Protective Effects of Endothelial Progenitor Cell-Derived Extracellular Mitochondria in Brain Endothelium

Abstract

Endothelial progenitor cells (EPCs) have been pursued as a potential cellular therapy for stroke and central nervous system injury. However, their underlying mechanisms remain to be fully defined. Recent experimental studies suggest that mitochondria may be released and transferred between cells. In this proof-of-concept study, we asked whether beneficial effects of EPCs may partly involve a mitochondrial phenomenon as well. First, EPC-derived conditioned medium was collected and divided into supernatant and particle fractions after centrifugation. Electron microscopy, Western blots, and flow cytometry showed that EPCs were able to release mitochondria. ATP and oxygen consumption assays suggested that these extracellular mitochondria may still be functionally viable. Confocal microscopy confirmed that EPC-derived extracellular mitochondria can be incorporated into normal brain endothelial cells. Adding EPC particles to brain endothelial cells promoted angiogenesis and decreased the permeability of brain endothelial cells. Next, we asked whether EPC-derived mitochondria may be protective. As expected, oxygen-glucose deprivation (OGD) increased brain endothelial permeability. Adding EPC-derived mitochondria particles to the damaged brain endothelium increased levels of mitochondrial protein TOM40, mitochondrial DNA copy number, and intracellular ATP. Along with these indirect markers of mitochondrial transfer, endothelial tightness was also restored after OGD. Taken together, these findings suggest that EPCs may support brain endothelial energetics, barrier integrity, and angiogenic function partly through extracellular mitochondrial transfer. Stem Cells 2018;36:1404-1410.

Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

“…123 Brain endothelial cells that endocytose exMTs from endothelial progenitor cells are protected against oxygen-glucose deprivation-induced injury. 124 Macrophages that endocytose exMTs released from mesenchymal stem cells are transformed into highly phagocytic and anti-inflammatory macrophages. 125,126 Bone marrow derived stromal cells transfer mitochondria into pulmonary alveoli to increase ATP production and protect mice against lipopolysaccharide-induced acute lung injury.…”

YBX-1 mediated sorting of miR-133 into hypoxia/reoxygenation-induced EPC-derived exosomes to increase fibroblast angiogenesis and MEndoT

“…Exosomes are small membrane vesicles that mediate intercellular signal transduction [6]. Previous studies have shown that EPC-derived exosomes can promote angiogenesis and reduce cardiomyocyte hypertrophy and apoptosis [7][8][9]. Furthermore, exosomes had been shown to carry different nucleic acids, including microRNAs (miRNAs), which are acquired by recipient cells to regulate their own fate [10,11].…”

Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells

“…On the other hand, cells can also release intact mitochondria which retain functional properties [19,20,53,56,57,60]. The transfer of healthy mitochondria has been demonstrated in different tissues and organs, where its main role is to maintain local homeostasis.…”

“…In the CNS, astrocytes provide healthy mitochondria to damaged neurons to restore normal OXPHOS both in vitro and in vivo [20,53]. Similarly, endothelial progenitor cells support brain endothelial energetics and barrier integrity through extracellular mitochondrial transfer [19]. Herein, we first investigated the protein content of EVs that are spontaneously released by NSCs.…”