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Senescent NPCs in Progressive Multiple Sclerosis: A New Therapeutic Target?

Review of “Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis” from PNAS by Stuart P. Atkinson

Recent studies from the laboratory of Stephen J. Crocker (University of Connecticut, USA) demonstrated the reduced ability of neural progenitor cells differentiated from induced pluripotent stem cells derived from patients with progressive multiple sclerosis (PMS-iPSC-NPCs) to provide neuroprotection to myelin injury or support the differentiation of oligodendrocyte progenitor cells in vitro [1], thereby limiting their regenerative/reparative capacity [2]. However, oligodendrocyte progenitor cells derived from PMS-iPSCs mature into myelin-forming oligodendrocytes as well as healthy NPCs, suggesting a progenitor-specific PMS phenotype [3]. Excitingly, the team now return with a new PNAS article that establishes senescent NPCs as a significant contributor to and potentially reversible factor in PMS [4], while also suggesting multiple sclerosis as an aging-related disease.

Initial analyses of human autopsy brain tissue samples from PMS patients by Nicaise et al. identified SOX2-expressing senescent NPCs in demyelinated white matter lesions and discovered elevated markers of senescence in PMS-iPSC-NPCs when compared to age-matched control NPCs. Interestingly, treatment with rapamycin reversed the expression of cellular senescence genes in PMS-iPSC-NPCs and permitting them to support oligodendrocyte differentiation/maturation, thereby establishing the potential reversibility if cellular senescence through therapeutic intervention.

To discover what limited the oligodendrocyte differentiation of PMS-iPSC-NPCs, the authors employed proteomics and transcriptomics to finally identify the high-mobility group box-1 (HMGB1) protein [5] as a senescence-associated inhibitor of oligodendrocyte differentiation. The team established that senescent NPCs secreted HMGB1 in vitro, which then acted in a paracrine fashion to induce the expression of epigenetic regulators in oligodendrocyte progenitor cells that limit maturation and promote transcriptomic changes. To further strengthen the importance of this mechanism, the authors also identified senescent NPCs as a source of elevated HMGB1 in vivo in human white matter lesions.

Treatment strategies for multiple sclerosis concentrate on suppressing inflammation and blocking the access of immune cells into the central nervous system, even if this does not entirely prevent demyelination and axonal degeneration [6]. Of note, this approach does not provide any benefit to PMS patients [7]. Could cellular senescence in progenitor cells impair the regenerative potential of the lesion microenvironment and promote PMS? Furthermore, can small drugs that reverse the senescence phenotype, such as rapamycin, synergize with current treatment regimen to provide enhanced patient outcomes? Future work by the researchers will aim to answer these questions and discover whether vulnerability to cellular senescence is a predisposing risk factor in the development of PMS.

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References

  1. Nicaise AM, Banda E, Guzzo RM, et al., iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response. Experimental Neurology 2017;288:114-121.
  2. Huang JK, Fancy SPJ, Zhao C, et al., Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells. Neurotherapeutics 2011;8:650-658.
  3. Douvaras P, Wang J, Zimmer M, et al., Efficient Generation of Myelinating Oligodendrocytes from Primary Progressive Multiple Sclerosis Patients by Induced Pluripotent Stem Cells. Stem Cell Reports 2014;3:250-259.
  4. Nicaise AM, Wagstaff LJ, Willis CM, et al., Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proceedings of the National Academy of Sciences 2019;116:9030-9039.
  5. Davalos AR, Kawahara M, Malhotra GK, et al., p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. Journal of Cell Biology 2013;201:613.
  6. Brück W, Gold R, Lund BT, et al., Therapeutic decisions in multiple sclerosis: moving beyond efficacy. JAMA Neurology 2013;70:1315-1324.
  7. Comi G, Disease-modifying treatments for progressive multiple sclerosis. Multiple Sclerosis Journal 2013;19:1428-1436.