Functional Heterogeneity of Mouse and Human Brain OPCs: Relevance for Preclinical Studies in Multiple Sclerosis

Abstract

Besides giving rise to oligodendrocytes (the only myelin-forming cell in the Central Nervous System (CNS) in physiological conditions), Oligodendrocyte Precursor Cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present along the mouse and human CNS, both during development and in adulthood, yet how OPC physiological behavior is modified throughout life is not fully understood. The activity of adult human OPCs is still particularly unexplored. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In the present article, we have compared the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. By analyzing intact OPCs for the first time with 1H High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function for their stage of maturity. Moreover, their response to Fibroblast Growth Gactor-2 (FGF-2) and anosmin-1 (two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS)) differs in relation to their developmental stage and in the function of the species. Our data reveal that the behavior of adult human and mouse OPCs differs in a very dynamic way that should be very relevant when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.

The Current Challenges for Drug Discovery in CNS Remyelination

“…Bribián and colleagues [ 3 ] further investigated the differences between the mouse and human adult brain with respect to the respective OPC migratory properties. They showed that murine and human OPCs have similar migratory properties in response to FGF2 and anosmin-1 but differ from that of OPCs taken from early post-natal samples [ 3 ].…”

“…Bribián and colleagues [ 3 ] further investigated the differences between the mouse and human adult brain with respect to the respective OPC migratory properties. They showed that murine and human OPCs have similar migratory properties in response to FGF2 and anosmin-1 but differ from that of OPCs taken from early post-natal samples [ 3 ]. Altogether, these data are consistent with the observation that the markers expressed by oligodendrocyte populations at lesions change according to the inflammatory milieu and support the view that inflammation has important effects on the remyelination capability of OLs.…”

“…Axon–glial interactions represent one of the most complex cell-to-cell communication systems in the human body, thereby presenting several challenges for drug discovery. How neurons and the myelinating cells of the CNS, the oligodendrocytes (OLs), crosstalk and how this interaction evolves during acute and chronic pathological phases of demyelination diseases are matters of several ongoing studies [ 1 , 2 , 3 , 4 , 5 ]. Recent studies have provided a wealth of information providing the prospect of halting and eventually reversing the effects of devastating demyelination pathologies using pharmacological approaches [ 6 , 7 , 8 , 9 ].…”

“…Most of the literature so far is based on rodent animal models [ 11 ]. New data based on single cell analyses have revolutionized our understanding about how oligodendrocyte precursor cells (OPC) differentiate to mature OLs in man compared to mice [ 3 , 5 , 25 ].…”

“…The wealth of data obtained in in vitro models has helped in our understanding of the details of the remyelination process in vivo. New single cell analyses from the brains of rodent models and postmortem human samples and the development of isolation technologies allowing to derive OPCs from patient iPSCs will further improve future drug discovery programs [ 3 , 4 , 23 ]. The detailed description of the compound classes selected by the different screens and their prospective use in the clinic have been covered in many recent reviews [ 10 , 11 , 35 , 36 ].…”