Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

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

doi:10.1038/s41467-023-39046-8

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

Irene Molina-Gonzalez, Rebecca K. Holloway, Zoeb Jiwaji, Owen Dando, Sarah A. Kent, Katie Emelianova, Amy F. Lloyd, Lindsey H. Forbes, Ayisha Mahmood, Thomas Skripuletz, Viktoria Gudi, James A. Febery, Jeffrey A. Johnson, Jill H. Fowler, Tanja Kuhlmann, Anna Williams, Siddharthan Chandran, Martin Stangel, Andrew J. M. Howden, Giles E. HardinghamVeronique E. Miron (Lead / Corresponding author)

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

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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 demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that 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 in focally-lesioned male mice 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
Article number	3372
Number of pages	18
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-39046-8
Publication status	Published - 8 Jun 2023

Keywords

Male
Mice
Animals
Humans
Astrocytes/metabolism
NF-E2-Related Factor 2/genetics
Central Nervous System/metabolism
Oligodendroglia/metabolism
Myelin Sheath/metabolism
Nerve Regeneration/physiology
Cholesterol/metabolism

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

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10.1038/s41467-023-39046-8Licence: CC BY

Final Published VersionFinal published version, 7.07 MBLicence: CC BY

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Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O., Kent, S. A., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., Gudi, V., Febery, J. A., Johnson, J. A., Fowler, J. H., Kuhlmann, T., Williams, A., Chandran, S., Stangel, M., Howden, A. J. M., ... Miron, V. E. (2023). Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration. Nature Communications, 14, Article 3372. https://doi.org/10.1038/s41467-023-39046-8

@article{4c3e9e2a087c4e399375ca38a066d7ae,

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 demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that 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 in focally-lesioned male mice 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.",

keywords = "Male, Mice, Animals, Humans, Astrocytes/metabolism, NF-E2-Related Factor 2/genetics, Central Nervous System/metabolism, Oligodendroglia/metabolism, Myelin Sheath/metabolism, Nerve Regeneration/physiology, Cholesterol/metabolism",

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

note = "Funding Information: This work was funded by a studentship from the United Kingdom Multiple Sclerosis Society (to V.E.M.; grant no. 54), a Medical Research Council and United Kingdom Multiple Sclerosis Society Career Development Award (to V.E.M.; grant no. MR/M020827/1), a Medical Research Council Senior Non-Clinical Fellowship (to V.E.M.; grant no. MRC/V031260/1), funds from the Medical Research Council Centre for Reproductive Health (grant no. MR/N02256/1), and the John David Eaton Chair in Multiple Sclerosis Research from St. Michael{\textquoteright}s Hospital Foundation. The cuprizone studies were supported by the German Research Foundation (T.K.; grant no. SFBTR128-B7) and the Hannover Medical School (Hochschulinterne Leistungsf{\"o}rderung; M.S.). Copyright: {\textcopyright} 2023. The Author(s).",

year = "2023",

month = jun,

day = "8",

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

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Molina-Gonzalez, I, Holloway, RK, Jiwaji, Z, Dando, O, Kent, SA, Emelianova, K, Lloyd, AF, Forbes, LH, Mahmood, A, Skripuletz, T, Gudi, V, Febery, JA, Johnson, JA, Fowler, JH, Kuhlmann, T, Williams, A, Chandran, S, Stangel, M, Howden, AJM, Hardingham, GE & Miron, VE 2023, 'Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration', Nature Communications, vol. 14, 3372. 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 K.

AU - Jiwaji, Zoeb

AU - Dando, Owen

AU - Kent, Sarah A.

AU - Emelianova, Katie

AU - Lloyd, Amy F.

AU - Forbes, Lindsey H.

AU - Mahmood, Ayisha

AU - Skripuletz, Thomas

AU - Gudi, Viktoria

AU - Febery, James A.

AU - Johnson, Jeffrey A.

AU - Fowler, Jill H.

AU - Kuhlmann, Tanja

AU - Williams, Anna

AU - Chandran, Siddharthan

AU - Stangel, Martin

AU - Howden, Andrew J. M.

AU - Hardingham, Giles E.

AU - Miron, Veronique E.

N1 - Funding Information: This work was funded by a studentship from the United Kingdom Multiple Sclerosis Society (to V.E.M.; grant no. 54), a Medical Research Council and United Kingdom Multiple Sclerosis Society Career Development Award (to V.E.M.; grant no. MR/M020827/1), a Medical Research Council Senior Non-Clinical Fellowship (to V.E.M.; grant no. MRC/V031260/1), funds from the Medical Research Council Centre for Reproductive Health (grant no. MR/N02256/1), and the John David Eaton Chair in Multiple Sclerosis Research from St. Michael’s Hospital Foundation. The cuprizone studies were supported by the German Research Foundation (T.K.; grant no. SFBTR128-B7) and the Hannover Medical School (Hochschulinterne Leistungsförderung; M.S.). Copyright: © 2023. The Author(s).

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 demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that 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 in focally-lesioned male mice 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 demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that 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 in focally-lesioned male mice 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.

KW - Male

KW - Mice

KW - Animals

KW - Humans

KW - Astrocytes/metabolism

KW - NF-E2-Related Factor 2/genetics

KW - Central Nervous System/metabolism

KW - Oligodendroglia/metabolism

KW - Myelin Sheath/metabolism

KW - Nerve Regeneration/physiology

KW - Cholesterol/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85161452117&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-39046-8

DO - 10.1038/s41467-023-39046-8

M3 - Article

C2 - 37291151

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 3372

ER -

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

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