Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors.
Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors.
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DOI：
10.1016/j.ebiom.2018.09.035
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发表时间：
2018-10
期刊：
影响因子：
11.1
通讯作者：
Watada H
中科院分区：
文献类型：
--
作者：
Miura M;Miyatsuka T;Katahira T;Sasaki S;Suzuki L;Himuro M;Nishida Y;Fujitani Y;Matsuoka TA;Watada H
STAT3已被证明在维持胰腺中的细胞特性中起作用，而激活STAT3突变已与受损的β细胞功能相关。在体外和体内分析了STAT3在由Pdx 1、Neurog 3和Mafa的外源性表达诱导的β细胞新生中的作用。在表达Pdx 1和Mafa的细胞中均诱导磷酸化STAT3（pSTAT3）的表达，但大多数诱导的β细胞对pSTAT3呈阴性。STAT3信号的抑制，以及外源性表达的Pdx 1、Neurog 3和Mafa，显著增加了体外和体内重编程β细胞的数量，增强了小鼠胰岛样簇的形成，并改善了糖尿病小鼠的高血糖症。这些发现表明，STAT3抑制促进细胞重编程为β样细胞，由定义的转录因子协调，这可能导致建立用于治疗糖尿病的细胞疗法。JSPS、MEXT、武田科学基金会、Suzuken纪念基金会、安斯泰来代谢紊乱研究基金会、诺和诺德、礼来、默沙东、Life Scan、诺华和武田。STAT3通过Pdx 1或Mafa的外源性表达被激活，并在细胞重编程为β细胞期间被抑制。STAT3抑制与Pdx 1、Neurog 3和Mafa的外源性表达一起促进细胞重编程为β细胞。STAT3抑制，连同Pdx 1，Neurog 3和Mafa的外源性表达，改善糖尿病小鼠的高血糖症。
STAT3 has been demonstrated to play a role in maintaining cellular identities in the pancreas, whereas an activating STAT3 mutation has been linked to impaired β-cell function. The role of STAT3 in β-cell neogenesis, induced by the exogenous expression of Pdx1, Neurog3, and Mafa, was analyzed in vitro and in vivo. The expression of phosphorylated STAT3 (pSTAT3) was induced in both Pdx1-expressing and Mafa-expressing cells, but most of the induced β cells were negative for pSTAT3. The suppression of STAT3 signaling, together with exogenously expressed Pdx1, Neurog3, and Mafa, significantly increased the number of reprogrammed β cells in vitro and in vivo, enhanced the formation of islet-like clusters in mice, and ameliorated hyperglycemia in diabetic mice. These findings suggest that STAT3 inhibition promotes cellular reprogramming into β-like cells, orchestrated by defined transcription factors, which may lead to the establishment of cell therapies for curing diabetes. JSPS, MEXT, Takeda Science Foundation, Suzuken Memorial Foundation, Astellas Foundation for Research on Metabolic Disorders, Novo Nordisk, Eli Lilly, MSD, Life Scan, Novartis, and Takeda. STAT3 is activated by exogenous expression of Pdx1 or Mafa and suppressed during cellular reprogramming into β cells. STAT3 inhibition, together with exogenous expression of Pdx1, Neurog3, and Mafa, promotes cellular reprogramming into β cells. STAT3 inhibition, together with exogenous expression of Pdx1, Neurog3, and Mafa, ameliorated hyperglycemia in diabetic mice.
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影响因子：
7.7
作者：
Matsuoka TA;Kawashima S;Miyatsuka T;Sasaki S;Shimo N;Katakami N;Kawamori D;Takebe S;Herrera PL;Kaneto H;Stein R;Shimomura I
通讯作者：
Shimomura I
DOI：
10.1016/j.bbrc.2014.01.083
发表时间：
2014-02-21
影响因子：
3.1
作者：
Miyashita, Kazuyuki;Miyatsuka, Takeshi;Shimomura, Iichiro
通讯作者：
Shimomura, Iichiro
影响因子：
11.2
作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
通讯作者：
Resar LM
影响因子：
50.3
作者：
Fukuda A;Wang SC;Morris JP 4th;Folias AE;Liou A;Kim GE;Akira S;Boucher KM;Firpo MA;Mulvihill SJ;Hebrok M
通讯作者：
Hebrok M
影响因子：
8.8
作者：
Valdez IA;Dirice E;Gupta MK;Shirakawa J;Teo AKK;Kulkarni RN
通讯作者：
Kulkarni RN