Platelet-Derived Growth Factor Induces SASP-Associated Gene Expression in Human Multipotent Mesenchymal Stromal Cells but Does Not Promote Cell Senescence.

Uliana Dyachkova,Natalia Kalinina,Ekaterina Novoseletskaya,Olga Grigorieva,Alexander Ishkin,Mikhail Arbatskiy,Anastasia Efimenko

doi:10.3390/biomedicines9101290

Abstract

Activation of multipotent mesenchymal stromal cells (MSCs) is a central part of tissue response to damage. Platelet-derived growth factor (PDGF-BB), which is abundantly released in the damaged area, potently stimulates the proliferation and migration of MSCs. Recent evidence indicates that tissue injury is associated with the accumulation of senescent cells, including ones of MSC origin. Therefore, we hypothesized that PDGF-BB induces MSC senescence. To evaluate mechanisms of early activation of MSCs by PDGF-BB, we performed transcriptome profiling of human MSCs isolated from adipose tissue after exposure to PDGF-BB for 12 and 24 h. We demonstrated that PDGF-BB induced the expression of several genes encoding the components of senescence-associated secretory phenotype (SASP) in MSCs such as plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR), and some matrix metalloproteases. However, further experimental validation of transcriptomic data clearly indicated that PDGF-BB exerted mitogenic and pro-migratory effects on MSCs, and augmented their pro-angiogenic activity, but did not significantly stimulate MSC senescence.

Highlights

Tissue injury was associated with the accumulation of senescent cells, including those originating from multipotent mesenchymal stem/stromal cells (MSCs) [1]
platelet-derived growth factor (PDGF)-BB is a well-known regulator for stromal cells, such as fibroblasts and MSCs
Produced in high concentrations during the acute phase of tissue damage, it activates is a well‐known regulator as regulative fibroblasts and MSCs stromal cell proliferation and migration

Summary

Introduction

Tissue injury was associated with the accumulation of senescent cells, including those originating from multipotent mesenchymal stem/stromal cells (MSCs) [1]. Numerous studies have implicated MSCs in tissue regeneration upon damage, with paracrine activity being a central mechanism of their action [2,3,4,5]. Signals from damaged tissues could both activate MSCs and cause the acquisition of a senescent phenotype characterized by cell cycle arrest with p16INK4a, p21Waf1/Cip, and p53 expression activation, resistance to apoptosis, and specific senescence-associated secretory phenotype (SASP). MSCs respond to a multitude of factors, including abundantly presented platelet-derived growth factor (PDGF). These cells express PDGFRβ, which has the highest affinity for PDGF-BB dimer [9].

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