Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes.
Sensory neuropathy hampers nociception-mediated bone marrow stem cell release in mice and patients with diabetes.
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DOI：
10.1007/s00125-015-3735-0
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发表时间：
2015-11
期刊：
影响因子：
8.2
通讯作者：
Madeddu P
中科院分区：
文献类型：
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作者：
Dang Z;Maselli D;Spinetti G;Sangalli E;Carnelli F;Rosa F;Seganfreddo E;Canal F;Furlan A;Paccagnella A;Paiola E;Lorusso B;Specchia C;Albiero M;Cappellari R;Avogaro A;Falco A;Quaini F;Ou K;Rodriguez-Arabaolaza I;Emanueli C;Sambataro M;Fadini GP;Madeddu P
在组织损伤时，外周感觉神经元释放伤害性因子（如物质P [SP]），发挥局部和全身作用，包括募集具有旁分泌促血管生成特性的骨髓（BM）来源的造血干细胞和祖细胞（HSPCs）。我们在此探讨糖尿病神经病变是否干扰这些现象。我们首先通过免疫组织化学和形态计量学分析神经大小和密度，并通过ELISA评估SP释放来研究2型糖尿病患者BM中感觉神经病变的存在。接下来，我们分析了感觉神经病变与缺血或粒细胞集落刺激因子（G-CSF）直接刺激后HSPC释放改变的关系。流式细胞术检测BM和表达主要SP受体神经激肽1受体（NK1R）的循环HSPCs。在肢体缺血（LI）后的2型糖尿病小鼠模型中，我们最终评估了SP分泌调节的改变是否会干扰NK1R-HSPCs的动员和归巢。2型糖尿病患者和小鼠的BM中伤害性纤维减少。神经病变患者在缺血或G-CSF刺激下，NK1R-HSPC动员显著减少。LI后，糖尿病小鼠表现出BM、外周血和肢体肌肉之间SP梯度的改变，并伴有NK1R-HSPCs向缺血部位的募集减少。感觉神经病变转化为修复性造血干细胞释放和归巢缺陷。痛觉感受器可能是治疗糖尿病并发症的新靶点。本文的在线版本（doi:10.1007/s00125-015-3735-0）包含同行评审但未经编辑的补充材料，授权用户可使用。
Upon tissue injury, peripheral sensory neurons release nociceptive factors (e.g. substance P [SP]), which exert local and systemic actions including the recruitment of bone marrow (BM)-derived haematopoietic stem and progenitor cells (HSPCs) endowed with paracrine pro-angiogenic properties. We herein explore whether diabetic neuropathy interferes with these phenomena. We first investigated the presence of sensory neuropathy in the BM of patients with type 2 diabetes by immunohistochemistry and morphometry analyses of nerve size and density and assessment of SP release by ELISA. We next analysed the association of sensory neuropathy with altered HSPC release under ischaemia or following direct stimulation with granulocyte colony-stimulating factor (G-CSF). BM and circulating HSPCs expressing the neurokinin 1 receptor (NK1R), which is the main SP receptor, were measured by flow cytometry. We finally assessed whether an altered modulation of SP secretion interferes with the mobilisation and homing of NK1R-HSPCs in a mouse model of type 2 diabetes after limb ischaemia (LI). Nociceptive fibres were reduced in the BM of patients and mice with type 2 diabetes. Patients with neuropathy showed a remarkable reduction in NK1R-HSPC mobilisation under ischaemia or upon G-CSF stimulation. Following LI, diabetic mice manifested an altered SP gradient between BM, peripheral blood and limb muscles, accompanied by a depressed recruitment of NK1R-HSPCs to the ischaemic site. Sensory neuropathy translates into defective liberation and homing of reparative HSPCs. Nociceptors may represent a new target for treatment of diabetic complications. The online version of this article (doi:10.1007/s00125-015-3735-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.