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. 2023 Apr;41(4):902-912.
doi: 10.1002/jor.25431. Epub 2022 Sep 13.

Intravenous injection of adipose-derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model

Maryam F Afzali  1 , Stephen C Pannone  1 , Richard B Martinez  1 , Margaret A Campbell  1 , Joseph L Sanford  1 , Lynn M Pezzanite  2 , Jade Kurihara  2 , Valerie Johnson  2   3 , Steven W Dow  2 , Kelly S Santangelo  1
Affiliations

Intravenous injection of adipose-derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model

Maryam F Afzali et al. J Orthop Res. 2023 Apr.

Abstract

Osteoarthritis (OA) is a leading cause of morbidity among aging populations, yet symptom and/or disease-modification remains elusive. Adipose-derived mesenchymal stromal cells (adMSCs) have demonstrated immunomodulatory and anti-inflammatory properties that may alleviate clinical signs and interrupt disease onset and progression. Indeed, multiple manuscripts have evaluated intra-articular administration of adMSCs as a therapeutic; however, comparatively few evaluations of systemic delivery methods have been published. Therefore, the aim of this study was to evaluate the short-term impact of intravenous (IV) delivery of allogeneic adMSCs in an established model of spontaneous OA, the Hartley guinea pig. Animals with moderate OA received once weekly injections of 2 × 106 adMSCs or vehicle control for 4 weeks in peripheral veins; harvest occurred 2 weeks after the final injection. Systemic administration of adMSCs resulted in no adverse effects and was efficacious in reducing clinical signs of OA (as assessed by computer-aided gait analysis) compared to control injected animals. Further, there were significant decreases in key inflammatory mediators (including monocyte chemoattractant protein-1, tumor necrosis factor, and prostaglandin E2 ) both systemically (liver, kidney, and serum) and locally in the knee (joint tissues and synovial fluid) in animals treated with IV adMSCs relative to controls (as per enzyme-linked immunosorbent assay and/or immunohistochemistry, dictated by tissue sample). Thus, systemic administration of adMSCs by IV injection significantly improved gait parameters and reduced both systemic and intra-articular inflammatory mediators in animals with OA. These findings demonstrate the potential utility of alternative delivery approaches for cellular therapy of OA, particularly for patients with multiple affected joints.

Keywords: Hartley guinea pig; adipose-derived mesenchymal stromal cells; gait; inflammation; osteoarthritis (OA).

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Conflict of interest statement

Declaration of competing interest.

There is no conflict of interest.

Figures

Figure 1.
Figure 1.. Immunophenotyping of guinea pig adMSCs.
(A) Isolated adipose tissue from 4-month-old guinea pigs were subjected to FACS analysis on passage 3 after seeding to verify purity. (B) Overlaid histogram showing CD90.2 on the majority of the isolated cells (>99 %), (C) CD29 (>99%) and (D) CD44 (>97%). In contrast, very few mature hematopoietic markers (E) CD45 and (F) CD73 were detected (<2%).
Figure 2.
Figure 2.. IV adMSC administration improved gait outcomes.
Final minus baseline measurements of (A) stride length [adMSC (mean: 1.620 ± 0.8625) vs. control (mean: 0.2950 ± 0.5669); p = 0.0243] and (B) maximum speed length [adMSC (mean: 32 ± 8.367) vs. control (mean: 12.20 ± 13.01); p = 0.0426] in control and adMSC group. Black lines represent mean values. P-values were determined by unpaired non-parametric t-testx.
Figure 3.
Figure 3.. Biodistribution of adMSCs in major organ tissues.
Labeled adMSCs (red) with DAPI nuclear stain (blue) were detected in the lung (A, B), liver (D, E) and spleen (G, H) in all animals that received adMSC therapy.
Figure 4.
Figure 4.. Serum and synovial fluid protein concentrations of monocyte chemoattractant protein (MCP)-1 expression, tumor necrosis factor (TNF) and prostaglandin (PG)E2.
(A) Serum (n=10) MCP-1 protein [adMSC (mean: 52.33 ± 24.53 pg/ml) vs. control (mean: 178.5 ± 90.24); p = 0.0329], (B) TNF [adMSC (mean: 102.6 ± 13.08 pg/ml) vs. control (mean: 207.8 ± 48.5 pg/ml); p = 0.0068], and (C) PGE2 [adMSC (mean: 2991 ± 1431 pg/ml) vs. control (mean: 7936 ± 1144 pg/ml); p = 0.0004] decreased with adMSC administration. (D) Synovial fluid (n=10) TNF [adMSC (mean: 284 ± 65.34 pg/ml) vs. control (mean 418.2 ± 32.84 pg/ml); p = 0.0066] and (E) PGE2 [adMSC (mean: 210.6 ± 35.94 pg/ml) vs. control (mean: 271.9 ± 25.60 pg/ml); p = 0.0164] also decreased with treatment. P-values were determined by unpaired t-test Δ.
Figure 5.
Figure 5.
Representative photomicrographs of toluidine blue-stained sections from medial compartments of knee joint of (A) control (n=5) and (B) adMSC (n=5) treated guinea pigs. Comparison of total joint histology scores (C) adMSC and control groups [adMSC (mean: 31.80 ± 10.71) vs. control (mean: 27 ± 11.85); p = 0.5208]. Black lines represent the mean values. P-values were determined by unpaired t-test Δ.
Figure 6.
Figure 6.. Immunohistochemistry TNF expression in (A, B) liver, (D, E) kidney and (G, H) synovium tissues.
Quantitative analysis of TNF-stained tissue (n=10) subtracted from IgG control tissue used for statistical analysis. TNF was statistically decreased in (C) liver [adMSC (mean: 2530 ± 1714) vs. control (mean: 10962 ± 5766); p=0.0281], (F) kidney [adMSC (mean: 12041 ± 1521) vs. control (mean: 76962 ± 14814); p = 0.0006], and (I) synovium [adMSC (mean: 4041 ± 1997 vs. control (mean: 10376 ± 4985); p = 0.0439]. P-values were determined by unpaired t-test Δ.
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