Astrocyte plasticity ensures continued endfoot coverage of cerebral blood vessels and integrity of the blood brain barrier, with plasticity declining with normal aging
Posted on: 20 July 2021 , updated on: 21 July 2021
Preprint posted on 10 May 2021
Focal destruction of astrocytes? It’s not the ‘end’ for the Blood-Brain Barrier
Selected by Ranabir Chakraborty
Categories: cell biology, neuroscience
Background:
Besides the presence of electrically active neurons, the central nervous system also harbours roughly equal numbers of non-neuronal cells (1), collectively referred to as glia. The major type of glial cells in the brain are astrocytes, cells that possess a bushy appearance in vivo and make millions of contacts with synapses in the human brain to efficiently maintain functional homeostasis (2). One crucial way in which astrocytes regulate Central Nervous System (CNS) homeostasis is their contact with the brain vasculature. By wrapping tightly around the blood vessels with their endfeet, astrocytes serve the role of cellular gate-keepers at the blood-brain barrier (BBB). The BBB stringently regulates what enters the brain parenchyma, allowing for the movements of ions/nutrients, exchange of gases, but preventing any potential toxic/pathogenic agents. Covering over 99% of the cerebrovascular surface, astrocytes not only help in regulating the exchange of such molecules, but also act as neuro-vascular couplers by regulating the blood vessel diameter, and thereby the amount of blood flow, in regions of heightened neuronal activities (3).
Given the critical importance of the BBB in maintaining CNS health, any perturbations in its integrity can potentially cause debilitating pathophysiologies. Disruption of BBB integrity has been observed in several instances, including Multiple Sclerosis (MS), Alzheimer’s Disease (AD), Major Depressive Disorder (MDD), stroke, glioma, and many more. A major therapeutic hypothesis is the possibility of restoring the integrity of BBB in such disorders/diseases, which could eventually be brought into a clinical setting. In this preprint, Mills et al. share their findings on the structural and functional plasticity of astrocytes upon astrocyte end foot separation from blood vessels.
Key results:
The authors set out to understand the potential contribution of astrocytes in maintaining the integrity of the BBB. Using a 2Phatal focal ablation system (two-photon laser tuned for UV range detection used to induce single-cell apoptosis in Hoechst-stained target cells), astrocytes-of-interest from Aldh1l1-eGFP mice were targeted for ablation. Interestingly, BBB integrity was not lost in the process; instead, the structural plastic nature of astrocytes came to the rescue. Astrocytes near the targeted zone filled in for the loss by extending their processes, which remains a key demonstration of the importance of these cells in the maintenance of the BBB.
The authors also demonstrated a temporal difference between young and aged mice in this process. In mice aged 2-4 months, an endfoot replacement event occurred on average every 17 minutes before complete removal of the targeted cell, a phenomenon that is lost during normal ageing. In old mice, the same process happened almost a couple of hours after the complete removal of the targeted cell, which is suggestive of a relatively dampened plastic response of aged astrocytes.
Given the structural response of astrocytes involved the extension of its processes, it was logical to look for a possible case of astrogliosis bringing about the change. The pharmacologically active molecule AG490 is an inhibitor of JAK2, the kinase that phosphorylates STAT3. Subcutaneous injection of AG490 for a week attenuated the astrocytic response. As predicted by the authors, they uncovered the role of JAK/STAT signalling, an underlying cause of astrocyte reactivity, in mediating the phenomenon. This brings to our attention the protective functions of reactive astrocytes towards CNS homeostasis.
Focal ablation of a single astrocyte, however, becomes an artificial targeting approach towards understanding their structural plasticity. As such, the authors replicated a similar condition in mice with substantial physiological relevance, the Rose Bengal photothrombotic stroke model. Rose Bengal is a photo-sensitive dye that upon excitation with green laser forms clots. Upon focal stimulation post dye injection, this system faithfully recapitulates the pathology of transient ischemic attack (TIA), which causes focal apoptosis of cells. In such a system, surrounding astrocytes reached out towards the vacant BBB spaces with high fidelity to ensure an astrocyte-vascular continuum. Since TIA increases the possibility of a stroke, especially during older age, maintenance of the BBB integrity is of critical importance to lower stroke probability after an ischaemic event.
