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Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation.

ABSTRACT: The infrapatellar fat pad (IFP) serves as a reservoir of Mesenchymal Stem Cells (MSC), and with adjacent synovium plays key roles in joint disease including the production of Substance P (SP) affecting local inflammatory responses and transmitting nociceptive signals. Here, we interrogate human IFP-derived MSC (IFP-MSC) reaction to inflammatory and pro-fibrotic environments (cell priming by TNF?/IFN? and TNF?/IFN?/CTGF exposure respectively), compared with bone marrow-derived MSC (BM-MSC). Naïve IFP-MSC exhibit increased clonogenicity and chondrogenic potential compared with BM-MSC. Primed cells experienced dramatic phenotypic changes, including a sharp increase in CD10, upregulation of key immunomodulatory transcripts, and secreted growth factors/cytokines affecting key pathways (IL-10, TNF-?, MAPK, Ras and PI3K-Akt). Naïve, and more so primed MSC (both) induced SP degradation in vitro, reproduced with their supernatants and abrogated with thiorphan, a CD10 inhibitor. These findings were reproduced in vivo in a rat model of acute synovitis, where transiently engrafted human IFP-MSC induced local SP reduction. Functionally, primed IFP-MSC demonstrated sustained antagonism of activated human peripheral blood mononuclear cells (PBMC) proliferation, significantly outperforming a declining dose-dependent effect with naïve cohorts. Collectively, our in vitro and in vivo data supports cell priming as a way to enhance the immunoregulatory properties of IFP-MSC, which selectively engraft in areas of active synovitis/IFP fibrosis inducing SP degradation, resulting in a cell-based product alternative to BM-MSC to potentially treat degenerative/inflammatory joint diseases.

SUBMITTER: Kouroupis D

PROVIDER: S-EPMC6659713 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation.

Kouroupis Dimitrios D Bowles Annie C AC Willman Melissa A MA Perucca Orfei Carlotta C Colombini Alessandra A Best Thomas M TM Kaplan Lee D LD Correa Diego D

Scientific reports 20190726 1

The infrapatellar fat pad (IFP) serves as a reservoir of Mesenchymal Stem Cells (MSC), and with adjacent synovium plays key roles in joint disease including the production of Substance P (SP) affecting local inflammatory responses and transmitting nociceptive signals. Here, we interrogate human IFP-derived MSC (IFP-MSC) reaction to inflammatory and pro-fibrotic environments (cell priming by TNFα/IFNγ and TNFα/IFNγ/CTGF exposure respectively), compared with bone marrow-derived MSC (BM-MSC). Naïve ...[more]

PMID: 31350444

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Project description:BackgroundTo investigate the in vitro and in vivo anti-inflammatory/anti-fibrotic capacity of IFP-MSC manufactured as 3D spheroids. Our hypothesis is that IFP-MSC do not require prior cell priming to acquire a robust immunomodulatory phenotype in vitro in order to efficiently reverse synovitis and IFP fibrosis, and secondarily delay articular cartilage damage in vivo.MethodsHuman IFP-MSC immunophenotype, tripotentiality, and transcriptional profiles were assessed in 3D settings. Multiplex secretomes were assessed in IFP-MSC spheroids [Crude (non-immunoselected), CD146+ or CD146- immunoselected cells] and compared with 2D cultures with and without prior inflammatory/fibrotic cell priming. Functionally, IFP-MSC spheroids were assessed for their immunopotency on human PBMC proliferation and their effect on stimulated synoviocytes with inflammation and fibrotic cues. The anti-inflammatory and anti-fibrotic spheroid properties were further evaluated in vivo in a rat model of acute synovitis/fat pad fibrosis.ResultsSpheroids enhanced IFP-MSC phenotypic, transcriptional, and secretory immunomodulatory profiles compared to 2D cultures. Further, CD146+ IFP-MSC spheroids showed enhanced secretory and transcriptional profiles; however, these attributes were not reflected in a superior capacity to suppress activated PBMC. This suggests that 3D culturing settings are sufficient to induce an enhanced immunomodulatory phenotype in both Crude and CD146-immunoselected IFP-MSC. Crude IFP-MSC spheroids modulated the molecular response of synoviocytes previously exposed to inflammatory cues. Therapeutically, IFP-MSC spheroids retained substance P degradation potential in vivo, while effectively inducing resolution of inflammation/fibrosis of the synovium and fat pad. Furthermore, their presence resulted in arrest of articular cartilage degradation in a rat model of progressive synovitis and fat pad fibrosis.Conclusions3D spheroids confer IFP-MSC a reproducible and enhanced immunomodulatory effect in vitro and in vivo, circumventing the requirement of non-compliant cell priming or selection before administration and thereby streamlining cell products manufacturing protocols.

Dataset Information

Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation.

Publications

Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation.

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