Reactive astrogliosis in stroke: Contributions of astrocytes to recovery of neurological function

https://doi.org/10.1016/j.neuint.2016.12.016Get rights and content

Highlights

  • Reactive astrogliosis is an important influence on neurological recovery in stroke.

  • Distance from the infarct is a key determinant of the astrocytic responses.

  • Many features of reactive astrogliosis enhance recovery but some are inhibitory.

  • The influence of age, gender, comorbidities and reperfusion are not well understood.

Abstract

Alterations in neuronal connectivity, particularly in the “peri-infarct” tissue adjacent to the region of ischemic damage, are important contributors to the spontaneous recovery of function that commonly follows stroke. Peri-infarct astrocytes undergo reactive astrogliosis and play key roles in modulating the adaptive responses in neurons. This reactive astrogliosis shares many features with that induced by other forms of damage to the central nervous system but also differs in details that potentially influence neurological recovery. A subpopulation of astrocytes within a few hundred micrometers of the infarct proliferate and are centrally involved in the development of the glial scar that separates the damaged tissue in the infarct from surrounding normal brain. The intertwined processes of astrocytes adjacent to the infarct provide the core structural component of the mature scar. Interventions that cause early disruption of glial scar formation typically impede restoration of neurological function. Marked reactive astrogliosis also develops in cells more distant from the infarct but these cells largely remain in the spatial territories they occupied prior to stroke. These cells play important roles in controlling the extracellular environment and release proteins and other molecules that are able to promote neuronal plasticity and improve functional recovery. Treatments manipulating aspects of reactive astrogliosis can enhance neuronal plasticity following stroke. Optimising these treatments for use in human stroke would benefit from a more complete characterization of the specific responses of peri-infarct astrocytes to stroke as well as a better understanding of the influence of other factors including age, sex, comorbidities and reperfusion of the ischemic tissue.

Introduction

Stroke is a leading cause of death and a major cause of adult disability. Globally, there are more than 10 million new strokes each year and over 6 million deaths as a result of stroke (Feigin et al., 2015). Many stroke survivors have disabilities and these are often permanent. In 2013, the disease accounted for 113 million disability-adjusted life years (Feigin et al., 2015), a measure of the time lost to disability. Ischemic stroke, the focus of the present review, is the predominant form of this disorder accounting for approximately 70% of cases worldwide (Feigin et al., 2015). This type of stroke results from rapid occlusion of an artery in the brain, usually due either to an atherosclerotic thrombus formed in a major cerebral artery or an embolus generated elsewhere in the body.

Because of limited overlap in the arterial perfusion territories in the brain, local vessel occlusion leads to a core region of severely ischemic tissue surrounded by a more moderately ischemic “penumbra” (Hossmann, 2009). In the core, the large decrease in blood flow rapidly initiates changes that lead to infarction in which almost all cells die. Unless there is early restoration of blood flow, cell death in the penumbra is also triggered and the mature infarct typically incorporates essentially all of the core and penumbral tissue (Moskowitz et al., 2010).

Cells in the penumbra can be rescued, at least in part, if blood flow is restored within a few hours after the onset of stroke both in humans and in animal models (Anderson and Sims, 1999, Hacke et al., 2008, Memezawa et al., 1992, Wardlaw et al., 2003). Indeed, at present, the only widely available treatments for acute stroke involve reversing arterial occlusion using either thrombolytic agents (Hacke et al., 2008, Wardlaw et al., 2003) or the more recently adopted endovascular thrombectomy, in which the clot is retrieved mechanically (Balami et al., 2015, Berkhemer et al., 2015, Yarbrough et al., 2015). These treatments are not currently suitable for the majority of patients because of the need to initiate treatment within approximately six hours of stroke onset, as well as other patient-specific contraindications. Thus, there is considerable interest in treatments that can help to restore neurological function, particularly for the many patients who do not currently benefit from acute intervention.

Astrocytes play many roles that are essential for normal brain function, including maintaining the extracellular environment via uptake of amino acid neurotransmitters and modulation of the ionic content, providing metabolic precursors for substances including neurotransmitters and antioxidants, releasing trophic factors, helping to maintain the blood brain barrier and providing a conduit for passage of glucose and other metabolites between blood and the neurons (Pekny and Pekna, 2014, Rossi, 2015, Verkhratsky and Butt, 2013). Individual astrocytes interact with many synapses and also with capillaries and other cells. They are also interconnected to neighbouring astrocytes via gap junctions forming extended cellular networks with the potential to communicate over large distances. These properties provide the basis for an emerging view of astrocytes as global controllers in the central nervous system (CNS) that modulate the local environment but also coordinate cellular responses over much larger distances (Pekny and Pekna, 2014, Rossi, 2015, Verkhratsky and Butt, 2013).

