Inflammation Alters the Secretome and Immunomodulatory Properties of Human Skin-Derived Precursor Cells.

Joery De Kock,Tamara Vanhaecke,Joost Boeckmans,Haaike Colemonts-Vroninks,Matthias Rombaut,Jessie Neuckermans,Laurence Lagneaux,Makram Merimi,Karolien Buyl,Lieven Verhoye,Veerle De Boe,Steven Branson,Sien Lequeue,Robim Marcelino Rodrigues,Philip Meuleman,Mehdi Najar,Douaa Moussa Agha

doi:10.3390/cells9040914

Abstract

Human skin-derived precursors (SKP) represent a group of somatic stem/precursor cells that reside in dermal skin throughout life that harbor clinical potential. SKP have a high self-renewal capacity, the ability to differentiate into multiple cell types and low immunogenicity, rendering them key candidates for allogeneic cell-based, off-the-shelf therapy. However, potential clinical application of allogeneic SKP requires that these cells retain their therapeutic properties under all circumstances and, in particular, in the presence of an inflammation state. Therefore, in this study, we investigated the impact of pro-inflammatory stimulation on the secretome and immunosuppressive properties of SKP. We demonstrated that pro-inflammatory stimulation of SKP significantly changes their expression and the secretion profile of chemo/cytokines and growth factors. Most importantly, we observed that pro-inflammatory stimulated SKP were still able to suppress the graft-versus-host response when cotransplanted with human PBMC in severe-combined immune deficient (SCID) mice, albeit to a much lesser extent than unstimulated SKP. Altogether, this study demonstrates that an inflammatory microenvironment has a significant impact on the immunological properties of SKP. These alterations need to be taken into account when developing allogeneic SKP-based therapies.

Highlights

Human skin is an accessible and readily available tissue that contains a broad stem cell repertoire, including hematopoietic and endothelial precursors, resident epidermal and mesenchymal stromal cells (MSC), melanocytic stem cells and so-called human skin-derived precursor cells (SKP) [1].skin-derived precursors (SKP) represent a group of dermal stem/precursor cells that are obtained from primary dermal spheroids, cultivated under low attachment conditions in basic fibroblast growth factor (FGF) and epidermal growth factor (EGF) rich neurosphere medium [2]
We investigated the impact of pro-inflammatory stimulation on the biological properties, secretome, immunogenicity and immunosuppressive capacity of SKP
In the context of cellular immunogenicity, we investigated whether inflammation induces changes in the secretion of growth factors, chemokines and cytokines by SKP and whether SKP become more immunogenic

Summary

Introduction

SKP represent a group of dermal stem/precursor cells that are obtained from primary dermal spheroids, cultivated under low attachment conditions in basic fibroblast growth factor (FGF) and epidermal growth factor (EGF) rich neurosphere medium [2]. SKP were thought to represent a single multipotent dermal precursor cell type with multilineage differentiation capacity [2,7,8,9,10], but research by Izeta and colleagues has shown that. SKP represent a heterogeneous group of dermal precursor cells [11]. SKP are of particular interest for regenerative medicine as they share several properties with embryonic neural crest-derived stem cells, a group of highly plastic cells with unique properties that reside within the developing embryo [2,12,13]. We and others have shown that SKP are able to generate (1) neuronal cells such as Schwann cells [7,14,15], catecholaminergic [16], dopaminergic [17] and enteric [18]

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