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The Adult Oligodendrocyte Can Participate in Remyelination

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The Adult Oligodendrocyte Can Participate in Remyelination The adult oligodendrocyte can participate in remyelination Ian D. Duncana,1, Abigail B. Radcliffa, Moones Heidaria, Grahame Kiddb, Benjamin K. Augustc, and Lauren A. Wierengaa aDepartment of Medical Sciences, School of Veterinary Medicine, University of Wisconsin–Madison, Madison, WI 53706; bRenovo Neural, Inc., Cleveland, OH 44106; and cElectron Microscope Facility, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53706 Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved November 1, 2018 (received for review May 9, 2018) Endogenous remyelination of the CNS can be robust and restore drocytes, if there is persuasive evidence that they are capable of function, yet in multiple sclerosis it becomes less complete with time. participating in myelin repair. Promoting remyelination is a major therapeutic goal, both to restore The case against adult oligodendrocytes comes from both function and to protect axons from degeneration. Remyelination is in vivo and in vitro data. Blakemore and coworkers (17) have thought to depend on oligodendrocyte progenitor cells, giving shown that human oligodendrocytes transplanted into demyeli- rise to nascent remyelinating oligodendrocytes. Surviving, ma- nated areas of the rat spinal cord survived but were unable to ture oligodendrocytes are largely regarded as being uninvolved. remyelinate. Similarly, surviving endogenous postmitotic oligo- We have examined this question using two large animal models. dendrocytes did not remyelinate axons in areas of demyelination In the first model, there is extensive demyelination and remyelina- created by injection of antibody to Galactocerebroside (18). In tion of the CNS, yet oligodendrocytes survive, and in recovered vitro studies in which select stages of the oligodendrocyte lineage animals there is a mix of remyelinated axons interspersed between were added to cultures of retinal ganglion cells reported that only mature, thick myelin sheaths. Using 2D and 3D light and electron perinatal and adult OPCs developed into myelinating oligoden- microscopy, we show that many oligodendrocytes are connected to drocytes (19). Most recently, fate-mapping experiments reported mature and remyelinated myelin sheaths, which we conclude are that mature oligodendrocytes took no part in the remyelination of cells that have reextended processes to contact demyelinated axons focal, lysolecithin-induced demyelination in the mouse spinal cord while maintaining mature myelin internodes. In the second model (20). However, none of these data exclude the potential role of in vitamin B12-deficient nonhuman primates, we demonstrate that adult oligodendrocytes that lose some of their internodes follow- NEUROSCIENCE surviving mature oligodendrocytes extend processes and ensheath ing primary attack on myelin sheaths, yet remain intact and viable. demyelinated axons. These data indicate that mature oligodendro- The case for the possible role of the adult oligodendrocyte in cytes can participate in remyelination. remyelination is less well documented yet requires consideration. Initially it was proposed that mature oligodendrocytes could adult oligodendrocyte | remyelination | large animal models proliferate and provide more oligodendrocytes for remyelination (21). In vitro studies by Wood and Bunge (22) suggested that emyelination is the most effective and robust endogenous cell-sorted mature oligodendrocytes were more capable of gen- Rrepair mechanism of the central nervous system (CNS) and erating myelinating oligodendrocytes in cocultures than OPCs. can lead to complete remyelination of large and disseminated Transplantation of similarly sorted mature oligodendrocytes, areas of demyelination in the CNS, with resultant functional showed that they were also capable of myelinating axons in vivo recovery (1, 2). It has been known for some time that remyeli- (23, 24). In vitro studies of mature oligodendrocytes subjected to nation occurs in multiple sclerosis (MS) (3–5), although it has process disruption by various methods, have shown that these been reported as being limited, variable in patient populations, cells may demonstrate plasticity, regrow processes, and are ca- and more robust in early rather than late disease (6). There has pable of ensheathing and remyelinating axons. Oligodendrocyte been both extensive research and speculation into why this is so (2). Two detailed studies in 2006–2007 analyzed remyelination in Significance the forebrain of MS patients with different disease course and duration (7, 8). Perhaps surprisingly, extensive—albeit variable— Remyelination of the CNS is a critical process in restoring func- remyelination