Abstract
Hypoxic-ischemic brain injury is a significant cause of morbidity and mortality in the adult as well as in the neonate. Extensive pre-clinical studies have shown promising therapeutic effects of neural stem cell-based treatments for hypoxic-ischemic brain injury. There are two major strategies of neural stem cell-based therapies: transplanting exogenous neural stem cells and boosting self-repair of endogenous neural stem cells. Neural stem cell transplantation has been proved to improve functional recovery after brain injury through multiple by-stander mechanisms (e.g., neuroprotection, immunomodulation), rather than simple cell-replacement. Endogenous neural stem cells reside in certain neurogenic niches of the brain and response to brain injury. Many molecules (e.g., neurotrophic factors) can stimulate or enhance proliferation and differentiation of endogenous neural stem cells after injury. In this review, we first present an overview of neural stem cells during normal brain development and the effect of hypoxic-ischemic injury on the activation and function of endogenous neural stem cells in the brain. We then summarize and discuss the current knowledge of strategies and mechanisms for neural stem cell-based therapies on brain hypoxic-ischemic injury, including neonatal hypoxic-ischemic brain injury and adult ischemic stroke.
1. Introduction
Neural stem cells (NSCs) are self-renewing and multipotent cells. They hold the potential to differentiate into multiple cell lineages, such as the neuron, astrocyte, and oligodendrocyte. NSCs distribute throughout the developing brain and reside in two major neurogenic niches –subventricular zone (SVZ) and subgranular zone (SGZ) in the adult brain. After brain injury, the endogenous quiescent NSCs become active and participate in the process of brain repair. However, the self-repair process is usually inadequate and transient. Aiming to promote the neurorestorative process, the investigations of neural stem cell therapies on either enhancing endogenous neurogenesis or applying exogenous NSCs have remarkably surged during the last decade. In this review, we summarize the current knowledge about the neural stem cell therapy on hypoxic-ischemic (HI) brain injury, specifically neonatal HI brain injury and adult ischemic stroke.
2. Brief overview of NSCs in the brain development
The journey of neural development starts from the neuroepithelial (NE) cells, a group of pseudostratified cells lined the cerebral ventricles of the neural tube. NE cells are multipotential NSCs with two end feet, touching both the pial surface and the ventricular surface (Figure 1). Initially, NE cells self-renew and symmetrically divide to increase the number (Haubensak et al., 2004). This period is critical and affects the final thickness of the neocortex (Dehay et al., 2015; Sun and Hevner, 2014). As neurogenesis progresses, NE cells transform into radial glial (RG) cells, starting to express glial markers, such as astrocyte-specific glutamate transporter (GLAST) and glial fibrillary acidic protein (GFAP) (Gotz and Huttner, 2005; Kriegstein and Alvarez-Buylla, 2009). RG cells retain within the ventricular zone (VZ) and share some similar characteristics with NE cells, like long apical and basal processes. However, unlike NE cells, RG cells divide asymmetrically, producing one daughter RG cell and one intermediate neural progenitor cell (nIPC), which will differentiate into neurons. Some RG cells also become postmitotic neurons directly. Moreover, the process of RG cells like a scaffold guides the newly-born neurons to migrate out of the ventricular zone. Time-lapse imaging evidence has shown neurons move along the radial fiber of RG cells to their final location of the cortical plate (Noctor et al., 2004; Noctor et al., 2008). Another mitotic feature of RG cells, reserved from NE cells, is interkinetic nuclear migration (INM). In the cell cycle, the nuclear changes its position depending on the phase of cell cycle. During the G2 phase, nuclei move towards the apical surface, and on the opposite, they move basal ward in the period of G1 (Taverna and Huttner, 2010). INM has been proven an essential step to avoid overcrowd of RG cells and ensure normal brain histogenesis (Okamoto et al., 2013). The regulation of symmetric and asymmetric division has been extensively reviewed elsewhere (Homem et al., 2015; Jiang and Nardelli, 2016; Lui et al., 2011), and we only briefly discuss it here. The Notch signaling pathway is a critical regulator to determine the proliferative or differentiative state of RG cells. Oscillatory expression of Notch effector gene Hes1 exhibits in self-renewal RG cells, leading to maintenance of the progenitor identity (Shimojo et al., 2008). Conversely, diminish of this oscillatory expression by upregulating proneural factors cause neuronal differentiation (Imayoshi et al., 2013). Interestingly, intercellular communication between RG cells and differentiated daughter cells also participate in the regulation of cell fate, through the Notch signaling pathway. RG differentiated daughter cells express Notch ligands, e.g., Delta-like 1 (Dll1), which bind to Notch receptors of their neighbor RG cells and activate the Notch signal to maintain the undifferentiated status of RG cells (Dong et al., 2012; Homem et al., 2015; Nelson et al., 2013). Other intrinsic factors include β-catenin (Draganova et al., 2015; Masuda and Ishitani, 2017), Sox2 (Avilion et al., 2003; Hutton and Pevny, 2011), glycogen synthase kinase 3 (GSK-3) (Kim et al., 2009), etc. For example, conditional deletion of GSK-3 significantly increases proliferation of mouse neural progenitors, via dysregulation of the Notch/β-catenin signaling pathway.
