Dynamics of oligodendrocyte generation
in multiple sclerosis
Nature, January 23, 2019
a) Animal models of MS often do not represent what actually happens in humans. This paper measured myelin producing cells in persons with MS.
b) Myelin-producing brain cells are called oligodendrocytes. There are two forms of oligodendrocytes, mature forms that can make myelin, and immature or precursor oligodendrocytes that have the potential to mature and make myelin.
c) Using radioactive carbon as a marker, the researchers were able identify the ages of oligodendrocytes in autopsy tissues of MS brains.
d) A minority of persons with MS had the capacity to generate new oligodendrocytes. Only 24% of persons with MS in this study (7 out of 29) had this capacity. Their tissues showed a 3-fold increase in new, immature oligodendrocytes in areas of normal-appearing myelin. All these individuals had severe, rapidly progressive disease. Other persons in the study also with severe, aggressive disease did not show increased oligodendrocyte generation. Other researchers have also noted differences in the ability of persons with MS to form new myelin.
e) Shadow plaques are regions where myelin was lost and new myelin was formed. However the thickness of the myelin in shadow plaques is much less than found in normal myelin.
f) Oligodendrocytes in shadow plaques were isolated and studied. Numbers of oligodendrocytes in shadow plaques were similar to numbers found in normal tissue. All oligodendrocytes in shadow plaques were mature or “old” cells, present even before the time of tissue injury. These cells survived the attack on myelin, and were probably responsible for new, though less dense, myelin formation.
g) While brains of some persons with MS can generate large numbers of new oligodendrocytes in normal tissue, numbers of new or immature oligodendrocytes in shadow plaques was greatly reduced.
h) These observations raise at least two important questions. What is the reason for the differences in the abilities of some persons with MS to form new myelin? What is there in regions of tissue injury in MS that prevents the generation of new oligodendrocytes, impairing the formation of new myelin and healing? Answers to these questions could lead to important new treatments.
This is a most interesting paper. It utilized carbon-14, a radioactive form of carbon that increased greatly in air after 1955 with the testing of nuclear weapons. The carbon was inhaled and incorporated into tissues, including oligodendrocytes, the cells of the brain that make myelin. The amounts of carbon-14 in these cells were used to measure the age of the cells. With this technique the authors were able to measure the generation of new oligodendrocytes, called immature or precursor oligodendrocytes, and identify mature oligodendrocytes, the cells with the capacity to make new myelin. Cells were obtained from autopsy specimens of persons with MS and those without MS.
The researchers noted two populations of persons with MS, a minority (24%) that generated new precursor oligodendrocytes and those that did not. The new oligodendrocytes were mainly found in normal brain tissue adjacent to areas of myelin loss. They also noted that individuals with newly generated oligodendrocytes had very aggressive, rapidly progressive disease. However, some patients with equally aggressive disease did not generate new oligodendrocytes. These observations extended those of other researchers that also found two populations of persons with MS, those that had an increased ability to form new myelin and those that did not.
These investigators also studied oligodendrocytes in relatively uncommon sites of tissue damage called “shadow plaques.” Shadow plaques are regions where myelin was destroyed but new myelin was regenerated. The regenerated myelin is not “normal” myelin in that there are many fewer wrappings of myelin around nerve cell processes (axons), making the myelin much thinner. Numbers of oligodendrocytes in shadow plaques were similar to numbers of oligodendrocytes in normal tissues, indicating that these cells were not depleted by the immune attack on myelin. However, all these oligodendrocytes were mature, or “old” oligodendrocytes, present before the attack occurred. In other words, there was no evidence of new oligodendrocyte formation in scarred areas, only in adjacent areas of normal tissue, and the only in a subpopulation of persons with MS.
As is often the case, these findings raise even more questions. Why do only some persons with MS have the capacity to generate new oligodendrocytes? Why are new oligodendrocytes generated in normal tissues and and not in regions of tissue injury? What prevents the mature oligodendrocytes in shadow plaques from making normal myelin? Why are shadow plaques relatively uncommon? Answers to these questions could lead to much-needed therapies to promote tissue healing in MS.
Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths1. Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process2,3,4. Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans5,6,7,8,9, it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of 14C derived from nuclear testing in genomic DNA10, we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques—thinly myelinated lesions that are thought to represent remyelinated areas—were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.