was seen in older patients, some of whom had long- tion and protecting nerve fibers from degeneration in multiple standing MS. Although it was not known when remyelination sclerosis and other demyelinating diseases. It is currently thought occurred in these patients, these observations underscore the ability that myelin can only be repaired by the generation of new oli- of even the mature brain in long-lasting MS to remyelinate or godendrocytes from progenitor cells and that remaining mature sustain earlier myelin repair. However, the lack of complete en- cellsareunabletoparticipate.Hereweshow,usinguniquelarge dogenous response has led to remyelination becoming a major animal models, including a nonhuman primate, that oligoden- therapeutic target, both to restore function and as the ultimate drocytes that are partially injured can participate in myelin re- form of neuroprotection (9–13). pair. The capacity of mature oligodendrocytes to remyelinate in The origin of remyelinating oligodendrocytes in MS and in demyelinating disease remains unknown, yet it provides an ad- experimental models of demyelination has been the subject of ditional cell source for recruitment for myelin repair. considerable interest. The weight of available evidence suggests Author contributions: I.D.D. designed research; A.B.R., B.K.A., and L.A.W. performed re- that remyelinating oligodendrocytes arise from oligodendrocyte search; G.K. contributed new reagents/analytic tools; I.D.D., M.H., and G.K. analyzed data; progenitor cells (OPCs) that reside either in or adjacent to and I.D.D. wrote the paper. demyelinated lesions, or adult neural stem cells residing in the The authors declare no conflict of interest. subependymal zone (14, 15). Experimental proof that OPCs This article is a PNAS Direct Submission. generate remyelinating oligodendrocytes comes from many Published under the PNAS license. transplant studies in de- and dysmyelinating models, as well as 1To whom correspondence should be addressed. Email: [email protected]. from toxin-induced demyelinating disorders (15, 16). However, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. new strategies to promote remyelination should consider recruiting 1073/pnas.1808064115/-/DCSupplemental. all cells of the oligodendrocyte lineage, including adult oligoden- www.pnas.org/cgi/doi/10.1073/pnas.1808064115 PNAS Latest Articles | 1of10 Downloaded by guest on September 28, 2021 processes disrupted by transection or exposure to NMDA, Examination for Cell Death in Acute or Chronic Disease. Apoptotic retracted back to the cell body but regrew within 36 h (25). cells, if present, can be readily detected in 1-μm plastic sections Reextension or recovery of processes of mature oligodendro- (31) but despite examining multiple sections at all levels of the cytes following damage has also been shown in vivo. In a model spinal cord, optic nerves and brain from 14 cats, few or no of focal cerebral ischemia, McIver, et al. (26) showed that some pyknotic nuclei were seen at any stage of the disease. Similarly, oligodendrocytes survived, although with fragmented processes. cells at the early stage of apoptosis with condensed chromatin Oligodendrocytes that had been prelabeled with eGFP were (31), or pyknotic cells, were rarely seen on ultrastructural anal- found 1 wk later in areas of ischemia with intact processes, yses during acute disease. To confirm these observations, we used the TUNEL assay on spinal cord tissue from four cats suggesting that they may be able to participate in white matter + during acute disease. In one affected cat, no TUNEL cells were repair (26). Similarly, mature oligodendrocytes at the edge of + demyelinated lesions in the spinal cord, that overexpressed observed. In the other three affected cats, only 3 to 12 TUNEL cells were counted in the whole spinal cord cross-section (SI ERK1/2, extended processes into the lesions and remyelinated Appendix C D + axons (27). , Fig. S1 and ). Several of the TUNEL cells found in the affected cat tissue were within myelin vacuoles (SI Ap- Despite these data, the dominant opinion remains that remyelination pendix D SI Ap- is dependent upon the OPC, yet it is critical to consider more , Fig. S1 ), suggesting they were macrophages ( pendix, Fig. S1D). The tissue sections from cats on the normal mature cells of the oligodendrocyte lineage if alternative models + diet did not contain any TUNEL cells (SI Appendix, Fig. S1A), provide the opportunity to reexamine this question. We have ex- while all positive control tissue sections showed many brown, plored this issue in two models. The first unique model is fe- darkly stained nuclei throughout the section (SI Appendix, line irradiated food-induced demyelination (FIDID), in which Fig. S1B). demyelinated and remyelinated axons
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