Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier?

Mocchi, Michela; Dotti, Silvia; Bue, Maurizio Del; Villa, Riccardo; Bari, Elia; Perteghella, Sara; Torre, Maria Luisa; Grolli, Stefano

doi:10.3390/cells9061453

Cited by 48 publications

(49 citation statements)

References 122 publications

(169 reference statements)

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“…Future use of the secretome or some of its components, such as exosomes, as biotechnological products in regenerative medicine, provides the basis for a cell-free therapeutic strategy that avoids some drawbacks of cell therapy [ 20 , 21 , 22 ]. They have shown their efficacy in a wide variety of pathologies, mainly in the human species [ 23 , 24 , 25 , 26 ] but studies in veterinary medicine are still scarce [ 22 , 27 , 28 , 29 ]. Therefore, it is essential to characterize the secretome and its components before their possible clinical use.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of the Secretome and Exosomes of Feline Adipose-Derived Mesenchymal Stem Cells

Villatoro

Martín-Astorga

Alcoholado

et al. 2021

Animals

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Mesenchymal stem cells (MSCs) have been shown to have therapeutic efficacy in different complex pathologies in feline species. This effect is attributed to the secretion of a wide variety of bioactive molecules and extracellular vesicles, such as exosomes, with significant paracrine activity, encompassed under the concept of the secretome. However, at present, the exosomes from feline MSCs have not yet been studied in detail. The objective of this study is to analyze and compare the protein profiles of the secretome as a whole and its exosomal fraction from feline adipose-derived MSCs (fAd-MSCs). For this, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein–Protein Interaction Networks Functional Enrichment Analysis (STRING) were utilized. A total of 239 proteins were identified in the secretome, and 228 proteins specific to exosomes were identified, with a total of 133 common proteins. The proteins identified in the secretome were located in the extracellular regions and in the cytoplasm, while the exosomal proteins were located mainly in the membrane, cytoplasm and cytosol. Regarding function, in the secretome, proteins involved in different metabolic pathways, in pathways related to the immune system and the endocrine system and in the processing of proteins in the endoplasmic reticulum predominated. In contrast, proteins specific to exosomes were predominantly associated with endocytosis, cell junctions, platelet activation and other cell signaling pathways. The possible future use of the secretome, or some of its components, such as exosomes, would provide a non-cell-based therapeutic strategy for the treatment of different diseases that would avoid the drawbacks of cell therapy.

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Section: Introductionmentioning

confidence: 99%

Proteomic Analysis of the Secretome and Exosomes of Feline Adipose-Derived Mesenchymal Stem Cells

Villatoro

Martín-Astorga

Alcoholado

et al. 2021

Animals

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“…Instead, the main actors of MSCs benefit are now considered several bioactive molecules (including proteins, cytokines, chemokines, growth factors, but also nucleic acid) released by cells and involved in cell-to-cell communication and cross-talk [11]. Known as secretome, this complex set of secreted factors and vesicles seems to represent a valid alternative as a cell-free therapy, offering several advantages in comparison to cell-based therapy, such as lower immunogenicity, ease of storage and handling, and lower cost ensuring usefulness and feasibility in the clinic [12,13]. However, addressing a suitable medicinal product is challenging, and further investigations are needed to shed light on secretome composition, properties, and in vivo behavior.…”

Section: Introductionmentioning

confidence: 99%

Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use

et al. 2021

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In the last decades, it has been demonstrated that the regenerative therapeutic efficacy of mesenchymal stromal cells is primarily due to the secretion of soluble factors and extracellular vesicles, collectively known as secretome. In this context, our work described the preparation and characterization of a freeze-dried secretome (Lyosecretome) from adipose tissue-derived mesenchymal stromal cells for the therapy of equine musculoskeletal disorder. An intraarticular injectable pharmaceutical powder has been formulated, and the technological process has been validated in an authorized facility for veterinary clinical-use medicinal production. Critical parameters for quality control and batch release have been identified regarding (i) physicochemical properties; (ii) extracellular vesicle morphology, size distribution, and surface biomarker; (iii) protein and lipid content; (iv) requirements for injectable pharmaceutical dosage forms such as sterility, bacterial endotoxin, and Mycoplasma; and (v) in vitro potency tests, as anti-elastase activity and proliferative activity on musculoskeletal cell lines (tenocytes and chondrocytes) and mesenchymal stromal cells. Finally, proteins putatively responsible for the biological effects have been identified by Lyosecretome proteomic investigation: IL10RA, MXRA5, RARRES2, and ANXA1 modulate the inflammatory process RARRES2, NOD1, SERPINE1, and SERPINB9 with antibacterial activity. The work provides a proof-of-concept for the manufacturing of clinical-grade equine freeze-dried secretome, and prototypes are now available for safety and efficacy clinical trials in the treatment of equine musculoskeletal diseases

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“…The MSC secretome or EVs thus have the potential to be developed into a stand-alone therapeutic product or a coadministered agent to enhance the effectiveness of cell therapy by modulating the microenvironment into a regeneration conducive milieu [ 328 ]. Indeed, recently cell-free secretome therapies have shown great potential in vitro and in pioneering clinical applications [ 329 , 330 , 331 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Regenerative Medicine for Equine Musculoskeletal Diseases

Ribitsch

Oreff

Jenner

2021

Animals

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Musculoskeletal injuries and chronic degenerative diseases commonly affect both athletic and sedentary horses and can entail the end of their athletic careers. The ensuing repair processes frequently do not yield fully functional regeneration of the injured tissues but biomechanically inferior scar or replacement tissue, causing high reinjury rates, degenerative disease progression and chronic morbidity. Regenerative medicine is an emerging, rapidly evolving branch of translational medicine that aims to replace or regenerate cells, tissues, or organs to restore or establish normal function. It includes tissue engineering but also cell-based and cell-free stimulation of endogenous self-repair mechanisms. Some regenerative medicine therapies have made their way into equine clinical practice mainly to treat tendon injures, tendinopathies, cartilage injuries and degenerative joint disorders with promising results. However, the qualitative and quantitative spatiotemporal requirements for specific bioactive factors to trigger tissue regeneration in the injury response are still unknown, and consequently, therapeutic approaches and treatment results are diverse. To exploit the full potential of this burgeoning field of medicine, further research will be required and is ongoing. This review summarises the current knowledge of commonly used regenerative medicine treatments in equine patients and critically discusses their use.

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Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier?

Cited by 48 publications

References 122 publications

Proteomic Analysis of the Secretome and Exosomes of Feline Adipose-Derived Mesenchymal Stem Cells

Proteomic Analysis of the Secretome and Exosomes of Feline Adipose-Derived Mesenchymal Stem Cells

Equine Mesenchymal Stem/Stromal Cells Freeze-Dried Secretome (Lyosecretome) for the Treatment of Musculoskeletal Diseases: Production Process Validation and Batch Release Test for Clinical Use

Regenerative Medicine for Equine Musculoskeletal Diseases

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