Mesenchymal stem cells (MSC) are non-haematopoietic, fibroblast-like multipotent stromal cells. In the injured pancreas, these cells are assumed to secrete growth factors and immunomodulatory molecules, which facilitate the regeneration of pre-existing β-cells. However, when MSC are delivered intravenously, their majority is entrapped in the lungs and does not reach the pancreas. Therefore, the aim of this investigation was to compare the regenerative support of hTERT-MSC (human telomerase reverse transcriptase mesenchymal stem cells) via intrapancreatic (IPR) and intravenous route (IVR). hTERT-MSC were administered by IPR and IVR to 50% pancreatectomized NMRI nude mice. After eight days, blood glucose level, body weight, and residual pancreatic weight were measured. Proliferating pancreatic β-cells were labelled and identified with bromodeoxyuridine (BrdU) in vivo. The number of residual islets and the frequency of proliferating β-cells were compared in different groups with sequential pancreatic sections. The pancreatic insulin content was evaluated by enzyme-linked immunosorbent assay (ELISA) and the presence of hTERT-MSC with human Alu sequence. Murine gene expression of growth factors, β-cell specific molecules and proinflammatory cytokines were inspected by real-time polymerase chain reaction (RT-PCR) and Western blot. This study evaluated the regenerative potential of the murine pancreas post-hTERT-MSC administration through the intrapancreatic (IPR) and intravenous route (IVR). Both routes of hTERT-MSC transplantation (IVR and IPR) increased the incorporation of BrdU by pancreatic β-cells compared to control. MSC induced epidermal growth factor (EGF) expression and inhibited proinflammatory cytokines (IFN-γ and TNF-α). FOXA2 and PDX-1 characteristics for pancreatic progenitor cells were activated via AKT/ PDX-1/ FoxO1 signalling pathway. The infusion of hTERT-MSC after partial pancreatectomy (Px) through the IVR and IPR facilitated the proliferation of autochthonous pancreatic β-cells and provided evidence for a regenerative influence of MSC on the endocrine pancreas. Moderate benefit of IPR over IVR was observed which could be a new treatment option for preventing diabetes mellitus after pancreas surgery.

中文翻译：

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间充质干细胞通过下调FoxO1途径促进胰腺β细胞再生

间充质干细胞（MSC）是非造血，成纤维细胞样多能基质细胞。在受损的胰腺中，假定这些细胞分泌生长因子和免疫调节分子，从而促进先前存在的β细胞的再生。然而，当MSC通过静脉内递送时，它们的大部分被截留在肺中并且没有到达胰腺。因此，本研究的目的是通过胰腺内（IPR）和静脉内途径（IVR）比较hTERT-MSC（人端粒酶逆转录酶间充质干细胞）的再生支持。通过IPR和IVR将hTERT-MSC给予50％胰腺切除的NMRI裸鼠。8天后，测量血糖水平，体重和残余胰腺重量。在体内用溴脱氧尿苷（BrdU）标记和鉴定增殖的胰腺β细胞。比较了不同组胰腺的残余胰岛数目和β细胞的增殖频率。通过酶联免疫吸附测定（ELISA）和具有人类Alu序列的hTERT-MSC的存在来评估胰腺胰岛素含量。通过实时聚合酶链反应（RT-PCR）和蛋白质印迹检查了生长因子，β细胞特异性分子和促炎细胞因子的鼠基因表达。这项研究评估了通过胰腺内（IPR）和静脉内途径（IVR）施用hTERT-MSC后鼠胰腺的再生潜力。与对照相比，hTERT-MSC的两种移植途径（IVR和IPR）均增加了胰腺β细胞对BrdU的掺入。MSC诱导表皮生长因子（EGF）的表达并抑制促炎细胞因子（IFN-γ和TNF-α）。通过AKT / PDX-1 / FoxO1信号通路激活了胰腺祖细胞的FOXA2和PDX-1特性。通过IVR和IPR输注部分胰腺切除术（Px）后的hTERT-MSC促进了自体胰腺β细胞的增殖，并提供了MSC对内分泌胰腺产生再生影响的证据。观察到IPR优于IVR，这可能是预防胰腺手术后糖尿病的一种新的治疗选择。MSC诱导表皮生长因子（EGF）的表达并抑制促炎细胞因子（IFN-γ和TNF-α）。通过AKT / PDX-1 / FoxO1信号通路激活了胰腺祖细胞的FOXA2和PDX-1特性。通过IVR和IPR输注部分胰腺切除术（Px）后的hTERT-MSC促进了自体胰腺β细胞的增殖，并提供了MSC对内分泌胰腺产生再生影响的证据。观察到IPR优于IVR，这可能是预防胰腺手术后糖尿病的一种新的治疗选择。MSC诱导表皮生长因子（EGF）的表达并抑制促炎细胞因子（IFN-γ和TNF-α）。通过AKT / PDX-1 / FoxO1信号通路激活了胰腺祖细胞的FOXA2和PDX-1特性。通过IVR和IPR输注部分胰腺切除术（Px）后的hTERT-MSC促进了自体胰腺β细胞的增殖，并提供了MSC对内分泌胰腺产生再生影响的证据。观察到IPR优于IVR，这可能是预防胰腺手术后糖尿病的一种新的治疗选择。通过IVR和IPR输注部分胰腺切除术（Px）后的hTERT-MSC促进了自体胰腺β细胞的增殖，并提供了MSC对内分泌胰腺产生再生影响的证据。观察到IPR优于IVR，这可能是预防胰腺手术后糖尿病的一种新的治疗选择。通过IVR和IPR输注部分胰腺切除术（Px）后的hTERT-MSC促进了自体胰腺β细胞的增殖，并提供了MSC对内分泌胰腺产生再生影响的证据。观察到IPR优于IVR，这可能是预防胰腺手术后糖尿病的一种新的治疗选择。