Secreted Factors and Extracellular Vesicles Account for the Immunomodulatory and Tissue Regenerative Properties of Bone-Marrow-Derived Mesenchymal Stromal Cells for Osteoarthritis

Abstract

Bone-marrow-derived mesenchymal stromal cells (BMSCs) showed therapeutic potential in the treatment of musculoskeletal diseases, including osteoarthritis (OA). Their soluble mediators and extracellular vesicles (EVs), which make up the secretome, suppress immune response, attenuate inflammation and promote cartilage repair. EVs, as well as the whole secretome, have been investigated as cell free approaches for OA although, to date, a disease-tailored molecular fingerprint is missing. In this study, soluble mediators and miRNAs were sifted in the BMSCs’ secretome and EVs, respectively, and analyzed in the frame of cell types and factors involved in OA. The majority of identified molecules repress the activation of immune cells and the production of OA-related inflammatory mediators, as well as promote cartilage protection by acting on both chondrocytes homeostasis and extracellular matrix-degrading enzymes. These data provide the molecular ground for the therapeutic potential of BMSCs for regenerative applications for OA and support the use of secretome or EVs as cell-free applications in joint diseases.

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

“…Indeed, miRNAs were shown to be a crucial player for MSC-EVs function. This paradigm has been confirmed for EVs released by MSCs obtained from several sources such as adipose tissue, bone marrow, and amniotic membrane as studied by the group of L. de Girolamo* (Ragni et al, 2020;Ragni et al, 2021a;Ragni et al, 2022a). With respect to EV-miRNA activity for orthopedic conditions, a complex scenario has emerged with respect to how they can function/contribute to MSC therapeutic potential.…”

Therapeutics of the future: Navigating the pitfalls of extracellular vesicles research from an osteoarthritis perspective

“…were among the first to show that MSC‐conditioned medium can enhance chondrocyte proliferation and matrix formation in vitro (Wu et al., 2011 ). Others followed suit, and more recent reports have been published that further support the therapeutic capacity of MSC‐secretome in OA (Khatab et al., 2018 ; Ragni et al., 2022 ).…”

“…A major component of any cell's secretome is EVs (Baglio et al., 2012 ; Ragni et al., 2022 ). As important mediators of cellular communication and trophic effects, this warrants the question: to what extent are EVs involved in the therapeutic effects observed by MSC‐secretome administration?…”

“…• Immunomodulatory and chondroprotective effect in vitro (Dong et al, 2021;Ragni et al, 2022) miR-125a-5p, miR-326, miR-9-5p, miR-3960, lncRNA MEG-3, lncRNA-KLF3-AS1 and TGFB1 mRNA…”

Secretome-based acellular therapy of bone marrow-derived mesenchymal stem cells in degenerative and immunological disorders: A narrative review

“…Regulation of stem cell fate and differentiation, lineage regulation, and angiogenesis 5. Immunoregulation, tissue repair, and wound healing [ 25 , [28] , [29] , [30] , [31] , [32] ] Immunomodulation: Sphingosine-1-phosphate ( S1P ), Thrombospondin-1 ( TSP1 ),TGF-β, IL-1a, IL-1b, IL-6, IL-8, IL-10, IL-12, Forkhead box P3 (FOXP3), Human leukocyte antigen G ( HLA - G ), Galectin 1/9, Nitric oxide (NO), Vascular endothelial growth factor (VEGF), Prostaglandin E2 ( PGE2 ), Krüppel-like factor 3 antisense RNA 1 (KLF3- AS1 ), Annexin, Indoleamine 2,3-dioxygenase ( IDO ), IGF-1R Angiogenesis: CXCR4, Hepatocyte growth factor (HGF), VEGF, Hypoxia-inducible factor 1-alpha (HIF-1a), Transcription factor 4 (TCF4), Hairy and enhancer of split-1(HES1), Protein kinase B (PKB), Cluster differentiation (CD)105, Angiopoietin 1 ( Ang1 ) Chemokines: CXCL1, CXCL2, CXCL6, CXCL8, CXCL9, CXCL10 CXCL16, CXCL20, C–C motif chemokine ligand 2 (CCL2), CCL5, C–C motif chemokine receptor 2 (CCR2), Defensin alpha 1 (DEFA1), Interferon-induced transmembrane (IFITM) Cell adhesion and binding: Calmodulin-like protein 5 (CALML5), Dolichyl-diphosphooligosaccharide–protein glycosyltransferase non-catalytic subunit ( DDOST ), G protein subunit alpha I3 (GNAI3), Transmembrane protein 119 (TMEM119), HLA-A, Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), Integrin subunit beta 3 (ITGB3), Mammalian class I myosin (MYO1), Gap junction protein alpha 1 (GJA1), Matrix metalloproteinase-14 (MMP14), GLI pathogenesis related 2 (GLIPR2), Ras-associated binding protein 23 (RAB23), Staphylococcal nuclease and tudor domain containing 1 (SND1), Plexin-B2 (PLXNB2), Plastin 3 (PLS3), Extended synaptotagmin-1 (ESYT1), PDZ and LIM Domain 5 (PDLIM5), CD29,CD44,CD49 A/C, CD59, CD166 Degradation: 20s proteasome member, CD10, CD13 Adipogenesis: KLF Transcription Factor 7 (KLF7), CCAAT enhancer-binding protein alpha (CEBPA) Extracellular matrix and protein-protein interaction: Aldolase, Fructose-Bisphosphate C (ALDOC), Fibronectin, Galectin-1, Actinin Alpha 1 (ACTN1), Collagen Type VI Alpha 1 Chain (COL6A1/3), Aminopeptidase N (ANPEP), Filamin C (FLNC), Vesicle Amine Transport 1 (VAT1), MMP14, Hemoglobin Subunit Beta (HBB), Low-density lipoprotein receptor–related protein-1 ( LRP1 ), FLNB, Vimentin (VIM), CD95 Apoptotic regulation: POU Class 3 Homeobox 1 (POU3F1), SP1, GATA-4, Wnt4, CD73 Growth factors: FGF, Keratinocyte growth factor (KGF), Platelet-derived growth factor-D (PDGF-D), Glial Cell Line-Derived Neurotrophic Factor (GDNF), HGF, Ciliary neurotrophic factor (CNTF) …”