Characterization of mesenchymal stem cells of "no-options" patients with critical limb ischemia treated by autologous bone marrow mononuclear cells.
Characterization of mesenchymal stem cells of "no-options" patients with critical limb ischemia treated by autologous bone marrow mononuclear cells.
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DOI：
10.1371/journal.pone.0073722
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Madaric J
中科院分区：
文献类型：
--
作者：
Altaner C;Altanerova V;Cihova M;Hunakova L;Kaiserova K;Klepanec A;Vulev I;Madaric J
在 6 个月的随访期间，对患有晚期严重肢体缺血 (CLI) 的“别无选择”患者应用自体骨髓单核细胞，73% 的患者避免了主要肢体截肢。我们研究了有反应和无反应患者的骨髓基质细胞（也称为骨髓来源的间充质干细胞）的哪些特性对于无截肢生存至关重要。从用于治疗的单核骨髓浓缩物中分离出 41 名不适合血运重建的 CLI 患者的间充质干细胞。根据治疗的临床结果，我们将患者分为两组：有反应者和无反应者。根据其增殖能力、体外分化能力、细胞表面标志物的定量表达、27种细胞因子、趋化因子和生长因子的分泌以及15种间充质干细胞重要基因的相对表达，对应答者和无应答者的间充质干细胞的生物学特性进行表征。有反应者 (n=27) 和无反应者 (n=14) 之间的分泌物组比较显示，有反应者组中 IL-4、IL-6 和 MIP-1b 的分泌值显着较高。与无反应者相比，反应者的间充质干细胞中细胞标记物 CD44 和 CD90 的表达显着较高（p<0.01）。在 22 名患者中分析的间充质干细胞表面标志物的表达在糖尿病患者组 (n=13) 和非糖尿病患者组 (n=9) 之间没有差异。在无反应者中发现 E-钙粘蛋白和 PDX-1/IPF1 基因的表达具有统计学意义的较高水平，而在有反应者中 Snail 的表达较高。间充质干细胞的细胞表面标志物、分泌因子和干细胞基因表达的质量对治疗结果起着重要作用。旁分泌机制是 CLI 患者修复过程诱导的主要驱动力。讨论了间充质干细胞特性的差异与其参与修复过程的关系。
Application of autologous bone marrow mononuclear cells to “no option” patients with advanced critical limb ischemia (CLI) prevented major limb amputation in 73% patients during the 6-month follow-up. We examined which properties of bone marrow stromal cells also known as bone-marrow derived mesenchymal stem cells of responding and non-responding patients are important for amputation-free survival. Mesenchymal stem cells of 41 patients with CLI unsuitable for revascularisation were isolated from mononuclear bone marrow concentrate used for their treatment. Based on the clinical outcome of the treatment, we divided patients into two groups: responders and non-responders. Biological properties of responders’ and non-responders’ mesenchymal stem cells were characterized according to their ability to multiply, to differentiate in vitro, quantitative expression of cell surface markers, secretion of 27 cytokines, chemokines and growth factors, and to the relative expression of 15 mesenchymal stem cells important genes. Secretome comparison between responders (n=27) and non-responders (n=14) revealed significantly higher secretion values of IL-4, IL-6 and MIP-1b in the group of responders. The expression of cell markers CD44 and CD90 in mesenchymal stem cells from responders was significantly higher compared to non-responders (p<0.01). The expression of mesenchymal stem cells surface markers that was analyzed in 22 patients did not differ between diabetic (n=13) and non-diabetic (n=9) patient groups. Statistically significant higher expression of E-cadherin and PDX-1/IPF1 genes was found in non-responders, while expression of Snail was higher in responders. The quality of mesenchymal stem cells shown in the expression of cell surface markers, secreted factors and stem cell genes plays an important role in therapeutic outcome. Paracrine mechanisms are main drivers in the induction of reparatory processes in CLI patients. Differences in mesenchymal stem cells properties are discussed in relation to their involvement in the reparatory process.
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