Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation.
Stromal netrin 1 coordinates renal arteriogenesis and mural cell differentiation.
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DOI：
10.1242/dev.201884
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发表时间：
2023-11-15
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肾血管系统具有复杂的结构，其对于肾功能是必不可少的。指导肾血管发育的分子机制的特点很差。我们确定了一种区域限制性的基质源性信号分子netrin 1（Ntn 1），作为小鼠肾血管模式的调节因子。基质祖细胞（SP）特异性消融Ntn 1（Ntn 1 SPKO）导致肾脏变小，肾小球减少，以及肾动脉严重缺陷和短暂血流中断。值得注意的是，Ntn 1消融导致动脉血管平滑肌细胞（vSMC）覆盖的损失和异位SMC沉积在肾脏表面。与此同时，产后持续存在的动脉树分支急剧减少。Ntn 1 SPKO肾脏的转录组学分析揭示vSMC分化的失调，包括Klf 4的下调，我们发现Klf 4在SP的子集中表达。基质Klf 4缺失类似地导致平滑肌覆盖和动脉分支减少，然而，没有在Ntn 1 SPKO中观察到的肾动脉图案化和灌注的破坏。这些数据表明，基质Ntn 1-Klf 4轴，调节间质分化，并加强间质来源的平滑肌作为肾血管形成的关键调节。总结：由肾脏中的皮质基质祖细胞分泌的Netrin 1调节肾动脉树的血管图案化，以及通过Klf 4调节血管平滑肌细胞分化。
The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally restricted, stroma-derived signaling molecule, netrin 1 (Ntn1), as a regulator of renal vascular patterning in mice. Stromal progenitor (SP)-specific ablation of Ntn1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4, which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching without, however, the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation and reinforces stromal-derived smooth muscle as a key regulator of renal blood vessel formation. Summary: Netrin 1 secreted by cortical stromal progenitors in the kidney regulates vascular patterning of the renal arterial tree, as well as vascular smooth muscle cell differentiation via Klf4.
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