Development of the Renal Arterioles

描述(申请人提供)：肾血管的起源、谱系关系和形态发生尚不清楚。我们假设胚胎肾间质至少有两个不同的早期祖细胞，它们产生肾小动脉及其血管周围室的所有其他细胞：1)能够产生红系和肾小动脉内皮细胞(ECs)的血源性内皮细胞前体(scl+，血管母细胞)；2)Foxd1+细胞，所有其他血管和血管周围/外膜细胞起源于Foxd1+细胞。此外，肾血管母细胞可能产生Flk1+前体细胞，而Flk1+前体细胞可能不仅贡献血源性ECs，还可能贡献血管SMCs。所有这些细胞类型之间的谱系关系尚不清楚，肾小动脉分化和组装的机制也不清楚。鞘氨醇1-磷酸(S1P)是一种具有生物活性的鞘磷脂代谢物，在包括血管生成在内的许多生物学过程中起着至关重要的作用。S1P1和S1P3在肾小动脉的前体细胞和确定细胞中高表达，可能在小动脉细胞的分化和组装中发挥重要作用。这些研究将检验两个相互关联的假说：1)肾动脉树起源于血源性和非血源性基质细胞前体2)局部产生的S1P(由血源性内皮)与S1P1和S1P3受体相互作用对肾小动脉的成熟和组装是至关重要的，目前关于控制肾动脉树形态发生的关键事件的信息非常有限。这项拟议的工作将填补我们知识中的这一重要空白，通过定义准确的细胞起源和机制，这些早期和中期前体导致成功形成肾动脉树，没有这棵树就没有功能的肾脏。按照设计，拟议的实验将解决现有的挑战，并产生与再生和血管发展领域相关的新的令人兴奋的信息，有可能使患有肾脏和血管疾病的儿童和成人受益。

DESCRIPTION (provided by applicant): The origin, lineage relationships and morphogenesis of the kidney vasculature are not well understood. We hypothesize that the embryonic renal stromal compartment has at least two distinct early progenitor cells that give rise to all other cells of the kidney arterioles and their perivascular compartment: 1) A precursor of hemogenic endothelium (Scl+, hemangioblast) capable of giving rise to erythroid and endothelial cells (ECs) of the renal arteriole and 2) A Foxd1+ cell from which all other vascular and perivascular/adventitial cells originate. Further, renal hemangioblasts may give rise to Flk1+ precursors that in turn may contribute not only hemogenic ECs but also vascular SMCs. The lineage relationship among all these cell types has not been clarified and the mechanisms underlying the differentiation and assembly of the kidney arterioles are unclear. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite crucial in many biological processes, including angiogenesis. S1P1 and S1P3 are highly expressed in precursors and definitive cells of the kidney arteriole and may play an important role in the differentiation and assembly of arteriolar cells. The proposed studies will test two interrelated hypotheses: 1) The renal arterial tree originates from hemogenic and non-hemogenic- stromal cell precursors 2) Locally generated S1P (by hemogenic endothelium) interacting with S1P1 and S1P3 receptors is crucial for the maturation and assembly of the renal arterioles There is currently very limited information regarding the crucial events that govern the morphogenesis of the renal arterial tree. The proposed work will fill this important gap in our knowledge by defining the precise cellular origin and mechanisms whereby those early and intermediate precursors lead to the successful formation of the renal arterial tree, without which there is no functioning kidney. As designed, the proposed experiments will solve an existing challenge and generate new and exciting information of relevance to the fields of regeneration and hemo-vascular development with the potential to benefit children and adults with kidney and vascular diseases.