TY - JOUR
T1 - Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination
AU - Hill, Bianca M.
AU - Holloway, Rebecca K.
AU - Forbes, Lindsey H.
AU - Davies, Claire L.
AU - Monteiro, Jonathan K.
AU - Brown, Christina M.
AU - Rose, Jamie
AU - Fudge, Neva
AU - Plant, Pamela J.
AU - Mahmood, Ayisha
AU - Brand-Arzamendi, Koroboshka
AU - Kent, Sarah A.
AU - Molina-Gonzalez, Irene
AU - Gyoneva, Stefka
AU - Ransohoff, Richard M.
AU - Wipke, Brian
AU - Priller, Josef
AU - Schneider, Raphael
AU - Moore, Craig S.
AU - Miron, Veronique E.
N1 - Publisher Copyright:
© 2025 Hill et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2025/4
Y1 - 2025/4
N2 - The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2−/−), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.
AB - The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2−/−), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.
UR - http://www.scopus.com/inward/record.url?scp=105002793717&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.3003073
DO - 10.1371/journal.pbio.3003073
M3 - Article
AN - SCOPUS:105002793717
SN - 1544-9173
VL - 23
JO - PLoS Biology
JF - PLoS Biology
IS - 4 April
M1 - e3003073
ER -