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

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.

In Vitro Cellular and Molecular Interplay between Human Foreskin-Derived Mesenchymal Stromal/Stem Cells and the Th17 Cell Pathway

“…These genes are subsequently modulated by inflammation and seem to be involved in regulating the immunological fate of FSK-MSCs [ 32 , 33 , 34 , 35 ]. In line with these findings, we have previously shown that an inflammatory milieu has a significant impact on the molecular profile of skin-derived precursors [ 14 ] and adult-derived human liver stromal/stem/progenitor cells [ 63 ]. These immunological changes need to be further characterized to guarantee a safe cellular product with consistent quality and high therapeutic efficacy [ 55 ].…”

“…Immunomodulation assays were performed as previously described [ 14 ]. Briefly, peripheral blood mononuclear cells (PBMC) were obtained by Ficoll-Hypaque gradient centrifugation of peripheral blood from healthy donors with informed consent.…”

Inflammation Differentially Modulates the Biological Features of Adult Derived Human Liver Stem/Progenitor Cells

“…Altogether, our data showed that ADHLSC, like for Adipose tissue MSC and skin progenitors [ 56 , 57 ], is a responsive therapeutic unit that can sense specific signals related to injury and responds accordingly. Thus, 9 day-sustained inflammatory environment negatively affected ADHLSC viability without impacting the potential of surviving cells’ hepatocytic differentiation.…”

Dichotomic Potency of IFNγ Licensed Allogeneic Mesenchymal Stromal Cells in Animal Models of Acute Radiation Syndrome and Graft Versus Host Disease

“…Previous study had shown that proinflammatory cytokine cocktail (IFNγ, IL-1β, TNFα and IFNα) activated human skin-derived precursors displayed lesser efficacy compared to unstimulated counter parts in mitigating graft vs host response in an animal model ( 37 ). In contrast, a recent study has demonstrated that cytokine cocktail (IFNγ, IL-17, IL-1β, TNFα) stimulated human cord blood tissue derived MSCs (CBti MSCs) improved the outcome of xenogeneic mouse model of GvHD ( 38 ).…”