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Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: the risk of senescent drift induction in secretome-based therapeutics
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Anna Smirnova1, 2, Elena Yatsenko1, Denis Baranovskii1, Ilya Klabukov1, 2, *
Military Medical Research | 2024, 11(5) : 792 - 793
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Military Medical Research | 2024, 11(5): 792-793
• COMMENTARY •
Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: the risk of senescent drift induction in secretome-based therapeutics
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Anna Smirnova1, 2, Elena Yatsenko1, Denis Baranovskii1, Ilya Klabukov1, 2, *
Affiliations
  • 1National Medical Research Radiological Center, Obninsk 249036, Russia
  • 2Obninsk Institute for Nuclear Power Engineering, National Research Nuclear University MEPhI, Obninsk 249031, Russia
Published: 2024-10-10 doi: 10.1186/s40779-023-00498-0
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Cell therapy  /  Inflammaging  /  Secretome  /  Senescence
Anna Smirnova, Elena Yatsenko, Denis Baranovskii, Ilya Klabukov. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: the risk of senescent drift induction in secretome-based therapeutics[J]. Military Medical Research, 2024 , 11 (5) : 792 -793 . DOI: 10.1186/s40779-023-00498-0
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Regulatory changes in senescent cells could potentially affect the composition of extracellular vehicles (EVs), specifically altering their size and cargo. As a result, the released senescent EVs contain an unpredictable cocktail of growth factors and cytokines. These biomolecules have dual effects, potentially guiding the induction of senescence in affected cells and promoting an inflammation-related “domino effect” within the cellular environment, ultimately leading to tissue inflammaging.
Based on this view, we read with great interest the paper by Ding et al.[1] regarding the key biomedical issues of applying mesenchymal stem cell (MSC)-derived EVs for skin wound treatment. EVs secreted by cells have gained significant attention in recent years due to their potential therapeutic applications. These microvesicles are believed to play a crucial role in intercellular communication and have been investigated for their ability to deliver therapeutic cargo to target cells. However, we suppose it is important to critically evaluate in more detail the potential risks associated with EVs applications that may induce the senescence drift in recipient’s cells.
The authors noted the heterogeneity of EVs including size, yield and quantity, contents, and functional effects on recipient cells. Indeed, variations in isolation techniques, purification protocols, and storage conditions can significantly affect the quality and potency of EVs. The lack of standardization raises concerns about the reproducibility and reliability of EV-based therapies, making it difficult to compare results from studies with different designs.
MSCs derived from different sources, such as bone marrow, adipose tissue, and umbilical cord, display distinct differentiation tendencies, secrete unique paracrine factors, and have different immunomodulatory capabilities[2]. A recent study has shown that MSCs may be characterized by a senescence phenotype and reinforced growth arrest, termed the “senescence-associated secretory phenotype”[3]. The secretome of MSCs with senescent phenotypes generates a proinflammatory microenvironment affecting surrounding cells[4]. Human MSCs could enter the senescence phenotype, during expansion passing or cryopreservation[2]. Injections of the proinflammatory secretome of senescent cells could potentially induce a sequence of processes known as “inflammaging” in the affected tissues, consequently resulting in side effects.
Although scientific and clinical efforts have failed to develop a universal diagnostic kit for senescent cells, there are currently various laboratory assays available for the evaluation of the senescence components of EVs in clinical practice. These assays include enzyme-linked immunosorbent assay, which enables accurate assessment of a wide range of proteins, and matrix-assisted laser desorption/ionization mass spectrometry, which provides an approximate assessment through shotgun analysis. It is worth noting that there is a lack of affordable and precise methods to quantify the composition of cellular secretomes. However, advanced microfluidic-based cell assays may provide a potential solution.
Therefore, inflammaging associated with the secretome may pose a challenge for the clinical applications of EVs derived from the secretome of multipotent cells[5]. Prior to their use in therapy, it is crucial to assess the immunomodulatory potential of MSCs and senescent cell content, determine the functionality of isolated MSCs[2], and analyze the composition of MSC-derived secreted proteins.
The perspective we offer is expected to shed light on the impact of cell secretion and prevent potential complications and adverse events associated with the cellular senescent phenotype in EV-based therapies.
Abbreviations
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EVs: Extracellular vesicles; MSC: Mesenchymal stem cell;
Acknowledgements
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Authors’ contributions
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AS, IK, and DB wrote the main manuscript text. EY supervised the work. All authors read and approved the final draft for publication.
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The authors declare that they have no competing interests.
Author details
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1National Medical Research Radiological Center, Obninsk 249036, Russia. 2Obninsk Institute for Nuclear Power Engineering, National Research Nuclear University MEPhI, Obninsk 249031, Russia.
References
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1.
Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, et al. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res. 2023;10(1):36.
2.
Kizilay Mancini Ö, Lora M, Shum-Tim D, Nadeau S, Rodier F, Colmegna I. A proinflammatory secretome mediates the impaired immunopotency of human mesenchymal stromal cells in elderly patients with Atherosclerosis. Stem Cells Transl Med. 2017;6(4):1132–40.
3.
Zhang Y, Ravikumar M, Ling L, Nurcombe V, Cool SM. Age-related changes in the inflammatory status of human mesenchymal stem cells: implications for cell therapy. Stem Cell Rep. 2021;16(4):694–707.
4.
Wu X, Xu X, Xiang Y, Fan D, An Q, Yue G, et al. Exosome-mediated effects and applications in inflammatory diseases of the digestive system. Eur J Med Res. 2022;27(1):163.
5.
Lyamina S, Baranovskii D, Kozhevnikova E, Ivanova T, Kalish S, Sadekov T, et al. Mesenchymal stromal cells as a driver of inflammaging. Int J Mol Sci. 2023;24(7):6372.
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Year 2024 volume 11 Issue 5
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doi: 10.1186/s40779-023-00498-0
  • Online Date：2025-11-19
  • Published：2024-10-10
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Affiliations
    1National Medical Research Radiological Center, Obninsk 249036, Russia
    2Obninsk Institute for Nuclear Power Engineering, National Research Nuclear University MEPhI, Obninsk 249031, Russia

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表12种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
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Percentage of
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Genus		 种数
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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