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Background <p>Mesenchymal Stem Cells-derived Small Extracellular Vesicles endowed with regenerative cargo from their parent cells, have emerged as a promising avenue for cell-free therapeutics in regenerative medicine. Notably, deliberate induction of apoptosis in MSCs before sEV isolation has been identified as a strategy to augment the regenerative capabilities of MSCs-sEVs. This study explores a novel approach to enhance the immunomodulatory potential of MSC-sEVs through apoptosis induction and optimal tissue source to ensure consistent and improved clinical outcomes.</p> Methods <p>Apoptosis was induced in tissue-specific MSCs using Staurosporine. sEVs<sup>V</sup> and sEVs<sup>Apo</sup> were isolated via ultracentrifugation. <i>Invitro</i> immune response was assessed via T-cell proliferation, T-regulatory cell induction &amp; macrophage polarization assay. Mitochondrial bioenergetics was studied using MitoSOX staining and Seahorse assay in H2O2-treated HuH7 cells. These findings were validated <i>invivo</i> in the CCL4-induced Chronic Liver Disease model via Histopathological staining, biochemical parameters, and fibrotic, pro-inflammatory, and anti-inflammatory markers and assessed the mechanism by targeting TGF-β/SMAD pathway.</p> Results <p>Our results demonstrate that sEVs<sup>Apo</sup> exhibited significantly higher concentrations and superior immunomodulatory effects by suppressing CD3 + T-cell proliferation, promoting T-regulatory cell differentiation, and polarized macrophages towards M2-phenotype. In terms of tissue specificity, it was observed that WJ-sEVs were faring better. sEVs<sup>Apo</sup> effectively reduced mitochondrial ROS &amp; significantly improved oxidative phosphorylation. <i>Invitro</i> findings were corroborated in an <i>invivo</i> CLD model, wherein sEVs<sup>Apo</sup> ameliorated fibrosis and inflammation, by inhibiting TGF-β/ SMAD2/3 pathway.</p> Conclusion <p>This study concludes that apoptosis induction can be considered as minimum manipulation strategy to enhance the immunoregulatory and regenerative potential of MSCs-sEVs, thereby expanding their implication in immune disorder.</p>

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Uncovering the bequeathing potential of apoptotic mesenchymal stem cells via small extracellular vesicles for its enhanced immunomodulatory and regenerative ability

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月7日

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  • Meenakshi Mendiratta,
  • Mohini Mendiratta,
  • Yashvi Sharma,
  • Ranjit Kumar Sahoo,
  • Neena Malhotra,
  • Sujata Mohanty

摘要

Background

Mesenchymal Stem Cells-derived Small Extracellular Vesicles endowed with regenerative cargo from their parent cells, have emerged as a promising avenue for cell-free therapeutics in regenerative medicine. Notably, deliberate induction of apoptosis in MSCs before sEV isolation has been identified as a strategy to augment the regenerative capabilities of MSCs-sEVs. This study explores a novel approach to enhance the immunomodulatory potential of MSC-sEVs through apoptosis induction and optimal tissue source to ensure consistent and improved clinical outcomes.

Methods

Apoptosis was induced in tissue-specific MSCs using Staurosporine. sEVsV and sEVsApo were isolated via ultracentrifugation. Invitro immune response was assessed via T-cell proliferation, T-regulatory cell induction & macrophage polarization assay. Mitochondrial bioenergetics was studied using MitoSOX staining and Seahorse assay in H2O2-treated HuH7 cells. These findings were validated invivo in the CCL4-induced Chronic Liver Disease model via Histopathological staining, biochemical parameters, and fibrotic, pro-inflammatory, and anti-inflammatory markers and assessed the mechanism by targeting TGF-β/SMAD pathway.

Results

Our results demonstrate that sEVsApo exhibited significantly higher concentrations and superior immunomodulatory effects by suppressing CD3 + T-cell proliferation, promoting T-regulatory cell differentiation, and polarized macrophages towards M2-phenotype. In terms of tissue specificity, it was observed that WJ-sEVs were faring better. sEVsApo effectively reduced mitochondrial ROS & significantly improved oxidative phosphorylation. Invitro findings were corroborated in an invivo CLD model, wherein sEVsApo ameliorated fibrosis and inflammation, by inhibiting TGF-β/ SMAD2/3 pathway.

Conclusion

This study concludes that apoptosis induction can be considered as minimum manipulation strategy to enhance the immunoregulatory and regenerative potential of MSCs-sEVs, thereby expanding their implication in immune disorder.