Tissue-Protective and Anti-Inflammatory Landmark of PRP-Treated Mesenchymal Stromal Cells Secretome for Osteoarthritis
Abstract
:1. Introduction
2. Results
2.1. PRP Characterization
2.2. PRP-Treated BMSCs’ Characterization
2.3. PRP-BMSCs’ Secreted Factors
2.4. EVs’ Characterization
2.5. EV-miRNAs’ Identification
2.6. OA-Related Targets for PRP-BMSC EV-miRNAs
2.7. PRP Effects on BMSC-Secreted Factors and EV-miRNAs
3. Discussion
4. Materials and Methods
4.1. PRP Collection, Activation and Storage
4.2. ELISA Characterization of Activated PRP
4.3. Bone Marrow Collection, BMSCs’ Isolation and Expansion
4.4. Flow Cytometry Characterization of PRP-Treated BMSCs
4.5. ELISA Characterization of PRP-Treated BMSCs Secretome
4.6. Protein–Protein Interaction Networks
4.7. Characterization of EVs in PRP-Treated BMSCs’ Secretomes
4.8. Total RNA Isolation from EVs’ and miRNAs’ Quantification
4.9. Identification of miRNAs’ Target
4.10. Comparison of PRP-Treated vs. Untreated BMSCs’ Secretomes
4.11. Statistical and Computational Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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TYPE | FACTOR | (pg/mL) | |
---|---|---|---|
CYT | ICAM2 | 790,983 | Intercellular adhesion molecule 2 |
CYT | PLG | 182,992 | Plasminogen |
REC | VCAM1 | 102,461 | Vascular cell adhesion protein 1 |
CYT | IL13RA2 | 94,449 | Interleukin-13 receptor subunit alpha-2 |
CHE | IL9 | 73,686 | Interleukin-9 |
GF | IGFBP4 | 72,637 | Insulin-like growth factor binding protein 4 |
REC | MICB | 66,893 | MHC class I polypeptide-related sequence B |
GF | TGFB1 | 58,819 | Transforming growth factor beta-1 |
CHE | PF4 | 56,183 | Platelet factor 4 |
CYT | IL23A | 47,225 | Interleukin-23 subunit alpha |
CYT | FLT1 | 47,188 | Vascular endothelial growth factor receptor 1 |
INF | PDGFB | 47,171 | Platelet-derived growth factor subunit B |
CHE | IL31 | 38,293 | Interleukin-31 |
GF | BMP7 | 35,835 | Bone morphogenetic protein 7 |
CYT | SIGLEC5 | 35,491 | Sialic-acid-binding Ig-like lectin 5 |
GF | IGFBP3 | 34,608 | Insulin-like growth factor binding protein 3 |
CHE | CCL26 | 34,511 | C-C motif chemokine 26 |
GF | FGF4 | 33,301 | Fibroblast growth factor 4 |
CHE | SPP1 | 30,604 | Osteopontin |
GF | BMP4 | 28,461 | Bone morphogenetic protein 4 |
GF | IGFBP2 | 27,669 | Insulin-like growth factor binding protein 2 |
REC | IL21R | 26,521 | Interleukin-21 receptor |
REC | SELL | 25,729 | L-selectin |
GF | CSF1R | 24,163 | Macrophage-colony-stimulating factor 1 receptor |
CYT | IL6ST | 23,811 | Interleukin-6 receptor subunit beta |
INF | IL6R | 23,412 | Interleukin-6 receptor subunit alpha |
CHE | CCL21 | 23,105 | C-C motif chemokine 21 |
INF | TIMP2 | 22,795 | Metalloproteinase inhibitor 2 |
REC | TNFRSF17 | 22,355 | Tumor necrosis factor receptor superfamily member 17 |
CHE | IFNL1 | 19,506 | Interferon lambda-1 |
CYT | CDH1 | 17,919 | Cadherin-1 |
CYT | IL13RA1 | 16,766 | Interleukin-13 receptor subunit alpha-1 |
GF | KDR | 15,881 | Vascular endothelial growth factor receptor 2 |
CYT | TREM1 | 15,662 | Triggering receptor expressed on myeloid cells 1 |
CYT | CTSS | 15,538 | Cathepsin S |
REC | TNFRSF18 | 13,410 | Tumor necrosis factor receptor superfamily member 18 |
CYT | LGALS7 | 12,956 | Galectin-7 |
CYT | TNFRSF10D | 12,579 | Tumor necrosis factor receptor superfamily member 10D |
CYT | PDGFA | 12,454 | Platelet-derived growth factor subunit A |
INF | TNFRSF1A | 12,348 | Tumor necrosis factor receptor superfamily member 1A |
GF | TGFA | 12,273 | Protransforming growth factor alpha |
INF | TIMP1 | 12,041 | Metalloproteinase inhibitor 1 |
GF | FGF7 | 11,984 | Fibroblast growth factor 7 |
CYT | IL2RB | 11,830 | Interleukin-2 receptor subunit beta |
CYT | SERPINE1 | 11,194 | Plasminogen activator inhibitor 1 |
CHE | CXCL16 | 10,931 | C-X-C motif chemokine 16 |
INF | ICAM1 | 10,930 | Intercellular adhesion molecule 1 |
INF | CCL5 | 10,751 | C-C motif chemokine 5 |
INF | TNFRSF1B | 10,501 | Tumor necrosis factor receptor superfamily member 1B |
pg/Million Cells | |||||||
---|---|---|---|---|---|---|---|
TYPE | FACTOR | B1 | B2 | B3 | MEAN | SD | |
GF | IGFBP4 | 146,361 | 166,965 | 160,221 | 157,849 | 8577 | Insulin-like growth factor binding protein 4 |
CHE | PF4 | 118,491 | 127,082 | 177,384 | 140,985 | 25,975 | Platelet factor 4 |
GF | IGFBP3 | 67,919 | 65,875 | 69,956 | 67,917 | 1666 | Insulin-like growth factor binding protein 3 |
GF | TGFB1 | 25,432 | 43,973 | 51,332 | 40,245 | 10,897 | Transforming growth factor beta-1 |
INF | TIMP2 | 37,691 | 43,548 | 37,878 | 39,706 | 2718 | Metalloproteinase inhibitor 2 |
CHE | IFNL1 | 25,976 | 26,330 | 49,299 | 33,869 | 10,912 | Interferon lambda-1 |
CYT | INHBA | 25,821 | 24,754 | 27,428 | 26,001 | 1099 | Inhibin beta A chain |
GF | VEGFA | 18,261 | 24,211 | 24,511 | 22,328 | 2878 | Vascular endothelial growth factor A |
INF | TIMP1 | 19,604 | 23,458 | 20,658 | 21,240 | 1626 | Metalloproteinase inhibitor 1 |
CYT | SERPINE1 | 20,131 | 20,479 | 16,545 | 19,052 | 1778 | Plasminogen activator inhibitor 1 |
GF | BMP4 | 6102 | 33,281 | 8863 | 16,082 | 12,213 | Bone morphogenetic protein 4 |
GF | IGFBP6 | 9679 | 14,168 | 13,933 | 12,593 | 2063 | Insulin-like growth factor binding protein 6 |
CRT | ||||||
---|---|---|---|---|---|---|
miRBase ID | B1 | B2 | B3 | Mean | SD | % Weight |
hsa-miR-24-3p | 12.24 | 12.53 | 12.40 | 12.39 | 0.12 | 20.12142652 |
hsa-miR-193b-3p | 12.96 | 13.40 | 13.28 | 13.21 | 0.18 | 11.35032031 |
hsa-miR-222-3p | 12.93 | 13.66 | 13.57 | 13.38 | 0.32 | 10.08398807 |
hsa-miR-574-3p | 13.72 | 13.83 | 14.34 | 13.96 | 0.27 | 6.762989192 |
hsa-miR-191-5p | 13.75 | 13.90 | 14.25 | 13.97 | 0.21 | 6.730254585 |
hsa-miR-1274B | 14.28 | 14.08 | 13.84 | 14.06 | 0.18 | 6.295528960 |
hsa-miR-320a-3p | 14.35 | 14.78 | 14.81 | 14.65 | 0.21 | 4.197880228 |
