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Single‐cell analysis of mouse and human prostate reveals novel fibroblasts with specialized distribution and microenvironment interactions
Author(s) -
Joseph Diya B,
Henry Gervaise H,
Malewska Alicia,
Reese Jeffrey C,
Mauck Ryan J,
Gahan Jeffrey C,
Hutchinson Ryan C,
Malladi Venkat S,
Roehrborn Claus G,
Vezina Chad M,
Strand Douglas W
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5751
Subject(s) - stromal cell , biology , wnt signaling pathway , prostate , fibroblast , microbiology and biotechnology , hyperplasia , pathology , extracellular matrix , cell type , cell , cancer research , cell culture , signal transduction , endocrinology , medicine , genetics , cancer
Stromal–epithelial interactions are critical to the morphogenesis, differentiation, and homeostasis of the prostate, but the molecular identity and anatomy of discrete stromal cell types is poorly understood. Using single‐cell RNA sequencing, we identified and validated the in situ localization of three smooth muscle subtypes (prostate smooth muscle, pericytes, and vascular smooth muscle) and two novel fibroblast subtypes in human prostate. Peri‐epithelial fibroblasts ( APOD +) wrap around epithelial structures, whereas interstitial fibroblasts ( C7 +) are interspersed in extracellular matrix. In contrast, the mouse displayed three fibroblast subtypes with distinct proximal–distal and lobe‐specific distribution patterns. Statistical analysis of mouse and human fibroblasts showed transcriptional correlation between mouse prostate ( C3 +) and urethral ( Lgr5 +) fibroblasts and the human interstitial fibroblast subtype. Both urethral fibroblasts ( Lgr5 +) and ductal fibroblasts ( Wnt2 +) in the mouse contribute to a proximal Wnt/Tgfb signaling niche that is absent in human prostate. Instead, human peri‐epithelial fibroblasts express secreted WNT inhibitors SFRPs and DKK1 , which could serve as a buffer against stromal WNT ligands by creating a localized signaling niche around individual prostate glands. We also identified proximal–distal fibroblast density differences in human prostate that could amplify stromal signaling around proximal prostate ducts. In human benign prostatic hyperplasia, fibroblast subtypes upregulate critical immunoregulatory pathways and show distinct distributions in stromal and glandular phenotypes. A detailed taxonomy of leukocytes in benign prostatic hyperplasia reveals an influx of myeloid dendritic cells, T cells and B cells, resembling a mucosal inflammatory disorder. A receptor–ligand interaction analysis of all cell types revealed a central role for fibroblasts in growth factor, morphogen, and chemokine signaling to endothelia, epithelia, and leukocytes. These data are foundational to the development of new therapeutic targets in benign prostatic hyperplasia. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.