Original articleHuman mesenchymal stromal cells from different tissues exhibit unique responses to different inflammatory stimuli
Introduction
Mesenchymal stromal cells (MSC) are adherent cells of fibroblastoid appearance, with certain surface marker phenotype, that can be induced to various mesodermal phenotypes [[1], [2], [3]]. Properties of MSC, such as secretion of soluble bioactive factors capable of stimulating recovery of injured cells and their anti-inflammatory/immunomodulatory functions have led to clinical interest as potential therapeutic utility for a variety of indications in over 950 clinical trials [1,2].
MSC cells have been isolated from a wide variety of adult and fetal tissues [4], with bone marrow (BM-MSC), adipose tissue (AT-MSC), and umbilical cord (UC-MSC) currently representing the most commonly used tissue sources for MSC therapy [5]. The immunoregulatory properties and the tissue reparative functions of MSC may be induced or potentiated by inflammatory cytokines at damaged tissue sites [6]. Therefore, pre-treatment modification of MSC with cytokines or drugs may improve their efficiency in clinical use [5]. Inflammatory cytokines most frequently utilized for MSC activation are IFN-γ, TNFα, IL-1β; however, different cytokine combinations can produce different effects [7]. After stimulation at the damaged tissue sites, the newly immigrated MSCs release a plethora of cytokines, immunosuppressive factors, growth factors and adhesion molecules [6]. These factors then orchestrate local tissue/cell responses to promote tissue regeneration and repair.
There are individual studies accessible comparing different cytokine stimulation effects [8,9], however, comparative studies of MSC secretion profiles gathered from different organ origin sites with distinct cytokine stimulations are currently lacking. Here, we aim to investigate whether the MSC’s origin (bone marrow, adipose tissue and umbilical cord) would affect its transcriptome and secretome at baseline and after stimulation with proinflammatory mediators (TNFα, IL-1β and SAA). Additionally, we aimed to explore whether such differences would be reflected in the functional effects of MSC-conditioned medium (CM) on migration, proliferation and apoptosis of normal human lung fibroblasts (NHLF). These results could shed light on a more suitable cell/molecular source selection for better clinical utility of MSCs.
Section snippets
Cells. MSC isolation and culturing
All cell types, UC-MSC, AT-MSC and BM-MSC were obtained from voluntary donors after the approval of the National Medical Ethics Committee (code 136/02/12, 21/09/07 and 89/06/17) respectively, and donors' signed informed consent. UC-MSC were obtained by explant culture, AT-MSC from lipoaspirate by collagenase digestion and BM-MSC from bone marrow by direct seeding of cells into culture flasks. All cell types were cultured in growth media composed of DMEM/F-12, 10 % fetal bovine serum (FBS), 1
Characterization of mRNA profiles of MSC from different sources
Of the original 11 gene expressions analyzed, 3 were expressed at very low basal levels in all samples (iNOS, HLA-G and CCL4 – data not shown) and 8 exhibited higher expression levels, namely cytokines (SDF1, CCL5), adhesion molecules (VCAM-1), immunomodulatory factors (PDE, PGC-1α, IDO1) and growth factors (IGFBP2, VEGF).
Overall, relatively low gene expression levels were exhibited in resting state MSCs (Fig. 2). BM-MSC expressed highest basal mRNA levels of SDF1 and VCAM-1, while the other
Discussion
Plasticity of the immunoregulatory role of MSC relies on the inflammatory status [6] and here we comparatively show that tissue of origin and inflammatory stimuli uniquely influence MSC responses. While TNFα stimulation induced high gene expression of two immunomodulatory mediators IDO1 and CCL5, predominantly in AT-MSC, IL-1β most potently activated MSC secretion profile of IL-6, IL-8, and MCP-1, but to a comparable level in all MSC tissue sources in our study. Literature data confirm that IDO
Conclusions
Our results show that BM-MSC, UC-MSC and AT-MSC exhibit certain tissue of origin-specific profiles and inflammatory activation responses. Among MSC types, UC-derived MSC emerges as most distinct – they did not respond with highly increased IDO1 and CCL5 expression after IL-1β or TNFα stimulation as seen in BM- and AT-MSC, they exert highest basal IL-6, IL-8, MCP-1, ICAM1, HGF, MMP1 and CH3L1 secretion and their CM is unique in inhibiting wound closure. NHLFs treated with different non-activated
Declaration of competing interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgments
Funding for this work was obtained from the Slovenian Research Agency for the National Research Program #P3-0314.
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