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Stem Cell-derived Extracellular Mitochondria: A New Means to Promote Recovery from Stroke?

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Review of “Protective Effects of Endothelial Progenitor Cell‐Derived Extracellular Mitochondria in Brain Endothelium” from STEM CELLS by Stuart P. Atkinson

Circulating migratory endothelial progenitor cells (EPCs) contribute to neurovascular recovery after stroke, and while the exact mechanisms involved remain unknown, many studies have highlighted the beneficial effects of paracrine acting EPC secreted factors. As part of their secretome, stem cells can also release extracellular mitochondria [1-3], leading researchers from the laboratories of Kazuhide Hayakawa, Eng H. Lo (Harvard Medical School, Charlestown, MA, USA), and Anna Rosell (VHIR, Barcelona, Spain) to ask whether human EPCs transfer functional extracellular mitochondria to brain endothelial cells as a means to promote recovery from stroke [4]. 

The authors of this new STEM CELLS article began by collecting EPC‐derived conditioned medium before centrifugation and division into supernatant and particle fractions for testing. Electron microscopy, western blots, and flow cytometry all demonstrated the presence of EPC-derived mitochondria in the particle fraction, while ATP and oxygen consumption assays suggested the functional viability of extracellular mitochondria. Subsequent confocal microscopy analysis confirmed the incorporation of EPC‐derived extracellular mitochondria into normal brain endothelial cells, leading to increased angiogenesis, enhanced VE‐cadherin membrane localization, and decreased trans‐cellular permeability.

To test for a protective role of EPC‐derived extracellular mitochondria, the study incubated EPC‐derived mitochondria particles with brain endothelial cells exposed to oxygen‐glucose deprivation (known to increase trans‐cellular endothelial permeability). Excitingly, alongside the presence of a number of indirect markers of mitochondrial transfer (increased levels of mitochondrial protein TOM40, mtDNA copy number, and intracellular ATP in brain endothelial cells), the authors also observed the restoration of endothelial permeability. 

This new report provides proof‐of‐concept to the hypothesis of mitochondrial transfer from EPCs and brain endothelial cells, and the authors now hope to discover the intracellular signals that link upstream mitochondrial incorporation to downstream regulation of endothelial function. However, they do note certain caveats to their study, including the unknown nature of the EPC mitochondrial release‐uptake mechanism, the possible influence of exosomes and microvesicles as part of the conditioned medium particles, and the possible involvement of other important brain cell types, such as pericytes.

For more on the fascinating topic of stem cell-derived extracellular mitochondria and their potential as a new means to promote recovery from stroke, stay tuned to the Stem Cells Portal!

References

  1. Sinclair KA, Yerkovich ST, Hopkins PM-A, et al., Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Research & Therapy 2016;7:91.
  2. Islam MN, Das SR, Emin MT, et al., Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature Medicine 2012;18:759.
  3. Huang PJ, Kuo CC, Lee HC, et al., Transferring Xenogenic Mitochondria Provides Neural Protection Against Ischemic Stress in Ischemic Rat Brains. Cell Transplant 2016;25:913-27.
  4. Hayakawa K, Chan SJ, Mandeville ET, et al., Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium. STEM CELLS 2018;36:1404-1410.