During stroke, disruption of these many important astrocytic functions contributes both to an initial rapid impairment of neurotransmission and to subsequent development of the infarct (George and Steinberg, 2015, Moskowitz et al., 2010, Turner et al., 2013). Astrocytes are also key players in responses of the brain to the tissue damage that is induced by stroke. The present review discusses the astrocytic responses to tissue damage in stroke and the influence of these cells on the prospects for neurological recovery. It primarily focuses on astrocytes located in the “peri-infarct tissue” that immediately surrounds the ischemic lesion.

It is common for those affected by stroke to show improvements in neurological function within the first weeks to months after disease onset. Furthermore, the extent of recovery can be promoted by a range of treatments such as limb-restraint therapies, electromagnetic stimulation and electronic device-assisted therapies, albeit sometimes with only short-lasting effects and considerable variability between patients in the benefits produced (Cramer, 2008a, George and Steinberg, 2015). Similar interventions and a wide range of other treatments can improve recovery in animal models of stroke without altering the size of the infarct (Cramer, 2008a, George and Steinberg, 2015, Murphy and Corbett, 2009).

Spontaneous recovery in part involves the restoration of functions that are initially impaired in viable neurons outside the infarct. Analyses of brain responses to stimulation following stroke in humans and in animal models reveal initial widespread functional depression, particularly in tissue connected to the site of the infarct, followed over several weeks by abnormal activation patterns involving contralateral and distant ipsilateral sites. There is then a return to more normal patterns as neurological function improves (Benowitz and Carmichael, 2010, Cramer, 2008b, Jablonka et al., 2010, Lim et al., 2014, Murphy and Corbett, 2009). Animal studies have provided direct evidence for decreases in neuronal excitability in tissue surrounding the infarct that are seen within the first 24 h and can persist for many weeks (Bolay and Dalkara, 1998, Bolay et al., 2002, Clarkson et al., 2010, Neumann-Haefelin and Witte, 2000). Morphological changes in neurons, including a loss of dendritic spines, develop in the peri-infarct tissue within a few millimetres of the lesion and contribute to the altered neuronal function (Brown et al., 2008). A partial reversal of many of these early changes in the structure and function of surviving neurons is an important contributor to improvements in neurological activity.

In addition, recovery also involves adaptive changes in which neurons form novel connections and, in some instances, assume the functions of cells that were lost in the infarct (Brown et al., 2009, Carmichael, 2016, Murphy and Corbett, 2009). Such changes are prominent in peri-infarct tissue, particularly for those strokes producing small cortical infarcts which have a greater potential for recovery (Carmichael, 2016). An increased turnover of dendritic spines in the peri-infarct tissue initiated shortly after the stroke and lasting several weeks as well as changes in connectivity to more distant neurons including those at sites in the hemisphere contralateral to the infarct contribute to the development of new patterns of brain activation (Brown et al., 2009, Carmichael, 2016). Many interventions that improve recovery in animal models result in enhancement of these adaptive responses (Carmichael, 2016, George and Steinberg, 2015, Murphy and Corbett, 2009).

The processes leading to cell death in the penumbral tissue are apparently irreversibly established within the initial three to twelve hours, with timing dependent in part on whether the arterial occlusion is permanent or temporary (Hossmann, 2009, Moskowitz et al., 2010, Sims and Muyderman, 2010). Studies of cells in culture suggest that astrocytes are much less susceptible than neurons to ischemia-like insults and related stressors (Almeida et al., 2002, Panickar and Norenberg, 2005, Xu et al., 2001). However, such differences are probably of only limited importance in stroke, at least once the infarct has fully matured. Selective neuronal death has been observed with focal ischemia lasting less than 30 min in rodents (Baron et al., 2014, Emmrich et al., 2015, Nedergaard, 1987). With the much longer periods of arterial occlusion that are typical for most stroke in humans, areas of differential neuronal loss are either absent or are restricted to a narrow band immediately adjacent to the outer rim of the infarct (Baron et al., 2014, Katsman et al., 2003). Thus, there is typically a sharp transition over a distance of a few hundred micrometers between the outer part of the infarct in which essentially all previously-resident cells are lost and tissue exhibiting a normal or near-normal cell composition. This pattern is even preserved following neuroprotective treatments in animal models. The infarct typically becomes smaller but an increase in selective survival of some cell populations is not usually seen. These observations suggest a strong interdependence in the viability of different cell populations during ischemia and post-ischemic reperfusion.

