Abstract
Osteoarthritis (OA) is characterized by cartilage degradation and chronic joint inflammation. Mesenchymal stem cells (MSCs) have shown promising results in OA, but their mechanism of action is not fully understood. We hypothesize that MSCs polarize macrophages, which are strongly associated with joint inflammation to more homeostatic sub-types. We tracked ferumoxytol (Feraheme™, iron oxide nanoparticle)-labeled murine MSCs (Fe-MSCs) in murine OA joints, and quantified changes to joint inflammation and fibrosis. 10-week-old C57BL/6 male mice (n = 5/group) were induced to undergo osteoarthritis by destabilization of medical meniscus (DMM) or sham surgery. 3 weeks post-surgery, mice were injected intra-articularly with either fluorescent dye-(DiR) labeled or DiR-Fe-MSC or saline to yield 4 groups (n = 5 per group for each timepoint [1, 2 and 4weeks]). 4 weeks after injection, mice were imaged by MRI, and scored for i) OARSI (Osteoarthritis Research Society International) to determine cartilage damage; ii) immunohistochemical changes in iNOS, CD206, F4/80 and Prussian Blue/Sca-1 to detect pro-inflammatory, homeostatic and total macrophages and ferumoxytol -labeled MSCs respectively, and iii) Masson’s Trichrome to detect changes in fibrosis. Ferumoxytol-labeled MSCs persisted at greater levels in DMM vs. SHAM-knee joints. We observed no difference in OARSI scores between MSC and vehicle groups. Sca-1 and Prussian Blue co-staining confirmed the ferumoxytol label resides in MSCs, although some ferumoxytol label was detected in proximity to MSCs in macrophages, likely due to phagocytosis of apoptotic MSCs, increasing functionality of these macrophages through MSC efferocytosis. MRI hypertintensity scores related to fluid edema decreased in MSC-treated vs. control animals. For the first time, we show that MSC-treated mice had increased ratios of %CD206+: %F4/80+ (homeostatic macrophages) (p<0.05), and decreased ratios of %iNOS+: %F4/80+ macrophages (p<0.01), supporting our hypothesis that MSCs may modulate synovial inflammation.
Highlights
Osteoarthritis (OA) is a common joint disease affecting 1 in 10 Canadians and is expected to increase to 1 in 4 by 2040
This murine study serves as a precursor to human trials using ferumoxytollabeled human Mesenchymal Stromal Cells (MSCs), intra-articularly injected into patients with knee osteoarthritis and viability and differentiation was assessed for both murine and human MSCs
We report for the first time, that Prussian Blue staining by immunohistochemistry is largely visible in cells that co-stain for Sca-1, a marker of bone marrow-derived mesenchymal stromal cells [24]
Summary
Osteoarthritis (OA) is a common joint disease affecting 1 in 10 Canadians and is expected to increase to 1 in 4 by 2040. The number of adults in the US with doctor-diagnosed arthritis is expected to increase to 25.9% of all adults by 2040.[1] It is a lasting condition in which cartilage breaks down, causing bones to rub against each other, resulting in stiffness, pain and loss of joint movement. Our pioneering Canadian trial (NCT02351011, clinicaltrials.gov) using autologous bone-marrow-derived MSCs showed significant improvement in symptoms and quality of life relative to baseline in osteoarthritic patients; for the first time, we showed clinically that MSCs reduced synovial joint levels of pro-inflammatory macrophages, a potent inflammatory mediator, suggestive of a possible mechanism of action [8]. Macrophages are the most prevalent immune cell in OA joints [9], are elevated in OA compared to healthy joints [10], and contribute to synovial inflammation and fibrosis, characteristic of OA
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