Uncovering the epigenomic determinants of kidney vascular development [scRNA-seq]

Renin cells are essential for survival. They control the morphogenesis of the kidney arterioles, and the composition and volume of our extracellular fluid, arterial blood pressure, tissue perfusion, and oxygen delivery. Renin cells and associated arteriolar cells descend from FoxD1+ progenitor cells. The chromatin states and transcription factors that determine the differentiation of these cells into those that compose the kidney vasculature are unknown. To answer these questions, we isolated progenitors and their descendants at different embryonic and postnatal stages, and using integrated scRNA-seq and scATAC-seq established the developmental trajectory that leads to the mosaic of cells that compose the kidney arterioles. We constructed a single-cell atlas of chromatin accessibility and gene expression profiles-including the critical transcription factors that determine the identity and fate of the mosaic of cells that occur during kidney vascular development. Furthermore, we identified the factors that determine the elusive, myo-endocrine adult renin-secreting juxtaglomerular cell. FoxD1+ cells, demarcating the renin lineage, were isolated at embryonic (E) day 12, E18, post-natal (P) day 5, and P30 and subjected to independent scRNA-seq and scRNA-seq to uncover the epigenomic determinants of kidney vascular development.肾素细胞（Renin cells）是维持机体生存的关键细胞类群。它们可调控肾脏微动脉的形态发生，并参与维持细胞外液的组分与容量、动脉血压、组织灌注及氧气输送。肾素细胞及其相关微动脉细胞均起源于FoxD1阳性祖细胞（FoxD1+ progenitor cells）。目前尚不明确调控这些细胞分化为肾脏血管组成细胞的染色质状态与转录因子。为解答上述科学问题，本研究在不同胚胎发育阶段与出生后阶段分离了祖细胞及其子代细胞，并通过整合单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与单细胞转座酶可及性测序（single-cell assay for transposase-accessible chromatin sequencing, scATAC-seq），构建了调控肾脏微动脉组成细胞镶嵌体形成的发育轨迹。本研究构建了涵盖肾脏血管发育过程中细胞镶嵌体身份与命运决定关键转录因子的染色质可及性与基因表达单细胞图谱。此外，本研究还鉴定出了调控难以捉摸的肌内分泌型成年肾素分泌球旁细胞（juxtaglomerular cell）分化的关键因子。本研究从胚胎第12天（E12）、胚胎第18天（E18）、出生后第5天（P5）及出生后第30天（P30）分离了标记肾素谱系的FoxD1+细胞，并分别进行独立的单细胞RNA测序（scRNA-seq）分析，以揭示肾脏血管发育的表观基因组调控决定因素。