CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation
CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation
复制标题
DOI：
10.1093/ejcts/ezr180
复制
发表时间：
2012-05-01
影响因子：
3.4
通讯作者：
Weder, Walter
中科院分区：
文献类型：
--
作者：
Jungraithmayr, Wolfgang;De Meester, Ingrid;Weder, Walter
CD 26抗原是一种跨膜糖蛋白，在活化的淋巴细胞和肺实质中组成性表达。该分子也被鉴定为二肽基肽酶-4（DPP-4），其切割许多生物活性肽。在此，我们的目的是确定一个重要的基质细胞衍生因子-1（SDF-1/CXCL 12）的底物CD 26/DPP-4-作为一个关键的调节剂，干细胞归巢连同其受体CXCR 4在响应缺血性损伤的lung. The原位单肺移植（Tx）之间进行同基因C57 BL/6小鼠。使用vildaglavine（10 mg/kg，每12 h一次）皮下注射抑制受体中的CD 26/DPP-4活性，并在植入前应用6 h缺血时间。Tx后48小时，评估肺组织学、肺、脾和血浆中的SDF-1水平（酶联免疫吸附测定）以及血液和肺中SDF-1受体CXCR 4的表达。与未处理的肺移植小鼠相比，Tx受体的全身DPP-4抑制导致血浆、脾和肺中SDF-1蛋白浓度增加。与此一致的是，携带SDF-1受体CXCR 4的细胞的频率在循环中以及DPP-4抑制受体的肺中显著升高。我们发现CXCR 4/CD 34在用vildagelatin治疗的动物移植物中共表达，并且干细胞标志物Flt-3和c-kit存在于显著增加的细胞数量上。DPP-4受体处理的移植物形态学显示，与未处理的受体相比，肺泡水肿较少。通过CD 26/DPP-4抑制作用靶向SDF-1-CXCR 4轴增加了移植物内祖细胞数量，有助于缺血再灌注肺损伤的恢复。内源性SDF-1的稳定化是可以实现的，并且可能是加强再生干细胞隔离的有前途的策略，因此作为一种新的治疗概念出现。
The CD26 antigen is a transmembrane glycoprotein that is constitutively expressed on activated lymphocytes and in pulmonary parenchyma. This molecule is also identified as dipeptidyl peptidase-4 (DPP-4) that cleaves a host of biologically active peptides. Here, we aimed to identify an important substrate of CD26/DPP-4-stromal cell-derived factor-1 (SDF-1/CXCL12)-as a key modulator for stem-cell homing together with its receptor CXCR4 in response to ischaemic injury of the lung.Orthotopic single lung transplantation (Tx) was performed between syngeneic C57BL/6 mice. Inhibition of CD26/DPP-4 activity in recipients was achieved using vildagliptin (10 mg/kg, every 12 h) subcutaneously, and 6 h ischaemia time was applied prior to implantation. Forty-eight hours after Tx, lung histology, SDF-1 levels (enzyme-linked immunosorbent assay) in lung, spleen and plasma, and expression of the SDF-1 receptor CXCR4 in blood and lung were assessed. Homing of regenerative progenitor cells to the transplanted lung was evaluated using fluorescent-activated cell sorting.Compared with untreated lung transplanted mice, systemic DPP-4 inhibition of Tx recipients resulted in an increase in protein concentration of SDF-1 in plasma, spleen and lung. Concordantly, the frequency of cells bearing the SDF-1 receptor CXCR4 rose significantly in the circulation and also in the lungs of DPP-4-inhibited recipients. We found co-expression of CXCR4/CD34 in the grafts of animals treated with vildagliptin, and the stem-cell markers Flt-3 and c-kit were present on a significantly increased number of cells. The morphology of grafts from DPP-4 inhibitor-treated recipients revealed less alveolar oedema when compared with untreated recipients.Targeting the SDF-1-CXCR4 axis through CD26/DPP-4 inhibition increased the intragraft number of progenitor cells contributing to the recovery from ischaemia-reperfusion lung injury. Stabilization of endogenous SDF-1 is achievable and may be a promising strategy to intensify sequestration of regenerative stem cells and thus emerges as a novel therapeutic concept.