Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Irene Molina-Gonzalez; Rebecca Holloway; Zoeb Jiwaji; Owen Dando; Sarah Kent; Katherine Emelianova; Amy F Lloyd; Lindsey Forbes; Ayisha Mahmood; Thomas Skripuletz; Viktoria Gudi; James A. Febery; Jeffrey A Johnson; Jill Fowler; Tanja Kuhlmann; Anna C Williams; Siddharthan Chandran; Martin Stangel; Andrew J M Howden; Giles E.  Hardingham; Véronique E Miron

doi:10.1038/s41467-023-39046-8

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Irene Molina-Gonzalez, Rebecca Holloway, Zoeb Jiwaji, Owen Dando, Sarah Kent, Katherine Emelianova, Amy F Lloyd, Lindsey Forbes, Ayisha Mahmood, Thomas Skripuletz, Viktoria Gudi, James A. Febery, Jeffrey A Johnson, Jill Fowler, Tanja Kuhlmann, Anna C Williams, Siddharthan Chandran, Martin Stangel, Andrew J M Howden, Giles E. HardinghamVéronique E Miron

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

Original language	English
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-39046-8
Publication status	Published - 8 Jun 2023

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10.1038/s41467-023-39046-8Final published version, 7.07 MBLicence: Creative Commons: Attribution (CC-BY)

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Molina-Gonzalez, I., Holloway, R., Jiwaji, Z., Dando, O., Kent, S., Emelianova, K., Lloyd, A. F., Forbes, L., Mahmood, A., Skripuletz, T., Gudi, V., Febery, J. A., Johnson, J. A., Fowler, J., Kuhlmann, T., Williams, A. C., Chandran, S., Stangel, M., Howden, A. J. M., ... Miron, V. E. (2023). Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration. Nature Communications, 14. https://doi.org/10.1038/s41467-023-39046-8

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title = "Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration",

abstract = "Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.",

author = "Irene Molina-Gonzalez and Rebecca Holloway and Zoeb Jiwaji and Owen Dando and Sarah Kent and Katherine Emelianova and Lloyd, {Amy F} and Lindsey Forbes and Ayisha Mahmood and Thomas Skripuletz and Viktoria Gudi and Febery, {James A.} and Johnson, {Jeffrey A} and Jill Fowler and Tanja Kuhlmann and Williams, {Anna C} and Siddharthan Chandran and Martin Stangel and Howden, {Andrew J M} and Hardingham, {Giles E.} and Miron, {V{\'e}ronique E}",

year = "2023",

month = jun,

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doi = "10.1038/s41467-023-39046-8",

language = "English",

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issn = "2041-1723",

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Molina-Gonzalez, I, Holloway, R, Jiwaji, Z , Dando, O, Kent, S, Emelianova, K, Lloyd, AF, Forbes, L, Mahmood, A, Skripuletz, T, Gudi, V, Febery, JA, Johnson, JA, Fowler, J, Kuhlmann, T, Williams, AC , Chandran, S, Stangel, M, Howden, AJM, Hardingham, GE & Miron, VE 2023, 'Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration', Nature Communications, vol. 14. https://doi.org/10.1038/s41467-023-39046-8

TY - JOUR

T1 - Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

AU - Molina-Gonzalez, Irene

AU - Holloway, Rebecca

AU - Jiwaji, Zoeb

AU - Dando, Owen

AU - Kent, Sarah

AU - Emelianova, Katherine

AU - Lloyd, Amy F

AU - Forbes, Lindsey

AU - Mahmood, Ayisha

AU - Skripuletz, Thomas

AU - Gudi, Viktoria

AU - Febery, James A.

AU - Johnson, Jeffrey A

AU - Fowler, Jill

AU - Kuhlmann, Tanja

AU - Williams, Anna C

AU - Chandran, Siddharthan

AU - Stangel, Martin

AU - Howden, Andrew J M

AU - Hardingham, Giles E.

AU - Miron, Véronique E

PY - 2023/6/8

Y1 - 2023/6/8

N2 - Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

AB - Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

U2 - 10.1038/s41467-023-39046-8

DO - 10.1038/s41467-023-39046-8

M3 - Article

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

ER -

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

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