Chronic demyelination in the CNS is one of the defining characteristics of progressive multiple sclerosis (PMS). A study recently published in PNAS has provided evidence that the decreased remyelination potential in patients with PMS is attributable to premature senescence of neural progenitor cells (NPCs) in the brain.

Credit: Philip Patenall/Springer Nature Limited

“We previously demonstrated that induced pluripotent stem cell (iPSC)-derived NPCs from patients with primary progressive MS (PPMS), unlike cells developed from age-matched controls, did not provide protection against demyelination, nor did they foster oligodendrocyte growth and maturation,” comments study leader Stephen Crocker, who is based at the University of Connecticut School of Medicine, USA. In the current study, Crocker and colleagues set out to further explore the molecular and cellular mechanisms underlying these observations.

For their new experiments, the researchers once again used iPSC lines derived from patients with PPMS. After differentiation into NPCs, these cell lines were found to express molecular markers of cellular senescence, including p16Ink4a, p53 and senescence-associated β-galactosidase.

In collaboration with Anna Williams at the University of Edinburgh, UK, the investigators also used immunohistochemistry to analyse post-mortem brain samples from patients with PMS. This analysis revealed that p16Ink4a was expressed by progenitor cells that accumulated in demyelinated lesions, thereby providing in vivo evidence of cellular senescence in association with demyelination.

Consistent with the earlier findings from Crocker’s group, the iPSC-derived NPCs from patients with PPMS had a reduced capacity to support the growth and maturation of oligodendrocytes — the myelinating cells of the CNS. This capacity was restored by treating the NPCs with rapamycin, a drug that has previously been shown to prevent cellular senescence. In addition, rapamycin reduced the expression of senescence-associated markers by the NPCs.

These findings support the idea of MS as a disease of ageing

“These findings support the idea of MS as a disease of ageing, even though the MS patient population is not what we would typically consider an aged population,” concludes Crocker. “We are currently using in vitro and in vivo models to explore how additional means of affecting cellular senescence can influence CNS myelination, and to examine whether functional differences in NPCs occur in other clinically defined subtypes of MS.”