hsa-miR-484 | 14.82 | 14.88 | 14.95 | 14.89 | 0.05 | 3.563581189 |
hsa-miR-197-3p | 15.65 | 16.11 | 15.73 | 15.83 | 0.20 | 1.854025114 |
hsa-miR-125b-5p | 15.98 | 16.10 | 15.70 | 15.93 | 0.17 | 1.733067865 |
hsa-miR-99a-5p | 15.98 | 15.97 | 16.34 | 16.09 | 0.17 | 1.542204224 |
hsa-miR-145-5p | 15.98 | 15.95 | 16.49 | 16.14 | 0.25 | 1.494152546 |
hsa-miR-19b-3p | 15.99 | 16.43 | 16.02 | 16.15 | 0.20 | 1.486233896 |
hsa-miR-214-3p | 15.79 | 16.40 | 16.37 | 16.18 | 0.28 | 1.447598052 |
hsa-miR-21-5p | 16.71 | 16.61 | 16.48 | 16.60 | 0.10 | 1.086479443 |
hsa-miR-342-3p | 16.33 | 16.67 | 16.86 | 16.62 | 0.22 | 1.070779162 |
hsa-miR-132-3p | 16.69 | 16.77 | 16.64 | 16.70 | 0.05 | 1.011849009 |
hsa-miR-16-5p | 16.55 | 16.69 | 16.94 | 16.73 | 0.16 | 0.995615635 |
hsa-miR-523-3p | 17.79 | 16.91 | 15.53 | 16.74 | 0.93 | 0.983952511 |
hsa-miR-409-3p | 17.10 | 16.84 | 16.96 | 16.97 | 0.11 | 0.841476316 |
hsa-miR-221-3p | 16.92 | 16.97 | 17.08 | 16.99 | 0.06 | 0.829124978 |
hsa-miR-1274A | 17.21 | 16.95 | 16.94 | 17.03 | 0.12 | 0.803847975 |
hsa-miR-636 | 22.93 | 15.48 | 12.76 | 17.06 | 4.30 | 0.790403154 |
hsa-let-7b-5p | 17.78 | 16.10 | 17.35 | 17.08 | 0.71 | 0.780602681 |
hsa-miR-210-3p | 16.83 | 17.27 | 17.13 | 17.08 | 0.18 | 0.779341548 |
hsa-miR-29a-3p | 16.82 | 17.47 | 17.27 | 17.19 | 0.27 | 0.722629345 |
hsa-miR-30b-5p | 17.38 | 17.40 | 17.32 | 17.36 | 0.03 | 0.639490414 |
hsa-miR-106a-5p | 17.23 | 17.58 | 17.47 | 17.43 | 0.15 | 0.610894287 |
hsa-miR-17-5p | 17.39 | 17.49 | 17.44 | 17.44 | 0.04 | 0.606534357 |
hsa-miR-30c-5p | 17.78 | 17.39 | 17.33 | 17.50 | 0.20 | 0.582633817 |
hsa-miR-720 | 17.94 | 17.54 | 17.49 | 17.66 | 0.20 | 0.521351303 |
hsa-miR-92a-3p | 17.43 | 17.95 | 17.63 | 17.67 | 0.21 | 0.517749975 |
hsa-miR-483-5p | 17.77 | 17.66 | 17.58 | 17.67 | 0.08 | 0.516555300 |
hsa-miR-20a-5p | 18.22 | 18.29 | 17.88 | 18.13 | 0.18 | 0.376397024 |
hsa-miR-138-5p | 17.69 | 18.53 | 18.18 | 18.13 | 0.34 | 0.375008235 |
hsa-miR-193a-5p | 18.03 | 18.53 | 18.51 | 18.36 | 0.23 | 0.321448809 |
hsa-miR-382-5p | 17.56 | 19.12 | 18.50 | 18.39 | 0.64 | 0.313599274 |
hsa-miR-28-3p | 18.39 | 18.76 | 18.57 | 18.57 | 0.15 | 0.276431568 |
hsa-miR-31-5p | 18.40 | 18.81 | 18.52 | 18.58 | 0.17 | 0.275793598 |
hsa-miR-199a-3p | 18.20 | 18.97 | 18.89 | 18.69 | 0.35 | 0.255134201 |
hsa-miR-376c-3p | 18.97 | 19.09 | 19.76 | 19.28 | 0.35 | 0.169888586 |
hsa-miR-520e-3p | 20.11 | 22.56 | 15.28 | 19.32 | 3.03 | 0.165204860 |
hsa-miR-29c-3p | 15.98 | 21.49 | 20.49 | 19.32 | 2.40 | 0.164899729 |
hsa-let-7e-5p | 18.14 | 19.62 | 20.32 | 19.36 | 0.91 | 0.160575943 |
hsa-miR-152-3p | 19.69 | 19.39 | 19.31 | 19.46 | 0.16 | 0.149097433 |
hsa-miR-30a-3p | 19.88 | 18.79 | 19.82 | 19.50 | 0.50 | 0.145490183 |
EXPRESSING CELL (>1%) | % WEIGHT | MAIN EV-miRNA (%) | FUNCTION | ||||
---|---|---|---|---|---|---|---|
C | S | H | T | ||||
CYTOKINES | |||||||
TNF | X | X | 2.34 | hsa-miR-125b-5p (1.73) | Pro-inflammatory | ||
