Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress.
Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress.
复制标题
二肽基肽酶 4 调节造血干细胞活化以应对慢性压力。
DOI：
10.1161/jaha.117.006394
复制
发表时间：
2017-07-14
影响因子：
5.4
通讯作者：
Cheng XW
中科院分区：
文献类型：
--
作者：
Zhu E;Hu L;Wu H;Piao L;Zhao G;Inoue A;Kim W;Yu C;Xu W;Bando YK;Li X;Lei Y;Hao CN;Takeshita K;Kim WS;Okumura K;Murohara T;Kuzuya M;Cheng XW
DPP 4（二肽基肽酶-4）-GLP-1（胰高血糖素样肽-1）及其受体（GLP-1 R）轴参与了几种细胞内信号通路。Adrβ3（β3-肾上腺素能受体）/CXCL 12（C-X-C基序趋化因子12）信号是造血所必需的。我们研究了慢性应激下骨髓（BM）造血干细胞（HSC）激活中DPP 4-GLP-1/GLP-1和Adrβ3/CXCL 12信号之间的新分子需求。对8周龄雄性小鼠进行4周间歇性束缚应激，并经口给予溶媒或DPP 4抑制剂阿格列汀（30 mg/kg/天）。对照小鼠不受干扰。应激增加血液和脑DPP 4水平、血浆肾上腺素和去甲肾上腺素水平以及BM龛细胞Adrβ3表达，并降低血浆GLP-1水平以及脑GLP-1 R和BM CXCL 12表达。这些变化被DPP 4抑制逆转。应激激活BM sca-1highc-Ki thigh CD 48 low CD 150 high HSC增殖，导致血液白细胞和单核细胞水平升高。应激激活的HSC增殖通过DPP 4耗竭和GLP-1 R激活逆转。最后，选择性药物阻断Adrβ3可减轻HSC活化，同时改善慢性应激时BM niche细胞中CXCL 12基因的表达。这些发现表明，DPP 4可以通过GLP-1/GLP-1 R轴介导的Adrβ3/CXCL 12依赖性机制调节慢性应激诱导的BM HSC活化和炎性细胞产生，这表明DPP 4抑制或GLP-1 R刺激可能用于治疗炎性疾病。
DPP4 (Dipeptidyl peptidase‐4)‐GLP‐1 (glucagon‐like peptide‐1) and its receptor (GLP‐1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3‐adrenergic receptor)/CXCL12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4‐GLP‐1/GLP‐1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress. Male 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP‐1 levels and the brain GLP‐1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca‐1highc‐Kithigh CD48low CD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP4 depletion and by GLP‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress. These findings suggest that DPP4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12‐dependent mechanism that is mediated by the GLP‐1/GLP‐1R axis, suggesting that the DPP4 inhibition or the GLP‐1R stimulation may have applications for treating inflammatory diseases.