Development of the Renal Arterioles

描述（由申请人提供）：肾脏血管的起源、谱系关系和形态发生尚不清楚。我们假设，胚胎肾间质室至少有两种不同的早期祖细胞，它们可以产生肾小动脉及其血管周围室的所有其他细胞：1)造血内皮（Scl+，成血管细胞）的前体，能够产生肾小动脉的红细胞和内皮细胞（ECs）； 2) Foxd1+细胞，所有其他血管细胞和血管周围/外壁细胞都起源于此细胞。此外，肾成血管细胞可能产生Flk1+前体，而Flk1+前体不仅可能产生造血内皮细胞，还可能产生血管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。鞘磷脂1-磷酸（S1P）是一种生物活性鞘脂代谢物，在许多生物过程中至关重要，包括血管生成。S1P1和S1P3在肾小动脉的前体细胞和终细胞中高度表达，可能在小动脉细胞的分化和组装中起重要作用。建议的研究将验证两个相互关联的假设：1)肾动脉树起源于造血和非造血基质细胞前体2)局部生成的S1P（通过造血内皮）与S1P1和S1P3受体相互作用对肾小动脉的成熟和组装至关重要。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。通过定义精确的细胞起源和机制，这些早期和中间前体导致肾动脉树的成功形成，没有肾动脉树就没有功能肾脏，所提出的工作将填补我们知识中的这一重要空白。按照设计，拟议的实验将解决现有的挑战，并产生与再生和血液血管发育领域相关的新的和令人兴奋的信息，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.