Dataset Information

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.

SUBMITTER: Molina-Gonzalez I

PROVIDER: S-EPMC10250470 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

Molina-Gonzalez Irene I Holloway Rebecca K RK Jiwaji Zoeb Z Dando Owen O Kent Sarah A SA Emelianova Katie K Lloyd Amy F AF Forbes Lindsey H LH Mahmood Ayisha A Skripuletz Thomas T Gudi Viktoria V Febery James A JA Johnson Jeffrey A JA Fowler Jill H JH Kuhlmann Tanja T Williams Anna A Chandran Siddharthan S Stangel Martin M Howden Andrew J M AJM Hardingham Giles E GE Miron Veronique E VE

Nature communications 20230608 1

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 analy ...[more]

PMID: 37291151

Similar Datasets

Project description:UnlabelledNeurotrauma, stroke, and neurodegenerative disease may result in widespread loss of neural cells as well as the complex interconnectivity necessary for proper central nervous system function, generally resulting in permanent functional deficits. Potential regenerative strategies involve the recruitment of endogenous neural stem cells and/or directed axonal regeneration through the use of tissue engineered "living scaffolds" built to mimic features of three-dimensional (3-D) in vivo migratory or guidance pathways. Accordingly, we devised a novel biomaterial encasement scheme using tubular hydrogel-collagen micro-columns that facilitated the self-assembly of seeded astrocytes into 3-D living scaffolds consisting of long, cable-like aligned astrocytic networks. Here, robust astrocyte alignment was achieved within a micro-column inner diameter (ID) of 180μm or 300-350μm but not 1.0mm, suggesting that radius of curvature dictated the extent of alignment. Moreover, within small ID micro-columns, >70% of the astrocytes assumed a bi-polar morphology, versus ∼10% in larger micro-columns or planar surfaces. Cell-cell interactions also influenced the aligned architecture, as extensive astrocyte-collagen contraction was achieved at high (9-12×10(5)cells/mL) but not lower (2-6×10(5)cells/mL) seeding densities. This high density micro-column seeding led to the formation of ultra-dense 3-D "bundles" of aligned bi-polar astrocytes within collagen measuring up to 150μm in diameter yet extending to a remarkable length of over 2.5cm. Importantly, co-seeded neurons extended neurites directly along the aligned astrocytic bundles, demonstrating permissive cues for neurite extension. These transplantable cable-like astrocytic networks structurally mimic the glial tube that guides neuronal progenitor migration in vivo along the rostral migratory stream, and therefore may be useful to guide progenitor cells to repopulate sites of widespread neurodegeneration.Statement of significanceThis manuscript details our development of novel micro-tissue engineering techniques to generate robust networks of longitudinally aligned astrocytes within transplantable micro-column hydrogels. We report a novel biomaterial encasement scheme that facilitated the self-assembly of seeded astrocytes into long, aligned regenerative pathways. These miniature "living scaffold" constructs physically emulate the glial tube - a pathway in the brain consisting of aligned astrocytes that guide the migration of neuronal progenitor cells - and therefore may facilitate directed neuronal migration for central nervous system repair. The small size and self-contained design of these aligned astrocyte constructs will permit minimally invasive transplantation in models of central nervous system injury in future studies.

Dataset Information

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

Publications

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets