Pericytes in Hypoxia and Ischemic Stroke
Enström, Andreas LU
(2023)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Molecular oxygen is essential for most living species. Consequently, hypoxic or ischemic conditions are major cellular stressors and prominent pathological features in ischemic stroke. Stroke is a global health problem and remains the second leading cause of death or disability worldwide. Current management of the disease focuses on rapid reperfusion by thrombolysis or thrombectomy but these therapies are time-critical and only administered to a minority of patients. Thus, improving our understanding of stroke pathogenesis is key to ensure rapid and accurate diagnostics to maximize benefits from existing reperfusion treatments but also to identify new therapeutic targets. Blood-brain barrier (BBB) breakdown is one of the pathological... (More)
- Molecular oxygen is essential for most living species. Consequently, hypoxic or ischemic conditions are major cellular stressors and prominent pathological features in ischemic stroke. Stroke is a global health problem and remains the second leading cause of death or disability worldwide. Current management of the disease focuses on rapid reperfusion by thrombolysis or thrombectomy but these therapies are time-critical and only administered to a minority of patients. Thus, improving our understanding of stroke pathogenesis is key to ensure rapid and accurate diagnostics to maximize benefits from existing reperfusion treatments but also to identify new therapeutic targets. Blood-brain barrier (BBB) breakdown is one of the pathological hallmarks of ischemic stroke, excerbating the ichemic brain injury and limiting the use of current clinical therapies. Ischemic stroke is also characterized by endogenous repair mechanisms such as angiogenesis to restore cerbral blood flow, and neurogenesis for functional recovery. Understanding when and how the brain transitions from injury to repair and how the responses of specific cells may orchestrate that transition could have key implications for future stroke therapies.
Brain pericytes, surounding capillaries at the blood–brain interface have received increased attention in stroke research as they have central roles in maintaining BBB integrity, regulating angiogenesis, and modulating inflammation. As such, pericyte dysfunction after ischemic injury may have an unfavourable impact on BBB breakdown due to pericyte detachment and/or disruption of blood-flow because of pericyte constriction. On the other hand, pericytes in the peri-infarct area supports poststroke recovery by inducing angiogenesis and neurogenesis. However, we still have limited knowledge of how pericytes sense and respond to hypoxic/ischemic insult and further insght are needed. Towards that end, this thesis has aimed at expanding the current knowledge of the role of pericytes in the hypoxia or ischemia challenged brain from different perspectives.
One of the first pericyte responses to hypoxia or ischemia is the rapid induction of Regulator of G-protein Signalling 5 (RGS5), a negative regulator of G-protein signalling. Using an experimental mouse model of ischemic stroke we established that loss of RGS5 preserved the perivascular coverage of pericytes associated with increased vascular density and BBB integrity. In cell cultures of human brain pericytes, we show that RGS5 expression desensitizes pericytes to important chemotactic cues such as platelet-derived growth factor (PDGFBB) necessary for pericyte recruitment and retention to the vascular wall.
Pericytes secrete various factors important for cell-cell communication. Using an in vitro BBB-model, we show that the pericyte secretome is altered under hypoxia and dependent on cell-cell interactions of other BBB-residing cells. Furthermore, circulating pericyte-derived microvesicles (MVs) showed an early and time-dependent increase in stroke patients, where functional annotation of secreted molecules within the MV cargo related to inflammation and vascular remodelling.
Using single-cell RNA sequencing in an ischemic stroke mouse model, we identified a stroke-specific subcluster of pericytes present at different time points of the acute phase, characterized by the upregulation of specific genes related to cytokine signalling and modulation of the immune and inflammatory response.
(Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/c1e32234-e605-45de-8de5-a62c7f376732
- author
- Enström, Andreas
LU
- supervisor
- opponent
-
- Associate Professor Montagne, Axel, University of Edinburgh
- organization
- publishing date
- 2023
- type
- Thesis
- publication status
- published
- subject
- keywords
- Pericytes, Ischemic stroke, Hypoxia, Secretome, Transcriptome, RGS5
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2023:62
- pages
- 80 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
- defense date
- 2023-05-11 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-402-5
- language
- English
- LU publication?
