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6 Stem-Cell-like Properties of Reactive Astrocytes and Endogenous Neuronal Differentiation of Reactive Astrocytes After Ischemic Stroke

6 Stem-Cell-like Properties of Reactive Astrocytes and Endogenous Neuronal Differentiation of Reactive Astrocytes After Ischemic Stroke

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Astrocytes as a Target for Ischemic Stroke



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Reactive astrocytes also affect the migration of neural progenitor cells after ischemia.

Young et al. [140] reported for the first time that ischemic stroke causes substantial

reactive astrogliosis in SVZ and the hypertrophic reactive astrocytes and their tortuous processes disrupt the neuroblast migratory scaffold and cause SVZ reorganization after a stroke [140]; thus, reactive astrocytes in SVZ might also play a

modulating role in neurogenesis thereby affecting stroke recovery.



2.7



Direct Astrocyte-to-Neuron Conversion After Ischemic

Stroke



The fact that reactive astrocytes express neural stem markers and can be transformed

into mature neurons after a prolonged time following ischemia indicate that reactive

astrocytes have the intrinsic potential to generate neurons and reactive astrocytes-toneuron conversion can be facilitated under permissive conditions such as overexpression of neurogenic factors. It has been recently reported that astrocytes indeed

can be converted into neuroblasts and neurons in vitro and in vivo by forced expression of a single transcriptional factor such as Sox2 [141, 142], Neurog-2 [143–145],

NeuroD1 [146], Ascl1 [147], or a combination of multiple transcriptional factors

such as Ascl1, Lmx1B, Nurr1, Oct4, Sox2, or Nanog [148, 149]. Astrocyteconverted neurons express mature neuronal markers such as Map2 and NeuN [141,

146]. Electrophysiological recording showed that cultured mouse astrocyteconverted neurons by NeuroD1 are glutamatergic; furthermore, astrocyte-converted

neurons by NeuroD1 in mouse brain can exhibit synaptic currents and integrate into

neural circuit in vivo [146]. In vitro direct reprogramming study of postnatal astrocytes showed that astrocyte-to-neuron conversion is swift, but different proneural

factors can elicit distinct transcriptional programs. Both Neurog-2 and Ascl1 rapidly

elicited neurogenic programs to induce glutamatergic and GABAergic neuronal

conversion but followed distinct paths with a few common genes in the neurogenic

cascades [145]. The study of shared target genes will allow identifying a particularly important subset of downstream targets capable of directly converting astrocytes into functional neurons.

Although, reactive astrocyte-to-neuron conversion by forced expression of transcription factors has not been reported in the context of strokes, these studies suggest that recruiting reactive astrocytes and directly converting them into neurons

might be a promising strategy for brain repair after ischemic stroke. Since reactive

astrocytes exhibit different proliferating rates at different times after FIS [68], there

might be an optimal timing to convert them into neurons using genetic manipulation

techniques such as astrocyte-specific inducible transgenic mice and viral transduction. Because stroke causes a large damage in the cortex, it is also interesting to

study whether reactive astrocytes in the cortex have the similar capacity of neuronal

transformation to striatal astrocytes. Future study is also needed to explore whether

any small molecular drugs targeting the signaling pathway of endogenous neuronal



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S. Ding



differentiation will facilitate astrocyte-to-neuron conversion [150, 151] and to determine whether astrocyte-derived neurons contribute to brain recovery and improvement of stroke outcomes.



3



Concluding Remarks



Despite tremendous investments in translational research, there are still limited

treatment options for stroke therapy. Tissue plasminogen activator (tPA) is the only

available FDA-approved drug for acute stroke treatment, but it is effective within a

narrow therapeutic window of a few hours after the onset of a stroke. Treatment of

a stroke is primarily dependent on supportive care, secondary prevention, and rehabilitation after the acute phase. tPA treatment is also associated with intracranial

bleeding. Although various mechanisms showing how ischemia leads to neuronal

death and brain damage have been identified using animal models, current neuroncentric strategies have not resulted in major breakthroughs in stroke therapy; therefore, alternative strategies to target astrocytes could be an important direction for

stroke therapy. Since astrocytes have intimate contact with neurons and vasculature

and undergo dynamic changes in Ca2+ signaling, morphology, proliferation, and

gene expression after ischemia, targeting reactive astrocytes is a promising strategy

