与FGF 2的细胞治疗减轻这些影响诱导TWIST 2。总之，这些发现表明，基础p53水平是必要的，以维持MSC的双能性，和氧诱导的p53表达的增加调节细胞命运和生存的决定。由于基础p53在间充质干细胞中的关键功能，我们的研究结果质疑使用p53空细胞系作为间充质干细胞替代物，也暗示了在p53相关骨骼疾病的病理生理学中功能失调的间充质干细胞反应。
Marrow-resident mesenchymal stem cells (MSCs) serve as a functional component of the perivascular niche that regulates hematopoiesis. They also represent the main source of bone formed in adult bone marrow, and their bifurcation to osteoblast and adipocyte lineages plays a key role in skeletal homeostasis and aging. Although the tumor suppressor p53 also functions in bone organogenesis, homeostasis, and neoplasia, its role in MSCs remains poorly described. Herein, we examined the normal physiological role of p53 in primary MSCs cultured under physiologic oxygen levels. Using knockout mice and gene silencing we show that p53 inactivation downregulates expression of TWIST2, which normally restrains cellular differentiation to maintain wild-type MSCs in a multipotent state, depletes mitochondrial reactive oxygen species (ROS) levels, and suppresses ROS generation and PPARG gene and protein induction in response to adipogenic stimuli. Mechanistically, this loss of adipogenic potential skews MSCs toward an osteogenic fate, which is further potentiated by TWIST2 downregulation, resulting in highly augmented osteogenic differentiation. We also show that p53−/− MSCs are defective in supporting hematopoiesis as measured in standard colony assays because of decreased secretion of various cytokines including CXCL12 and CSF1. Lastly, we show that transient exposure of wild-type MSCs to 21% oxygen upregulates p53 protein expression, resulting in increased mitochondrial ROS production and enhanced adipogenic differentiation at the expense of osteogenesis, and that treatment of cells with FGF2 mitigates these effects by inducing TWIST2. Together, these findings indicate that basal p53 levels are necessary to maintain MSC bi-potency, and oxygen-induced increases in p53 expression modulate cell fate and survival decisions. Because of the critical function of basal p53 in MSCs, our findings question the use of p53 null cell lines as MSC surrogates, and also implicate dysfunctional MSC responses in the pathophysiology of p53-related skeletal disorders.
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影响因子：
23.9
作者：
Liu Y;Elf SE;Miyata Y;Sashida G;Liu Y;Huang G;Di Giandomenico S;Lee JM;Deblasio A;Menendez S;Antipin J;Reva B;Koff A;Nimer SD
通讯作者：
Nimer SD
影响因子：
5.6
作者：
Asai, Takashi;Liu, Yan;Bae, Narae;Nimer, Stephen D.
通讯作者：
Nimer, Stephen D.
影响因子：
16.6
作者：
Marciano, David P.;Kuruvilla, Dana S.;Boregowda, Siddaraju V.;Asteian, Alice;Hughes, Travis S.;Garcia-Ordonez, Ruben;Corzo, Cesar A.;Khan, Tanya M.;Novick, Scott J.;Park, HaJeung;Kojetin, Douglas J.;Phinney, Donald G.;Bruning, John B.;Kamenecka, Theodore M.;Griffin, Patrick R.
通讯作者：
Griffin, Patrick R.
影响因子：
5.2
作者：
Lai, Wen-Tzu;Krishnappa, Veena;Phinney, Donald G.
通讯作者：
Phinney, Donald G.
影响因子：
20.3
作者：
Kojima, Kensuke;McQueen, Teresa;Andreeff, Michael
通讯作者：
Andreeff, Michael