Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging.

Makram Merimi,Rahma Melki,Karolien Buyl,Laurence Lagneaux,Vera Rogiers,Hassan Fahmi,Joery De Kock,Robim M Rodrigues,Tamara Vanhaecke,Mehdi Najar,Dhouha Daassi,Philippe Lewalle

doi:10.3390/ijms22147309

Abstract

Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches.

Highlights

Mesenchymal Stromal Cells (MSCs) have been shown to be a promising candidate for cell-based therapy [1]
We found that the expression of cytokines/chemokines (IL-6, IL-8, IL-1β, TNFα and CCL5), regulatory mediators (HGF, IDO1, PTGS1, PTGS2 and TGFβ) and Toll-like receptors (TLR) was constitutively different
Inflammation may increase the sensitivity and responsiveness of mesenchymal stromal cells (MSCs) to their surroundings by at least three means (i) upregulating their pattern of TLRs that act as sentinels of infection and injury/damage; (ii) inducing a shift in their cytokine profile which contribute to the homing and activation of immune cells with a proreparative and anti-inflammatory phenotype; (iii) triggering the expression of regulatory and protective mediators to guarantee tissue homeostasis

Summary

Introduction

Mesenchymal Stromal Cells (MSCs) have been shown to be a promising candidate for cell-based therapy [1] They are relevant for tissue repair and wound healing because of their therapeutic properties. MSCs harbor specific functions such as immunomodulation, trophic support and in vitro differentiation ability into certain connective tissue cells upon specific inductive conditions [2]. Their therapeutic effects are mainly based on their secretome that include a variety of biologically active molecules such as chemokines, cytokines and other regulatory factors. MSCs may induce functional changes of monocytes/macrophages, dendritic cells, T cells, B cells and natural killer cells to regulate the immune response [5]

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