Our understanding of kidney disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ’s multiple homeostatic functions. To help fill this knowledge gap, we characterized 57,979 cells from healthy mouse kidneys using unbiased single-cell RNA sequencing. Based on gene expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but have similar phenotypic manifestations share the same cell of origin. We also found that the kidney collecting duct in adult mice generates a spectrum of cell types via a newly identified transitional cell. Computational cell trajectory analysis and in vivo lineage tracing revealed that intercalated cells and principal cells undergo transitions mediated by the Notch signaling pathway. In mouse and human kidney disease, these transitions were shifted toward a principal cell fate and were associated with metabolic acidosis.

Tissues with rapid cellular turnover, such as the mammalian hematopoietic system or the intestinal epithelium, are dependent upon stem and progenitor cells, which through proliferation provide differentiated cells to maintain organismal health. Stem and progenitor cells, in turn, are thought to rely upon signals and growth factors provided by local niche cells to support their function and self-renewal. Several cell types have been proposed to provide the signals required for the proliferation and differentiation of the ISC in the crypt1–6. Here, we identify subepithelial telocytes as an important source of Wnt proteins, without which intestinal stem cells cannot proliferate and support epithelial renewal. Telocytes are large but rare mesenchymal cells that are marked by Foxl1 and PDGFRα expression and form a subepithelial plexus that extends from the stomach to the colon. While supporting the entire epithelium, Foxl1+ telocytes compartmentalize the production of Wnt ligands and inhibitors to enable localized pathway activation. Conditional gene ablation of Porcupine (Porcn), which is required for functional maturation of all Wnt proteins, in Foxl1+ telocytes causes rapid cessation of Wnt signaling to intestinal crypts, followed by loss of stem and transit amplifying cell proliferation and impaired epithelial renewal. Thus, Foxl1+ telocytes are an important source of niche signals to intestinal stem cells.

Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene-regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development.

Since the first description of ‘interstitial cells of Cajal’ in the mammalian gut in 1911, scientists have found structurally similar cells, now termed telocytes, in numerous tissues throughout the body. These cells have recently sparked renewed interest, facilitated through the development of a molecular handle to genetically manipulate their function in tissue homeostasis and disease. In this Primer, we discuss the discovery of telocytes, their physical properties, distribution and function, focusing on recent developments in the functional analysis of Foxl1-positive telocytes in the intestinal stem cell niche, and, finally, the current challenges of studying telocytes as a distinct cell type.

Conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets, along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.