Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells

Abstract

SummaryThe age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.

Remyelination alters the pattern of myelin in the cerebral cortex

“…The inability to recover fully from a demyelinating event raises the possibility that inflammation persists long after the initial trauma, or that OPCs in these regions are permanently altered as a result of exposure to this environment, if only for a short time (Baxi et al, 2015; Kirby et al, 2019). Like other progenitor cells, OPCs exhibit a decline in regenerative potential with age and can undergo senescence, a process that may be accelerated by exposure to inflammatory cytokines (Kirby et al, 2019; Neumann et al, 2019; Nicaise et al, 2019). It is also possible that there is a restricted time period during which OPCs can detect and respond to myelin loss; if there are inherent limits on OPC mobilization, as suggested by the uniform behavior of OPCs across cortical layers, then the inability to match the demand for new cells early may lead to prolonged deficits.…”

Proliferation is a requirement for differentiation of oligodendrocyte progenitor cells during CNS remyelination

“…The changes in OPC density, resulting from the block of proliferation, could hypothetically have also contributed to differentiation failure. However, we have recently shown that halving the cellular density per well, does not alter differentiation capacity of OPCs (Neumann et al, 2019). Together, our data suggest that proliferation is directly linked and required for differentiation in vitro and during remyelination in vivo .…”

“…A prevalent hypothesis to explain the decline in remyelination efficiency with age is a failure of OPCs to differentiate into mature oligodendrocytes in a timely fashion (Boda et al, 2015; Shen et al, 2008; Woodruff et al, 2004). Recently, we have shown that the exposure of aged OPCs to differentiation-enhancing compounds cannot enhance their differentiation, suggesting that aged OPCs cannot respond to differentiation signals (Neumann et al, 2019). Our finding that OPCs must undergo proliferation to differentiate might offer an intriguing explanation for this observation since aged OPCs have a markedly reduced capacity to proliferate both in vitro and in vivo (Ruckh et al, 2012; Segel et al, 2019).…”

“…Neonatal (P5-7) rats were decapitated after lethal injection with phenobarbital. The brains were removed quickly and placed into ice-cold isolation medium (Neumann et al, 2019) (alternatively Hibernate A Brainbits). The telencephalon and cerebellum were dissected in isolation medium; meninges, and the olfactory bulb were mechanically removed and the brain tissue was mechanically minced into 1mm 3 pieces.…”

“…As with most regenerative processes, the efficiency of remyelination declines with age (Absinta et al, 2016; Hampton et al, 2012; Neumann et al, 2019; Pfeifenbring et al, 2015; Shields et al, 1999; Sim et al, 2002), rendering axons vulnerable for degeneration and thereby contributing to the progressive phase of multiple sclerosis (MS) (Hampton et al, 2012). Hence, remyelination-enhancing therapies are regarded as one of the pillars of future treatments of MS (Franklin and ffrench-Constant, 2017; Reich et al, 2018).…”