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

Dimitrios Kouroupis, Annie C. Bowles, Melissa A. Willman, Carlotta Perucca Orfei, Alessandra Colombini, Thomas M. Best, Lee D. Kaplan, Diego Correa

Research output: Contribution to journalArticle

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 TNFα/IFNγ and TNFα/IFNγ/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-α, 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.

Original languageEnglish
Article number10864
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Substance P
Mesenchymal Stromal Cells
Adipose Tissue
Fibrosis
Inflammation
Phenotype
Synovitis
Bone Marrow
Thiorphan
Synovial Membrane
Joint Diseases
Phosphatidylinositol 3-Kinases
Osteoarthritis
Interleukin-10
Blood Cells
Intercellular Signaling Peptides and Proteins
Up-Regulation
Cell Proliferation
Cytokines

ASJC Scopus subject areas

  • General

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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; Bowles, Annie C.; Willman, Melissa A.; Perucca Orfei, Carlotta; Colombini, Alessandra; Best, Thomas M.; Kaplan, Lee D.; Correa, Diego.

In: Scientific Reports, Vol. 9, No. 1, 10864, 01.12.2019.

Research output: Contribution to journalArticle

Kouroupis, Dimitrios ; Bowles, Annie C. ; Willman, Melissa A. ; Perucca Orfei, Carlotta ; Colombini, Alessandra ; Best, Thomas M. ; Kaplan, Lee D. ; Correa, Diego. / Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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