As occurs with essentially all disorders resulting in damage to the brain, astrocytes in the tissue neighbouring an infarct exhibit major changes in cell morphology, gene expression, proliferation and function that are commonly termed reactive astrogliosis (Burda and Sofroniew, 2014, Liu and Chopp, 2016, Pekny and Pekna, 2014). These changes are accompanied by increases in expression of the intermediate filament protein, glial fibrillary acidic protein (GFAP), that are commonly used to identify reactive astrocytes. Although many features of reactive astrogliosis are shared in different forms of disease and injury, there is not a single pattern of responses for all disorders (Pekny and Pekna, 2014, Zamanian et al., 2012). Changes are affected by disease-specific factors such as the nature, location and severity of the tissue damage and can also be influenced by more general factors including age and gender (see section 2.5).

As summarized in Fig. 1 and further discussed in sections 2.1 Proliferation of peri-infarct astrocytes and the development of a glial scar, 2.2 Reactive astrogliosis in tissue beyond the developing glial scar, two broadly different patterns of reactive astrogliosis can be identified following stroke with the response of individual cells strongly influenced by distance from the lesion. A subgroup of the astrocytes immediately adjacent to the lesion proliferates. These cells (and perhaps non-proliferating neighbouring astrocytes) are particularly important for development of the glial scar which, in its mature form, is predominantly composed of the intertwined processes of these astrocytes as well as extracellular matrix. Astrocytes further from the lesion show changes in morphology but largely remain in the territory they occupied before stroke and retain many of the interactions with other cells that existed before the stroke. These cells have much greater potential to directly influence the adaptive responses of neighbouring neurons in the peri-infarct tissue.

This dual pattern of reactive astrogliosis is also seen in trauma of the brain and spinal cord and has been best characterized for spinal cord injury (Burda and Sofroniew, 2014, Sofroniew, 2015). The changes in stroke differ in details of some specific changes and also show important differences in the influence of the glial scar on subsequent recovery.

Within the first day of stroke, the infarct begins to be invaded by microglia from the surrounding tissue as well as immune cells from the blood including monocytes (that convert to tissue macrophages) and granulocytes. These cells are involved in removing the debris of dead cells and probably also assist in limiting the spread of potentially deleterious changes to surrounding tissue. Microglia and macrophages also accumulate in the peri-infarct tissue, mostly close to the site of the developing glial scar where they influence responses of astrocytes and other cells (see section 2.4.1).

Section snippets

Proliferation of peri-infarct astrocytes and the development of a glial scar

Proliferation of astrocytes in tissue immediately adjacent to the infarct is critical for the development of the glial scar following both traumatic and ischemic injury (Burda and Sofroniew, 2014, Sofroniew, 2015). Following a crush injury to the spinal cord, more than 60% of astrocytes within 500 μm of the damage undergo proliferation, resulting in an approximate doubling of astrocytes within this region (Wanner et al., 2013). Astrocytic proliferation is also induced following traumatic brain

Astrocytes as therapeutic targets to improve neurological recovery

Reactive astrogliosis is a central player in the CNS defences that helps to limit the spread of tissue damage and promote functional recovery in many CNS disorders. However, the ability of reactive astrogliosis to produce such outcomes following stroke could potentially be compromised by several factors including the more extensive tissue damage and disruption to neuronal circuitry that is often produced in this disorder. The capacity for stroke to influence the evolution of reactive

Final comments

The responses in peri-infarct tissue that contribute to recovery of neurological function following stroke are undoubtedly the product of complex interactions between multiple cell types. Astrocytes are important contributors to these responses through changes leading ultimately to the generation of the glial scar as well as changes that can more directly support recovery of neuronal function and promote neuronal plasticity. Many aspects of reactive astrogliosis enhance functional recovery but

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgements

Funding: This work was supported by the National Health and Medical Research Council, Australia [Application number 1026054] and the Flinders University Faculty of Health Sciences. Wai Ping Yew was supported by a Flinders University Research Scholarship.

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