The reason behind choosing this preprint:
Glial cells have long been the underdogs of the nervous system. With increasing evidence of their roles in maintaining homeostasis in the brain, the prospect of diving deeper into the biology of these cell types is becoming brighter. The general idea of plasticity in the brain revolves around neurons, especially during the critical period of development. Getting insights into the structural plasticity of astrocytes could pave the way for better understanding several neurological disorders, including the ones affecting the BBB in the context of this preprint. Multiple sclerosis, Alzheimer’s disease, dementia, stroke, glioma are all conditions which adversely affect the structural integrity of BBB, and potential therapeutics targeting astrocytes towards being more ‘plastic’ can help ameliorate these conditions.
Questions for the authors:
- Is there any signalling event coming from the lesioned cell (cues for the surrounding cells upon apoptosis) that brings about a rapid restructuring process, something that is possibly dampened with ageing, thereby causing the delay?
- If focal ablation in old mice is unable to cause BBB disruption even after a relatively long period of blood vessel vacancy, could increasing the number of ablated cells have a potential impact?
- Given the protective nature of astrogliosis upon 2Phatal ablation, are A2-specific transcriptomic signatures upregulated?
- Can the authors comment on any possible impact of astrocytic ablation on homeostatic status of perivascular macrophages?
References:
- Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, et Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain. Journal of Comparative Neurology. 2009;513(5):532-41.
- Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, et Uniquely hominid features of adult human astrocytes. Journal of Neuroscience. 2009;29(10):3276-87.
- Attwell D, Buchan AM, Charpak S, Lauritzen M, MacVicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature. 2010;468(7321):232-43.
doi: https://doi.org/10.1242/prelights.30126
Read preprint
(No Ratings Yet)Sign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Heart Scar-In-A-Dish: Tissue Culture Platform to Study Myocardial Infarct Healing In Vitro
Theodora Stougiannou
Optogenetic stimulation of Lbc GEF-mediated Rho activity dynamics promotes cell invasion
Vibha SINGH
TDP-43 directly inhibits RNA accumulation in neurites through modulation of RNA stability
Felipe Del Valle Batalla
Also in the neuroscience category:
Synapses drive local mitochondrial ATP synthesis to fuel plasticity
Felipe Del Valle Batalla
Fibroblast growth factor 21 regulates neuromuscular junction innervation through HDAC4 in denervation-induced skeletal muscle atrophy
Jórdan Sampar
Unexpected mechanisms of sex-specific memory vulnerabilities to acute traumatic stress
Jimeng Li
preLists in the cell biology category:
Keystone Symposium – Metabolic and Nutritional Control of Development and Cell Fate
This preList contains preprints discussed during the Metabolic and Nutritional Control of Development and Cell Fate Keystone Symposia. This conference was organized by Lydia Finley and Ralph J. DeBerardinis and held in the Wylie Center and Tupper Manor at Endicott College, Beverly, MA, United States from May 7th to 9th 2024. This meeting marked the first in-person gathering of leading researchers exploring how metabolism influences development, including processes like cell fate, tissue patterning, and organ function, through nutrient availability and metabolic regulation. By integrating modern metabolic tools with genetic and epidemiological insights across model organisms, this event highlighted key mechanisms and identified open questions to advance the emerging field of developmental metabolism.
| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 3) cell signalling and mechanosensing 4) (epi)genetics
| List by | Vibha SINGH et al. |
March in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) cancer biology 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics and genomics 6) other
| List by | Girish Kale et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
December in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) cell cycle and division 2) cell migration and cytoskeleton 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Matthew Davies et al. |
November in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
| List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
| List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
| List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
| List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
| List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
| List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
| List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
| List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
| List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
| List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
| List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
| List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
| List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
| List by | Dey Lab, Amanda Haage |
Also in the neuroscience category:
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 3) cell signalling and mechanosensing 4) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
| List by | Helen Zenner |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
| List by | Alex Eve |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
| List by | Sandra Malmgren Hill |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
| List by | Alex Eve |