IL1B | X | X | 1.09 | hsa-miR-21-5p (1.09) | Pro-inflammatory | ||
IL1A | X | X | 6.73 | hsa-miR-191-5p (6.73) | Pro-inflammatory | ||
CSF1 | X | X | X | 0.15 | hsa-miR-152-3p (0.15) | Macrophage activator | |
CXCL12 | X | X | 1.11 | hsa-miR-221-3p (0.83) | Articular cartilage matrix degeneration | ||
CCL5 | X | X | X | 1.45 | hsa-miR-214-3p (1.45) | Cartilage erosion | |
IL11 | X | X | X | 0.58 | hsa-miR-30c-5p (0.58) | Pro-inflammatory | |
GROWTH FACTORS | |||||||
TGFB1 | X | X | X | X | 26.88 | hsa-miR-24-3p (20.12) | Chondrocytes homeostasis, hypertrophy |
IGF1 | X | X | 1.14 | hsa-miR-29a-3p (0.72) | Promote chondrocyte anabolic activity | ||
FGF2 | X | X | 1.15 | hsa-miR-16-5p (1.00) | Promote catabolic and anti-anabolic effects | ||
BMP2 | X | X | X | 1.22 | hsa-miR-106a-5p (0.61) | Promote cartilage regeneration | |
VEGFA | X | X | X | 10.52 | hsa-miR-320a-3p (4.20) | Chondrocyte catabolism | |
HGF | X | X | 1.26 | hsa-miR-16-5p (1.00) | Osteophyte formation | ||
ANGPT2 | X | X | 3.22 | hsa-miR-125b-5p (1.73) | Abnormal angiogenesis in OA | ||
CTGF | X | X | X | 2.07 | hsa-miR-145-5p (1.49) | Osteophyte formation and ECM degradation | |
KITLG | X | X | X | 4.20 | hsa-miR-320a-3p (4.20) | Mast cell hyperplasia and inflammation | |
TGFB2 | X | X | X | 2.58 | hsa-miR-145-5p (1.49) | High level in joint tissue during OA | |
IGF2 | X | X | 1.73 | hsa-miR-125b-5p (1.73) | Promote cartilage matrix levels | ||
BDNF | X | 2.79 | hsa-miR-132-3p (1.01) | Promote joint pain and inflammation | |||
PROTEASES | |||||||
ADAM12 | X | X | 0.88 | hsa-miR-29a-3p (0.72) | Proteinase involved in ECM degradation | ||
ADAM17 | X | X | X | 1.64 | hsa-miR-145-5p (1.49) | Proteinase involved in ECM degradation | |
ADAMTS9 | X | 0.72 | hsa-miR-29a-3p (0.72) | Proteinase involved in ECM degradation | |||
MMP1 | X | 11.27 | hsa-miR-222-3p (10.08) | Proteinase involved in ECM degradation | |||
MMP2 | X | X | 4.05 | hsa-miR-125b-5p (1.73) | Proteinase involved in ECM degradation | ||
MMP9 | X | X | 1.17 | hsa-miR-132-3p (1.01) | Proteinase involved in ECM degradation | ||
MMP14 | X | X | 21.61 | hsa-miR-24-3p (20.12) | Proteinase involved in ECM degradation | ||
PLAU | X | X | 11.35 | hsa-miR-193b-3p (11.35) | ECM-degrading enzyme | ||
PLAT | X | X | 1.09 | hsa-miR-21-5p (1.09) | ECM-degrading enzyme | ||
APC | X | X | 2.34 | hsa-miR-125b-5p (1.73) | Promote MMP activity | ||
TIMP2 | X | X | 0.99 | hsa-miR-106a-5p (0.61) | MMP inhibitor | ||
TIMP3 | X | X | 12.61 | hsa-miR-222-3p (10.08) | MMP inhibitor |
% WEIGHT | ROLE | |
---|---|---|
CARTILAGE | ||
Protective | ||
hsa-miR-24-3p | 20.12 | Prevents ECM degradation, increases chondrocyte viability |
hsa-miR-193b-3p | 11.35 | Reduce cartilage degradation |
hsa-miR-222-3p | 10.08 | Reduce cartilage degradation |
hsa-miR-320a-3p | 4.20 | Increase chondrocyte viability |
hsa-miR-125b-5p | 1.73 | Prevents aggrecan loss |