- yes
- id
- c1e32234-e605-45de-8de5-a62c7f376732
- date added to LUP
- 2023-04-12 15:24:26
- date last changed
- 2023-04-24 08:51:02
@phdthesis{c1e32234-e605-45de-8de5-a62c7f376732,
abstract = {{Molecular oxygen is essential for most living species. Consequently, hypoxic or ischemic conditions are major cellular stressors and prominent pathological features in ischemic stroke. Stroke is a global health problem and remains the second leading cause of death or disability worldwide. Current management of the disease focuses on rapid reperfusion by thrombolysis or thrombectomy but these therapies are time-critical and only administered to a minority of patients. Thus, improving our understanding of stroke pathogenesis is key to ensure rapid and accurate diagnostics to maximize benefits from existing reperfusion treatments but also to identify new therapeutic targets. Blood-brain barrier (BBB) breakdown is one of the pathological hallmarks of ischemic stroke, excerbating the ichemic brain injury and limiting the use of current clinical therapies. Ischemic stroke is also characterized by endogenous repair mechanisms such as angiogenesis to restore cerbral blood flow, and neurogenesis for functional recovery. Understanding when and how the brain transitions from injury to repair and how the responses of specific cells may orchestrate that transition could have key implications for future stroke therapies.<br/><br/>Brain pericytes, surounding capillaries at the blood–brain interface have received increased attention in stroke research as they have central roles in maintaining BBB integrity, regulating angiogenesis, and modulating inflammation. As such, pericyte dysfunction after ischemic injury may have an unfavourable impact on BBB breakdown due to pericyte detachment and/or disruption of blood-flow because of pericyte constriction. On the other hand, pericytes in the peri-infarct area supports poststroke recovery by inducing angiogenesis and neurogenesis. However, we still have limited knowledge of how pericytes sense and respond to hypoxic/ischemic insult and further insght are needed. Towards that end, this thesis has aimed at expanding the current knowledge of the role of pericytes in the hypoxia or ischemia challenged brain from different perspectives.<br/><br/>One of the first pericyte responses to hypoxia or ischemia is the rapid induction of Regulator of G-protein Signalling 5 (RGS5), a negative regulator of G-protein signalling. Using an experimental mouse model of ischemic stroke we established that loss of RGS5 preserved the perivascular coverage of pericytes associated with increased vascular density and BBB integrity. In cell cultures of human brain pericytes, we show that RGS5 expression desensitizes pericytes to important chemotactic cues such as platelet-derived growth factor (PDGFBB) necessary for pericyte recruitment and retention to the vascular wall. <br/><br/>Pericytes secrete various factors important for cell-cell communication. Using an in vitro BBB-model, we show that the pericyte secretome is altered under hypoxia and dependent on cell-cell interactions of other BBB-residing cells. Furthermore, circulating pericyte-derived microvesicles (MVs) showed an early and time-dependent increase in stroke patients, where functional annotation of secreted molecules within the MV cargo related to inflammation and vascular remodelling. <br/><br/>Using single-cell RNA sequencing in an ischemic stroke mouse model, we identified a stroke-specific subcluster of pericytes present at different time points of the acute phase, characterized by the upregulation of specific genes related to cytokine signalling and modulation of the immune and inflammatory response.<br/>}},
author = {{Enström, Andreas}},
isbn = {{978-91-8021-402-5}},
issn = {{1652-8220}},
keywords = {{Pericytes; Ischemic stroke; Hypoxia; Secretome; Transcriptome; RGS5}},
language = {{eng}},
number = {{2023:62}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Pericytes in Hypoxia and Ischemic Stroke}},
url = {{https://lup.lub.lu.se/search/files/143754547/Avhandling_Andreas_Enstr_m.pdf}},
year = {{2023}},
}