Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures

Dimitrios Kouroupis,Lee D Kaplan,Thomas M Best

doi:10.1038/s41598-022-07569-7

Dimitrios Kouroupis, Lee D Kaplan + Show 1 more

Open Access

https://doi.org/10.1038/s41598-022-07569-7

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Abstract

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases. Our hypothesis is that IFP-derived mesenchymal stem cells (IFP-MSC) robust immunomodulatory therapeutic effects are largely exerted via their exosomal (IFP-MSC EXOs) secretome by attenuating synoviocytes and macrophages pro-inflammatory activation. IFP-MSC EXOs showed distinct miRNA and protein immunomodulatory profiles. Reactome analysis of 24 miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, including immune system. Exosomes were enriched for immunomodulatory and reparative proteins that are involved in positive regulation of cell proliferation, response to stimulus, signal transduction, signal receptor activity, and protein phosphorylation. Stimulated synoviocytes or macrophages exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation, altered inflammation-related molecular profiles, and reduced secretion of pro-inflammatory molecules compared to stimulated alone. In an acute synovial/IFP inflammation rat model, IFP-MSC EXOs therapeutic treatment resulted in robust macrophage polarization towards an anti-inflammatory therapeutic M2 phenotype within the synovium/IFP tissues. Based on these findings, we propose a viable cell-free alternative to MSC-based therapeutics as an alternative approach to treating synovitis and IFP fibrosis.

Highlights

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases
We recently reported human IFP derived Mesenchymal Stem Cells (IFP-MSC) acquiring a potent immunomodulatory phenotype, and actively reversing inflammation and fibrosis linked with macrophage polarization from an M1 in disease to an M2 phenotype after engraftment into areas of active synovitis/IFP fibrosis[9–14]
Our previous studies clearly demonstrated that IFP-derived mesenchymal stem cells (IFP-MSC) manufacturing under regulatory-compliant conditions results in a finetuned, regulatory-compliant, cell-based product with superior immunomodulatory properties that overcome any donor-to-donor variability in biological functionality[19–21]

Summary

Introduction

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases. Our hypothesis is that IFP-derived mesenchymal stem cells (IFP-MSC) robust immunomodulatory therapeutic effects are largely exerted via their exosomal (IFP-MSC EXOs) secretome by attenuating synoviocytes and macrophages pro-inflammatory activation. In an acute synovial/ IFP inflammation rat model, IFP-MSC EXOs therapeutic treatment resulted in robust macrophage polarization towards an anti-inflammatory therapeutic M2 phenotype within the synovium/IFP tissues Based on these findings, we propose a viable cell-free alternative to MSC-based therapeutics as an alternative approach to treating synovitis and IFP fibrosis. In pathological conditions, deranged chondrocyte metabolism results in release within the joint of AC degradation products and other damage-associated molecular patterns (DAMPs)[2–5] that incite local responses within the synovium/IFP tissues These responses include: (1) local infiltration of immune cells such as macrophages, (2) shift of resident macrophages to a pro-inflammatory M1 phenotype[2,6], (3) production of AC-degrading proteases (e.g., MMPs), and pro-inflammatory cytokines, adipokines and other mediators, and (4) sustained synovitis and progressive IFP fibrosis. Cell-free products have advantages compared with their replicative cell-based counterparts, including reduced variability, standardization, easy storage, superior safety profile and arguably a smoother regulatory landscape[17,18], constituting a promising therapeutic alternative

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