Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling

Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):2049-2066. doi: 10.1161/ATVBAHA.119.312732. Epub 2019 Jul 25.

Abstract

Objective: Perivascular adipose tissue (PVAT) plays a vital role in maintaining vascular homeostasis. However, most studies ascribed the function of PVAT in vascular remodeling to adipokines secreted by the perivascular adipocytes. Whether mesenchymal stem cells exist in PVAT and play a role in vascular regeneration remain unknown. Approach and Results: Single-cell RNA-sequencing allowed direct visualization of the heterogeneous PVAT-derived mesenchymal stem cells (PV-ADSCs) at a high resolution and revealed 2 distinct subpopulations, among which one featured signaling pathways crucial for smooth muscle differentiation. Pseudotime analysis of cultured PV-ADSCs unraveled their smooth muscle differentiation trajectory. Transplantation of cultured PV-ADSCs in mouse vein graft model suggested the contribution of PV-ADSCs to vascular remodeling through smooth muscle differentiation. Mechanistically, treatment with TGF-β1 (transforming growth factor β1) and transfection of microRNA (miR)-378a-3p mimics induced a similar metabolic reprogramming of PV-ADSCs, including upregulated mitochondrial potential and altered lipid levels, such as increased cholesterol and promoted smooth muscle differentiation.

Conclusions: Single-cell RNA-sequencing allows direct visualization of PV-ADSC heterogeneity at a single-cell level and uncovers 2 subpopulations with distinct signature genes and signaling pathways. The function of PVAT in vascular regeneration is partly attributed to PV-ADSCs and their differentiation towards smooth muscle lineage. Mechanistic study presents miR-378a-3p which is a potent regulator of metabolic reprogramming as a potential therapeutic target for vascular regeneration.

Keywords: adipose tissue; homeostasis; regeneration; stem cells; vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism*
  • Animals
  • Cell Differentiation / genetics
  • Cell Survival
  • Cells, Cultured
  • Disease Models, Animal
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Metabolomics / methods
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • Muscle, Smooth, Vascular / metabolism*
  • Oxygen Consumption
  • RNA, Small Interfering / genetics
  • Random Allocation
  • Sequence Analysis, RNA
  • Signal Transduction / genetics
  • Transforming Growth Factor beta1 / genetics*
  • Vascular Diseases / genetics
  • Vascular Diseases / metabolism
  • Vascular Remodeling / genetics*

Substances

  • MicroRNAs
  • RNA, Small Interfering
  • TGFB1 protein, human
  • Transforming Growth Factor beta1