Laboratory of Stem Cells and Development, Faculty of Sciences, Universidad de Chile, Las Palmeras 3425, Ñuñoa, 7800003, Santiago, Chile.
Stem Cell Res Ther. 2017 Sep 29;8(1):203. doi: 10.1186/s13287-017-0653-8.
Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) show remarkable therapeutic potential to repair tissue upon injury via paracrine signaling by secreting diverse trophic factors that promote angiogenesis. However, the mechanisms and signaling pathways that regulate the induction of these specific factors are still mostly unknown. Emerging evidence suggests that Sonic hedgehog (SHH) plays a central role in angiogenesis and tissue maintenance. However, its contribution to the angiogenic potential of MSC has not been fully addressed. The aim of this work was to characterize the expression of the SHH pathway components in WJ-MSC primary cultures and to evaluate their angiogenic responsiveness to SHH signaling.
Primary cell cultures obtained from human umbilical cords were treated with pharmacological modulators of the SHH pathway. We evaluated the modulation of diverse trophic factors in cell lysates, conditioned medium, and functional in vitro assays. In addition, we determined the angiogenic potential of the SHH pathway in the chicken chorioallantoic membrane, an in vivo model.
Our results show that WJ-MSC express components of the canonical SHH pathway and are activated by its signaling. In fact, we provide evidence of basal autocrine/paracrine SHH signaling in WJ-MSC. SHH pathway stimulation promotes the secretion of angiogenic factors such as activin A, angiogenin, angiopoietin 1, granulocyte-macrophage colony-stimulating factor, matrix metallometallopeptidase -9, and urokinase-type plasminogen activator, enhancing the pro-angiogenic capabilities of WJ-MSC both in vitro and in vivo.
WJ-MSC are a cell population responsive to SHH pathway stimulation. Basal SHH signaling is in part responsible for the angiogenic inductive properties of WJ-MSC. Overall, exogenous activation of the SHH pathway enhances the angiogenic properties of WJ-MSC, making this cell population an ideal target for treating tissue injury.
华通氏胶来源的间充质干细胞（WJ-MSC）通过分泌多种促进血管生成的营养因子，通过旁分泌信号在损伤后显示出显著的组织修复治疗潜力。然而，调节这些特定因子诱导的机制和信号通路在很大程度上仍然未知。新出现的证据表明，Sonic hedgehog（SHH）在血管生成和组织维持中发挥核心作用。然而，其对 MSC 血管生成潜力的贡献尚未得到充分解决。本工作的目的是描述 WJ-MSC 原代培养物中 SHH 途径成分的表达，并评估其对 SHH 信号的血管生成反应性。
从人脐带中获得原代细胞培养物，并对 SHH 途径的药理学调节剂进行处理。我们评估了细胞裂解物、条件培养基和体外功能测定中不同营养因子的调节。此外，我们还在鸡绒毛尿囊膜（一种体内模型）中确定了 SHH 途径的血管生成潜力。
我们的结果表明，WJ-MSC 表达经典 SHH 途径的组成部分，并被其信号激活。事实上，我们提供了 WJ-MSC 中基础自分泌/旁分泌 SHH 信号的证据。SHH 途径刺激促进了血管生成因子的分泌，如激活素 A、血管生成素 1、血管生成素 1、粒细胞-巨噬细胞集落刺激因子、基质金属蛋白酶-9 和尿激酶型纤溶酶原激活物，增强了 WJ-MSC 的促血管生成能力，无论是在体外还是体内。
WJ-MSC 是对 SHH 途径刺激有反应的细胞群体。基础 SHH 信号在一定程度上负责 WJ-MSC 的血管生成诱导特性。总体而言，外源性激活 SHH 途径增强了 WJ-MSC 的血管生成特性，使该细胞群体成为治疗组织损伤的理想靶标。
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