Pericytes, mesenchymal stem cells and vascular calcification in chronic kidney disease (CKD). Is hedgehog signaling the missing link between endothelial injury and vascular sclerosis?

慢性肾脏病 (CKD) 中的周细胞、间充质干细胞和血管钙化。

• 批准号: 215680355
• 负责人: Professor Dr. Rafael Kramann
• 金额: --
• 依托单位: Division of Nephrology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/215680355?language=en
• 关键词: Pericytes; mesenchymal; stem; cells; vascular

Cardiovascular disease accounts for more than half of all deaths in patients with chronic kidney disease (CKD). Vascular calcification is an important contributor to this cardiovascular mortality. Recent studies suggest that pericytal mesenchymal stem cells (MSC) are major players in the vascular calcification process. The current study is based on the hypothesis that, in the case of endothelial dysfunction/damage as in CKD, altered endothelial-mesenchymal hedgehog (Hh) signaling leads to activation and recruitment of MSC from the vascular tube as the stem cell niche to support the regenerative processes by their paracrine and biosynthetic activity. In response to metabolic and inflammatory stress, they (mal)differentiate into osteoblasts. Using genetic and pharmacologic tools, we propose three specific aims to identify the functional roles of Hh signaling and pericytal MSC in the vessel wall during the process of vascular calcification: 1) We plan to characterize at cellular resolution the vascular expression patterns of the Hh pathway ligands, Ihh and Shh, Hh receptors Ptc-1 and Smo and the transcriptional effectors Gli 1-3 during vascular calcification in a mouse model of CKD. 2) We will test the hypothesis that pericytal MSC respond to injury-induced endothelial Hh signals by secreting paracrine factors, proliferation and differentiation towards a prosynthetic osteogenic phenotype leading to extracellular matrix densification, sclerosis and finally calcification. We will use genetic lineage tracing and primary pericyte/MSC culture to address these questions. 3) Finally, we will try to determine in vivo whether Hh pathway activation or inhibition leads to increased or reduced vascular sclerosis and calcification in CKD mice.

心血管疾病占慢性肾病(CKD)患者死亡总数的一半以上。血管钙化是导致心血管死亡率的重要因素。最近的研究表明，周围间充质干细胞(MSC)是血管钙化过程中的主要参与者。目前的研究基于这样的假设，即在CKD的内皮功能障碍/损伤的情况下，内皮-间充质刺激物(HH)信号的改变导致MSC作为干细胞利基从血管中被激活和招募，以其旁分泌和生物合成活性来支持再生过程。为了应对新陈代谢和炎症压力，它们(正常)分化为成骨细胞。利用遗传学和药理学工具，我们提出了三个特定的目标来确定HH信号和细胞周MSC在血管钙化过程中的功能作用：1)我们计划在细胞分辨率上表征CKD小鼠血管钙化过程中HH途径配体IHH和Shh、HH受体PTC-1和Smo以及转录效应因子Gli 1-3的表达模式。2)我们将验证这一假设，即周细胞间充质干细胞通过分泌旁分泌因子、增殖和分化为一种前合成的成骨表型来响应损伤诱导的内皮HH信号，从而导致细胞外基质致密、硬化并最终钙化。我们将使用遗传谱系追踪和原代周细胞/间充质干细胞培养来解决这些问题。3)最后，我们将试图在体内确定HH通路的激活或抑制是否会导致CKD小鼠血管硬化和钙化的增加或减少。