hsa-miR-221-3p | 0.83 | Prevents ECM degradation |
hsa-miR-210-3p | 0.78 | Promotes chondrocyte and ECM deposition |
hsa-miR-17-5p | 0.61 | Induces autophagy |
hsa-miR-92a-3p | 0.52 | Increases collagen deposition |
hsa-miR-199a-3p | 0.26 | Anti-catabolic |
hsa-miR-30a-3p | 0.15 | cartilage homeostasis |
TOTAL | 50.62 | |
Destructive | ||
hsa-miR-21-5p | 1.09 | Negatively regulates chondrogenesis |
hsa-miR-16-5p | 1.00 | Cartilage degradation |
hsa-miR-30b-5p | 0.64 | Pro-apoptotic, ECM degradation |
hsa-miR-483-5p | 0.52 | Chondrocyte hypertrophy, ECM degradation and cartilage angiogenesis |
hsa-miR-138-5p | 0.38 | Cartilage degradation |
TOTAL | 3.61 | |
Dual | ||
hsa-miR-145-5p | 1.49 | Regulates chondrocyte proliferation and fibrosis |
SYNOVIUM | ||
Protective | ||
hsa-miR-29a-3p | 0.72 | Anti-fibrotic effects |
MACROPHAGE | ||
M1 | ||
hsa-miR-125b-5p | 1.73 | Pro-M1 |
hsa-miR-145-5p | 1.49 | Pro-M1 |
TOTAL | 3.23 | |
M2 | ||
hsa-miR-24-3p | 20.12 | Pro-M2, anti-M1 |
hsa-miR-222-3p | 10.08 | Pro-M2 |
hsa-let-7b-5p | 0.78 | Pro-M2 |
TOTAL | 30.99 | |
T CELL | ||
Pro-Activation | ||
hsa-miR-19b-3p | 1.49 | Reduces PTEN repressor |
hsa-miR-214-3p | 1.45 | Reduces PTEN repressor |
hsa-miR-21-5p | 1.09 | Reduces PTEN repressor |
hsa-miR-132-3p | 1.01 | Downregulate PIK3R1 |
hsa-miR-221-3p | 0.83 | Downregulate PIK3R1 |
hsa-let-7b-5p | 0.78 | Represses IL10 |
hsa-miR-106a-5p | 0.61 | Represses IL10 |
hsa-miR-17-5p | 0.61 | Reduces PTEN repressor and promotes IFNγ |
hsa-let-7e-5p | 0.16 | Represses IL10 |
TOTAL | 8.02 | |
Anti-Activation | ||
hsa-miR-24-3p | 20.12 | Represses IFNγ in activated CD4+ and CD8+ |
hsa-miR-125b-5p | 1.73 | Maintains T cell naïve state |
hsa-miR-342-3p | 1.07 | Downregulated upon activation |
TOTAL | 22.93 | |
Dual | ||
hsa-miR-31-5p | 0.28 | Upregulates IL2, downregulated with activation |
hsa-miR-210-3p | 0.78 | Upregulated in activated T cell, represses IL17 |
TOTAL | 1.06 |
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Ragni, E.; Perucca Orfei, C.; De Luca, P.; Libonati, F.; de Girolamo, L. Tissue-Protective and Anti-Inflammatory Landmark of PRP-Treated Mesenchymal Stromal Cells Secretome for Osteoarthritis. Int. J. Mol. Sci. 2022, 23, 15908. https://doi.org/10.3390/ijms232415908
Ragni E, Perucca Orfei C, De Luca P, Libonati F, de Girolamo L. Tissue-Protective and Anti-Inflammatory Landmark of PRP-Treated Mesenchymal Stromal Cells Secretome for Osteoarthritis. International Journal of Molecular Sciences. 2022; 23(24):15908. https://doi.org/10.3390/ijms232415908
Chicago/Turabian StyleRagni, Enrico, Carlotta Perucca Orfei, Paola De Luca, Francesca Libonati, and Laura de Girolamo. 2022. "Tissue-Protective and Anti-Inflammatory Landmark of PRP-Treated Mesenchymal Stromal Cells Secretome for Osteoarthritis" International Journal of Molecular Sciences 23, no. 24: 15908. https://doi.org/10.3390/ijms232415908