Mesenchymal stromal cells immunosuppress osteoarthritis synovial fluid modulated monocytes via IL-6 and CCL2.
8 affiliations
- 1Schroeder Arthritis Institute, University Health Network, Toronto, ON, M5T 0S8, Canada.
- 2Krembil Research Institute, University Health Network, Toronto, ON, M5T 0S8, Canada.
- 3Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
- 4Department of Surgery, Division of Orthopedic Surgery, University of Toronto, Toronto, ON, M5T 1P5, Canada.
- 5Schroeder Arthritis Institute, University Health Network, Toronto, ON, M5T 0S8, Canada. [email protected].
- 6Krembil Research Institute, University Health Network, Toronto, ON, M5T 0S8, Canada. [email protected].
- 7Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada. [email protected].
- 8Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada. [email protected].
Abstract
Mesenchymal stromal cell (MSC) interactions with monocytes/macrophages are central to their therapeutic effects in knee osteoarthritis (KOA); however, mechanisms of these interactions are not fully understood. We hypothesize that MSC soluble factors, particularly interleukin-6 (IL-6) and C-C motif chemokine ligand (CCL2) modulate monocytes in KOA environment. Using healthy donor CD14⁺ monocytes exposed to KOA synovial fluid (SF) in the presence or absence of marrow-derived MSC(M) directly or conditioned medium (CM), we evaluated cell surface markers and signaling via signal transducer and activator of transcription (STAT3), nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and c-Jun Terminal Kinase (JNK); functional responses were measured by secretion of tumor necrosis factor (TNF) and IL-1, and by phagocytosis of pHrodo Red E-coli. CD14⁺ monocytes demonstrated a mixed phenotype in KOA SF with increased CD163, CD206, and unchanged HLA-DR, CD86 marker expression. This was accompanied by activated STAT3, JNK, and NF-κB signaling. TNF and IL-1 secreted levels were unchanged, but phagocytosis was impaired, indicative of a net dysfunctional repair phenotype and functionality. CD14⁺ monocytes in KOA SF were hyporesponsive to additional lipopolysaccharide re-challenge, based on TNF and IL-1 secretion. Addition of MSC(M) to KOA SF programmed CD14⁺ monocytes resolved the dysfunctional phenotype and functionality, with significant increases in CD163, CD206; significant reductions in HLA-DR and CD86 expression; this was accompanied by significantly increased activated STAT3 and decreased activated JNK and NF-κB. TNF and IL-1 secretion were also significantly reduced, and phagocytic capacity restored. Blocking IL-6, or to a lesser extent, CCL2, partially abrogated MSC(M) soluble factor effects. MSC(M) experienced apoptosis in KOA SF; however, apoptotic bodies did not fully recapitulate MSC(M) soluble factor effects. IL-6, CCL2, other soluble factors and apoptotic bodies from MSC(M) secretome mitigate the dysfunctional effects of KOA SF on CD14⁺ monocytes resulting in immunosuppressed phenotype and functionality.
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BibTeX
@article{rasti2026mesenchymal,
title = {{Mesenchymal stromal cells immunosuppress osteoarthritis synovial fluid modulated monocytes via IL-6 and CCL2.}},
author = {Mozhgan Rasti and Aida Feiz Barazandeh and Shahrzad Nouri and Kevin P Robb and Rachel Low and Oreoluwa Kolade and Kevin Fan and Rajiv Gandhi and Sowmya Viswanathan},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09194-y},
url = {https://europepmc.org/article/MED/42875435},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mesenchymal stromal cells immunosuppress osteoarthritis synovial fluid modulated monocytes via IL-6 and CCL2.
AU - Mozhgan Rasti
AU - Aida Feiz Barazandeh
AU - Shahrzad Nouri
AU - Kevin P Robb
AU - Rachel Low
AU - Oreoluwa Kolade
AU - Kevin Fan
AU - Rajiv Gandhi
AU - Sowmya Viswanathan
PY - 2026
DA - 2026/08/14
JO - Cell death & disease
DO - 10.1038/s41419-026-09194-y
UR - https://europepmc.org/article/MED/42875435
AB - Mesenchymal stromal cell (MSC) interactions with monocytes/macrophages are central to their therapeutic effects in knee osteoarthritis (KOA); however, mechanisms of these interactions are not fully understood. We hypothesize that MSC soluble factors, particularly interleukin-6 (IL-6) and C-C motif chemokine ligand (CCL2) modulate monocytes in KOA environment. Using healthy donor CD14⁺ monocytes exposed to KOA synovial fluid (SF) in the presence or absence of marrow-derived MSC(M) directly or conditioned medium (CM), we evaluated cell surface markers and signaling via signal transducer and activator of transcription (STAT3), nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and c-Jun Terminal Kinase (JNK); functional responses were measured by secretion of tumor necrosis factor (TNF) and IL-1, and by phagocytosis of pHrodo Red E-coli. CD14⁺ monocytes demonstrated a mixed phenotype in KOA SF with increased CD163, CD206, and unchanged HLA-DR, CD86 marker expression. This was accompanied by activated STAT3, JNK, and NF-κB signaling. TNF and IL-1 secreted levels were unchanged, but phagocytosis was impaired, indicative of a net dysfunctional repair phenotype and functionality. CD14⁺ monocytes in KOA SF were hyporesponsive to additional lipopolysaccharide re-challenge, based on TNF and IL-1 secretion. Addition of MSC(M) to KOA SF programmed CD14⁺ monocytes resolved the dysfunctional phenotype and functionality, with significant increases in CD163, CD206; significant reductions in HLA-DR and CD86 expression; this was accompanied by significantly increased activated STAT3 and decreased activated JNK and NF-κB. TNF and IL-1 secretion were also significantly reduced, and phagocytic capacity restored. Blocking IL-6, or to a lesser extent, CCL2, partially abrogated MSC(M) soluble factor effects. MSC(M) experienced apoptosis in KOA SF; however, apoptotic bodies did not fully recapitulate MSC(M) soluble factor effects. IL-6, CCL2, other soluble factors and apoptotic bodies from MSC(M) secretome mitigate the dysfunctional effects of KOA SF on CD14⁺ monocytes resulting in immunosuppressed phenotype and functionality.
SN - 2041-4889
ER -