Delayed Maturation of Oligodendrocyte Progenitors by Microgravity: Implications for Multiple Sclerosis and Space Flight

Abstract

In previous studies, we examined the effects of space microgravity on human neural stem cells. To date, there are no studies on a different type of cell that is critical for myelination and electrical signals transmission, oligodendrocyte progenitors (OLPs). The purpose of the present study was to examine the behavior of space-flown OLPs (SPC-OLPs) as they were adapting to Earth’s gravity. We found that SPC-OLPs survived, and most of them proliferated normally. Nonetheless, some of them displayed incomplete cytokinesis. Both morphological and ontogenetic analyses showed that they remained healthy and expressed the immature OLP markers Sox2, PDGFR-α, and transferrin (Tf) after space flight, which confirmed that SPC-OLPs displayed a more immature phenotype than their ground control (GC) counterparts. In contrast, GC OLPs expressed markers that usually appear later (GPDH, O4, and ferritin), indicating a delay in SPC-OLPs’ development. These cells remained immature even after treatment with culture media designed to support oligodendrocyte (OL) maturation. The most remarkable and surprising finding was that the iron carrier glycoprotein Tf, previously described as an early marker for OLPs, was expressed ectopically in the nucleus of all SPC-OLPs. In contrast, their GC counterparts expressed it exclusively in the cytoplasm, as previously described. In addition, analysis of the secretome demonstrated that SPC-OLPs contained 3.5 times more Tf than that of GC cells, indicating that Tf is gravitationally regulated, opening two main fields of study to understand the upregulation of the Tf gene and secretion of the protein that keep OLPs at a progenitor stage rather than moving forward to more mature phenotypes. Alternatively, because Tf is an autocrine and paracrine factor in the central nervous system (CNS), in the absence of neurons, it accumulated in the secretome collected after space flight. We conclude that microgravity is becoming a novel platform to study why in some myelin disorders OLPs are present but do not mature.

Metabolomics Profile of the Secretome of Space-Flown Oligodendrocytes

“…Glutamine, on the other hand, promotes pluripotent cells via the removal of differentiated cells in culture [37]. The pivotal role of the glutamate-glutamine pair in cell lineage specification and developmental stage maintenance at the OLP stage points to its involvement in the effects of reduced gravity on maintaining them at a progenitor stage, as previously shown by the expression of early OLP markers by our cells flown to space with regard to the 1G OLPs [10]. Glutamate dysregulation has been linked to numerous pathologies such as epilepsy and neurodegenerative diseases.…”

“…In addition, more lactate (produced during anaerobic oxidation to fulfill energy needs) was also significantly released by the SPC OLPs. The use of extra energy in the SPC OLPs cannot be explained through a stimulation of myelin synthesis; glycerate, a building element in the formation of triglycerides, was secreted by these cells, indicating that they were still at the immature developmental stage, while the 1G OLPs may have been moving forward towards maturation as previously demonstrated by Tran et al [ 10 ]. Further studies are needed to ascertain the causes of such enhanced energy consumption by OLPs.…”

“…We previously performed the same secretome analysis of OLPs in sim-µG [ 9 , 10 ]. Although there was major difference in the measure of the secretome of OLPs, like time (3 days vs. 26 days) and method (µG in 3D-clinostat vs. SPC), it is interesting to compare the similarities and the differences.…”

“…More recently, we studied the effects of space-µG on OLPs and found enhanced proliferation [ 9 ], yet some of them displayed incomplete cytokinesis [ 10 ]. Moreover, based on the expression of stage-specific developmental markers, we discovered that these cells came back in a more immature stage than that of the ground control OLPs [ 10 ].…”

“…More recently, we studied the effects of space-µG on OLPs and found enhanced proliferation [ 9 ], yet some of them displayed incomplete cytokinesis [ 10 ]. Moreover, based on the expression of stage-specific developmental markers, we discovered that these cells came back in a more immature stage than that of the ground control OLPs [ 10 ]. Here we sought to determine A) the impact of space flight on the global metabolomic profile of the secretome produced by OLPs while in space-µG in order to start unraveling extracellular processes, as well as identifying gravitational-sensitive molecules, and B) the energetic status of OLPs after space flight.…”