for brain damage and repair after stroke. Knowledge regarding the dynamic changes

of function and signaling pathways that trigger reactive astrogliosis and facilitate

neuronal differentiation should provide information for effective strategies for ischemic brain therapy. Studies on genome-wide transcriptome profiles further provide

information for astrocyte-targeted therapeutic strategies for brain protection and

repair. However, as astrocytes exhibit heterogeneity in different regions, a comprehensive understanding of reactive astrogliosis is extremely vital to the designing

strategies to modulate reactive astrogliosis for brain repair. On the other hand, using

the stem-cell-like properties of reactive astrocytes, it is feasible to directly convert

them into neurons by expressing transcriptional factors. Thus, targeting astrocytes

for stroke therapy is an emerging and promising area.

Acknowledgments This work was supported by the National Institutes of Health [R01NS069726,

R01NS094539] and the American Heart Association [13GRNT17020004] to S.D.



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Microglia: A Double-Sided Sword in Stroke

Hong Shi, Mingyue Xu, Yejie Shi, Yanqin Gao, Jun Chen, and Xiaoming Hu



Abbreviations

CD200R

CNS

CX3CR1



CD200 receptor

Central nervous system

CX3C chemokine receptor 1



H. Shi

State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan

University, Shanghai, China

Department of Anesthesiology of Shanghai Pulmonary Hospital, Tongji University, Shanghai, China

e-mail: 13651958255@139.com

M. Xu • Y. Gao

State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan

University, Shanghai, China

Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine,

200 Lothrop Street, Pittsburgh, PA 15213, USA

e-mail: elune2009@126.com; yqgao@shmu.edu.cn

Y. Shi

Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine,

200 Lothrop Street, Pittsburgh, PA 15213, USA

e-mail: shiy3@upmc.edu

J. Chen • X. Hu (*)

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh,

Pittsburgh, PA, USA

State Key laboratory of Medical Neurobiology, Fudan University, Shanghai, China

e-mail: chenj2@upmc.edu; hux2@upmc.edu

© Springer International Publishing Switzerland 2016

J. Chen et al. (eds.), Non-Neuronal Mechanisms of Brain Damage

and Repair After Stroke, Springer Series in Translational Stroke Research,

DOI 10.1007/978-3-319-32337-4_7



133



134



H. Shi et al.



DCs

Gals

HMGB1

HSP

IFN-γ

IgSF

iNOS

KO

NO

Nox

NSC

OPC

pro-MMP-9

RAGE

ROS

SGZ

SVZ

TGF-β

TIMP-1

TNF-α

TREM

VEGF



1



Dendritic cells

Galectins

High-mobility group box 1

Heat shock protein

Interferon-gamma

Immunoglobulin superfamily

Inducible nitric oxide synthase

Knockout

Nitric oxide

NADPH oxidase

Neural stem cells

Oligodendrocyte progenitor cell

pro-matrix metalloproteinase-9

Receptor for advanced glycation endproducts

Reactive oxygen species

Subgranular zone

Subventricular zone

Transforming growth factor-β

Tissue inhibitor of metalloproteinases-1

Tumor necrosis factor-α

Triggering receptors expressed on myeloid cells

Vascular endothelial growth factor



Introduction



Microglia were first described by Pio del Rio Hortega as early as in 1919 [1].

Although the precise origin of microglia is still in debate up to date, it is commonly

accepted that the microglial progenitors are derived from the yolk sac. They migrate

into the central nervous system (CNS) during early embryogenesis and give rise to

microglia throughout the brain parenchyma [2, 3].

Microglia have multiple vital functions in the CNS. Under physiological state,

microglia display a ramified phenotype, characterized by a small cell body and

numerous branched processes. These so-called “resting microglia” actively survey

the surrounding environment and respond promptly to even subtle changes in the

CNS. When a microvascular or an isolated neuron is impaired, the surveying

microglia may offer structural and trophic support to them so that the normal functions could be preserved. Microglia also remove the sick individual neurons or other

CNS cells. These daily functions of microglia are called housekeeping activity,

which contributes to the maintenance of CNS homeostasis [1, 4–6]. Upon the noxious cues such as brain infection or injury, microglia expand their cell bodies and

retract their processes, becoming reactive microglia. These reactive microglia are

the first line of defense in the compromised brain. Due to the importance of microglia



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