Dynamics of oligodendrocyte generation in multiple sclerosis

Abstract

Oligodendrocytes wrap nerve fibers 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 appear to contribute to this process2–4. Considering the major differences in oligodendrocyte generation dynamics and adaptive myelination between rodents and humans5–9, it is uncertain how well experimental animals reflect the situation in multiple sclerosis. We have assessed the generation dynamics of oligodendrocytes in multiple sclerosis patients by measuring the integration of nuclear bomb test derived 14C in genomic DNA10. The generation of new oligodendrocytes was increased several-fold in normal appearing white matter in a subset of individuals with very aggressive disease, but not in the majority of subjects with multiple sclerosis, demonstrating an inherent potential to substantially increase oligodendrocyte generation but that this fails in most patients. Oligodendrocytes in shadow plaques, thinly myelinated lesion that are thought to represent remyelinated areas, were old in multiple sclerosis patients. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occur transiently or not at all, or that myelin is regenerated by preexisting, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, which should guide the use of current, and the development of new, therapies.

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…While considerable progress has been made in understanding the levels of de-and remyelination in experimental SCI, less is known about what occurs clinically. Humans often have poor remyelination efficiency in diseases like multiple sclerosis (MS; Goldschmidt, Antel, Konig, Bruck, & Kuhlmann, 2009;Patrikios et al, 2006;Yeung et al, 2019), and thus it is plausible that remyelination efficiency might be decreased after SCI relative to rodents. However, a limited number of pathological studies demonstrate there are relatively few demyelinated axons in most cases (Guest et al, 2005;Kakulas, 2004;Kakulas & Kaelan, 2015;Norenberg et al, 2004).…”

Grey matter myelination

“…Upon stimulation, however, the barrier is lowered and a larger fraction of the cells survive and form new myelin sheaths. Whether a similar mechanism operates in humans is difficult to find out, but the low number of proliferating cells within the human brain indicates that this may not be the case (Jakel et al, ; Yeung et al, ). Instead, a relatively large number of BCAS1 + premyelinating cells have been detected within the human cortex that persists until old age (Fard et al, ).…”

Stem cell derived oligodendrocytes to study myelin diseases

“…An intermediate OLIG2+/NKX2.2+ pre-OPC population can be identified before the emergence of SOX10+/NG2+ /CD140a+OPC (Hu et al, 2009). To enrich the percentage of OPC and eliminate the presence of remaining undifferentiated cells sorting for OPC markers is suggested during the differentiation process (Kim et al, 2017;Sundberg et al, 2011;Yeung et al, 2019). Different combinations of growth factors are used to endorse OPC differentiation to oligodendrocytes including BDNF, CNTF, IGF1, T3, NT3, AA, and cAMP (Piao et al, 2015;Stacpoole et al, 2013).…”