Figure 1. Neural stem cells in the neural development.
During early development, Neuroepithelial (NE) cells divide symmetrically to expand the number of NE cells. This is followed by transform of NE cells into radial glial (RG) cells, which divide asymmetrically producing one daughter RG cell and one intermediate neural progenitor cell (nIPC). nIPCs differentiate into neurons, which then migrate along the radial processes of RG cells to the cortical plate. Some RG cells also directly generate neurons. Around birth, large parts of RG cells change its morphology, detach from the VZ, and finally convert to astrocyte. RG-derived oIPCs generate oligodendrocytes to participate in oligogenesis. In the adult brain, NSCs reside in SVZ, known as Type B cells. These cells generate intermediate progenitor cells (Type C cells) and then become neuroblasts (Type A cells). MZ, marginal zone; MA, mantle; SVZ, subventricular zone; VZ, ventricular zone; oIPC, oligodendrocytic progenitor cell
Epigenetic modifications, including DNA methylation, histone modification, and non-coding RNAs are important mechanisms in the regulation of neural development (Yao et al., 2016). An important class of non-coding regulatory RNAs, micro RNAs (miRs) dynamically express during neurogenesis with various functions. For instance, let-7 family continuously express, whereas miR-124 increases starting from the mid or late phase of development (Miska et al., 2004; Yao et al., 2012). Moreover, substantial evidence from loss- and gain- of function studies indicate that miRs play a critical role in both proliferation and differentiation of NSCs during the development. For example, downregulation of miR-145 decreased the expression of mature neuronal markers, suggesting a crucial role of miR-145 in neuronal differentiation of NSCs. This effect is mediated by the Sox2-Lin28/Let-7 pathway (Morgado et al., 2016). Besides intrinsic regulators, the neurogenesis process is also modulated by many extrinsic factors, such as Colony Stimulating Factor-1 (CSF-1) (Nandi et al., 2012), and fibroblast growth factor (FGF) (Dee et al., 2016). At the end of cortical development, most RG cells translocate towards the cortical plate and transform into astrocytes. Meanwhile, some RG cells differentiate into intermediate progenitor cells that become oligodendrocytes.
In the adult brain, NSCs or neural progenitor cells mainly persist in the SVZ, known as B cells. B cells give rise to transient amplifying C cells that then produce immature neuroblasts (A cells). Under normal condition, neuroblasts migrate toward the olfactory bulb (OB) through the rostral migratory stream (RMS). In the OB, these cells differentiate into mature interneurons (Carleton et al., 2003). Of note, B cells hold many properties of RG cells, like the process to the ventricular surface and expression of astroglial markers, e.g., GFAP and GLAST (Kriegstein and Alvarez-Buylla, 2009). However, different from RG cells, these NSCs in adult SVZ remain largely quiescent. Recent studies indicate that metabolic states are important cues to regulate adult NSC quiescent (Ito and Suda, 2014), including but not limited to hypoxia and glycolysis. For example, mitochondrial kinase mutation induces glycolysis and impedes neuronal differentiation of NSCs (Agnihotri et al., 2017). Furthermore, abundant extrinsic and intrinsic signals are involved in regulating adult neurogenesis (reviewed by Faigle and Song, 2013).
Another major region that NSCs persist in the adult brain is the subgranular zone (SGZ) of the dentate gyrus (DG). The radial astrocytes, also referred to type I cells, serve as NSCs that generate granule neurons in the SGZ. These type I cells give rise to intermediate progenitor cells (type II cells), and then progressively differentiate into mature neurons through the neuroblast phase (Feliciano et al., 2015; Kriegstein and Alvarez-Buylla, 2009).
