Abstract
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. 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.
Highlights
Changes in the phenotype of Perivascular adipose tissue (PVAT) correlates with disease progression, such as atherosclerosis, and the increase of volume and upregulation of inflammatory factors secreted by adipocytes are associated with worse outcomes.[2]
We demonstrate the heterogeneity of PV-Adipose tissue-derived mesenchymal stem/stromal cells (ADSCs) at a single-cell level and uncover 2 distinct clusters with specific signature markers and signaling pathways
In consistency with the in vitro definition of Mesenchymal stem cells (MSCs) proposed by the International Society for Cellular Therapy,[34] phenotypic analysis, and multilineage differentiation capacities confirmed the existence of MSCs within the periaorta adipose tissue
Summary
The data that support the findings of this study are available from the corresponding author upon reasonable request. Detailed materials and methods are in the online-only Data Supplement. All animal procedures were approved by the UK Home Office. C57BL/6J mice were purchased from The Jackson Laboratory. Male mice aged 8 to 10 weeks were selected for surgery. Male mice were selected for minimization of data variation brought by difference of sex. Breeding pairs of miR378a-knockout mice (129SvEv/C57BL/6/mir-378-KO) were kindly provided by Dr Eric Olson (University Texas Southwestern Medical Centre, Dallas, TX) and crossed with C57Bl/10ScSnDmdmdx/J mice for testing miR-378a effects in Duchenne muscular dystrophy (other work, in preparation). Protocols from the Institutional Committee for Use and Care of Laboratory Animal and license issued by Home Office, United Kingdom, were followed in all animal procedures
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