Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants

Abstract

Exosomes are secreted nanovesicles that are able to transfer RNA and proteins to target cells. The emerging role of mesenchymal stem cell (MSC) exosomes as promoters of aerobic ATP synthesis restoration in damaged cells, prompted us to assess whether they contain an extramitochondrial aerobic respiration capacity. Exosomes were isolated from culture medium of human MSCs from umbilical cord of ≥37-wk-old newborns or between 28- to 30-wk-old newborns (i.e.,term or preterm infants). Characterization of samples was conducted by cytofluorometry. Oxidative phosphorylation capacity was assessed by Western blot analysis, oximetry, and luminometric and fluorometric analyses. MSC exosomes express functional respiratory complexes I, IV, and V, consuming oxygen. ATP synthesis was only detectable in exosomes from term newborns, suggestive of a specific mechanism that is not completed at an early gestational age. Activities are outward facing and comparable to those detected in mitochondria isolated from term MSCs. MSC exosomes display an unsuspected aerobic respiratory ability independent of whole mitochondria. This may be relevant for their ability to rescue cell bioenergetics. The differential oxidative metabolism of pretermvs.term exosomes sheds new light on the preterm newborn's clinical vulnerability. A reduced ability to repair damaged tissue and an increased capability to cope with anoxic environment for preterm infants can be envisaged.-Panfoli, I., Ravera, S., Podestà, M., Cossu, C., Santucci, L., Bartolucci, M., Bruschi, M., Calzia, D., Sabatini, F., Bruschettini, M., Ramenghi, L. A., Romantsik, O., Marimpietri, D., Pistoia, V., Ghiggeri, G., Frassoni, F., Candiano, G. Exosomes from human mesenchymal stem cells conduct aerobic metabolism in term and preterm newborn infants.

Metabolic Signature of Microvesicles from Umbilical Cord Mesenchymal Stem Cells of Preterm and Term Infants

“…These are anyway representative of each of the five respiratory chain complexes, as shown in Figure . Such results confirm the protein statistical analysis that highlighted MDH2 and ATP5O, as well as our previous findings of the capacity of exosomes from both Preterm and Term HUCMSC to conduct an aerobic metabolism, so that expression of proteins involved in aerobic metabolism is characteristic of EVs . In light of these results, we decided to assess whether these proteins were active in the process of OXPHOS also in MVs.…”

“…The metabolic signature of HUCMSC MVs is consistent with previous data on exosomes from the same cells . HUCMSC exosomes conduct an aerobic metabolism, but remarkably behave the opposite way with respect to MVs, in that an ATP synthetic ability was exclusive of Preterm exosomes, being undetectable in Term ones.…”

“…HUCMSC exosomes conduct an aerobic metabolism, but remarkably behave the opposite way with respect to MVs, in that an ATP synthetic ability was exclusive of Preterm exosomes, being undetectable in Term ones. As discussed previously, the presence in the exosome membranes of CD39 and CD73, two ecto‐enzymes that convert ATP to adenosine, may be the reason for missed detection of ATP . This would also justify the elevated blood adenosine content of the premature infants .…”

“…Due to their soluble and membrane‐bound protein and RNA content, once internalized, EVs act as “translational” organelles, altering the expression of target cells . Exosomes released from cultured Mesenchymal Stem Cells from Human Umbilical Cord (HUCMSC)of both Term and Preterm newborns consume oxygen and synthesize ATP .…”

Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

“…Mitochondria-derived vesicles (MDVs) can be formed during mitochondrial quality control (Sugiura et al, 2014). MDVs contain mitochondrial energetics, such as OxPhos (Panfoli et al, 2016). Recent work also suggests MDVs are induced by Pink1 and Parkin activity in response to mitochondrial oxidative stress ( Figure 2 ).…”