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Priming-Dependent Modulation of Secretome in Placenta- and Adipose-Derived Mesenchymal Stromal/Stem cells: Toward Cell-Free Immunoregenerative Therapies for Osteoarticular Disorders

ABSTRACT: Age-related bone degeneration is driven by structural deterioration, chronic inflammation, and impaired regenerative capacity, leading to an increased incidence of osteoarticular disorders. Mesenchymal stromal/stem cells (MSCs) have emerged as promising therapeutic candidates due to their immunomodulatory and regenerative properties, mediated largely through their secretome and extracellular vesicles (EVs). However, the therapeutic efficacy of MSC-derived products depends on both the cell source and the conditioning stimuli to which MSCs are exposed. In this study, we performed a comparative proteomic and exosomal microRNA (miRNA) profiling of secretomes derived from placenta-derived MSCs (PSCs) and adipose-derived MSCs (ASCs), and assessed the impact of priming strategies, including hypoxia, interferon-gamma (IFNγ), and interleukin-1 beta (IL1β), on paracrine properties of these cells. Proteomic analysis identified over 7,000 proteins, with PSC secretome enriched in pathways related to osteogenesis, chondrogenesis, extracellular matrix organization, angiogenesis, and immune regulation, whereas ASC secretome displayed limited enrichment in these processes. Functional scoring highlighted IL1β priming as the most effective strategy to enhance osteochondral and immunomodulatory protein signatures in PSCs. Differently, IFNγ priming selectively expanded the repertoire of exosomal miRNAs, with enrichment in signaling networks including Wnt/β-catenin, TGF-β, NF-κB, and T cell receptor pathways, underscoring its role in fine-tuning immune and regenerative functions. Together, these findings reveal that PSCs secrete a broader and more functionally relevant spectrum of bioactive molecules for osteoarticular applications compared with ASCs. Moreover, distinct priming strategies can differentially modulate their paracrine outputs. IL1β primarily enhances protein-driven regenerative and immunomodulatory activity, whereas IFNγ promotes a functionally enriched exosomal miRNA cargo. These results support PSC-derived secretomes as versatile candidates for next-generation, cell-free therapies in osteoarticular disease.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Margot Lo Pinto

LAB HEAD: Simone Dario Scilabra

PROVIDER: PXD068866 | Pride | 2026-06-15

REPOSITORIES: Pride

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Priming-Dependent Modulation of Secretome in Placenta- and Adipose-Derived Mesenchymal Stromal/Stem Cells: Toward Cell-Free Immunoregenerative Therapies for Osteochondral and Degenerative Joint Diseases.

Ligotti Mattia Emanuela ME Scalia Elisabetta E Scilabra Simone Dario SD Pinto Margot Lo ML Gallo Alessia A Vazzana Roberta R Cuscino Nicola N Re Oriana Lo OL Pipia Clara C Amico Giandomenico G Lopa Silvia S Colombini Alessandra A Ippolito Viviana V Maurizi Antonio A Rucci Nadia N Agnese Valentina V Conaldi Pier Giulio PG Moretti Matteo M Miceli Vitale V Bulati Matteo M

Stem cell reviews and reports 20260420 5

PMID: 42008225

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