3. Effect of hypoxic-ischemic brain injury on endogenous NSCs
3.1 Neurogenesis after neonatal hypoxic-ischemic brain injury
Hypoxic-ischemic (HI) injury remains one of most common causes of damage to the neonate’s brain. Neonatal HI brain injury occurs in 1–4 cases per 1,000 live births in the United States and accounts for about one-fourth neonatal deaths worldwide (Kurinczuk et al., 2010; Lawn et al., 2010). Of survived newborns, more than one million children develop severe and chronic neuropsychological impairments, including cerebral palsy and epilepsy, motor and cognitive deficits (Fernandez-Lopez et al., 2014; Gonzales-Portillo et al., 2014). The common reason for perinatal hypoxic brain injury is intrauterine asphyxia due to circulatory problems, including placental abruption, placental arterial clotting, and inflammatory processes (Fatemi et al., 2009). Moreover, it is worth to note that fetal stress that is a common consequence of gestational complications (e.g., hypoxia, diabetes, smoking, preeclampsia, infection) significantly increase the vulnerability of neonatal hypoxic-ischemic brain injury (Fajersztajn and Veras, 2017; Li et al., 2012).
Upon HI attack, oxygen and glucose supplies to the neonatal brain are transiently depleted, which causes an energy failure or energy-inefficient state and is regarded as the primary insult. This attack initiates a cascade of deleterious cellular events involving dysfunction of transcellular ion pumping and accumulation of excitatory glutamate and oxygen free radicals (Perlman, 2006; Yildiz et al., 2017). After transient resuscitation, secondary injuries may follow, which include inflammation, mitochondrial dysfunction, and cell death (Johnston et al., 2001; Perlman, 2006; Vannucci, 2000). To explore the pathophysiology of neonatal HI brain injury, several animal models have been developed during last decade (Yager and Ashwal, 2009). Among them, Rice-Vannucci model (Levine, 1960) is the most well-accepted, including unilateral common carotid artery ligation and subsequent hypoxic (8–10% O2) treatment. Using these models, studies have revealed several unique features of neonatal HI brain injury, which may relate to the immature nervous system. The immature brain has a limited activity of antioxidant enzymes (e.g., glutathione peroxidase, copper-zinc superoxide dismutase) around birth (Sheldon et al., 2004). Thus, the neonatal brain is more susceptible to oxidative damage caused by HI injury (Sheldon et al., 2004). Moreover, a “continuum” phenotype of cell death, hybrid features of apoptosis and necrosis, exist in the injured neonatal brain (Northington et al., 2007). Next, we will first focus on the response of endogenous NSCs to HI injury in the neonatal brain.
In the neonatal rat, severe brain HI insult was initially reported to delete 20% of total cells in SVZ within few hours, and the size of SVZ becomes smaller three weeks later (Levison et al., 2001). However, following studies have shown that not all the types of cells are affected by acute HI injury. Only the cells localized in the lateral area of SVZ suffer apoptosis, while cells within the medial SVZ resist HI injury. Calpain and caspase 3 are reported to participate in this apoptosis process (Romanko et al., 2007). The increased activity of Calpain occurs as early as four hours after HI, following by caspase 3 activation four hours later (Romanko et al., 2007). In vitro study indicates that B-cell lymphoma 2 (BCL-2)/adenovirus E1B 19 kDa interacting protein-3 (BNIP3) is another pathway involved in hypoxia-induced NSC/NPC apoptosis and is independent of caspase activity (Walls et al., 2009). Phenotype study showed that PSA-NCAM positive neuroblasts that locate in the lateral area of SVZ are vulnerable to HI; however, nestin-positive neural stem/progenitor cells resist to HI and close to the lateral ventricle (Romanko et al., 2004). One of the possible reasons for this phenomenon is that medial SVZ NSCs reside in the neurogenic niche that is normally an area of physiologic hypoxia. And hypoxia is the factor to keep NSC proliferation. So NSCs in this area may adapt the hypoxic environment and are more resistant to HI insult.
Different from the previous report, Jennifer Plane et al. demonstrated that HI injury on postnatal day 10 (P10) mice obviously enlarged the ipsilateral SVZ and significantly increased the cell proliferation three weeks after HI (Plane et al., 2004). This study further indicates that ectopic striatal migration of neuroblasts and neurogenesis in the ipsilateral striatum post-HI injury. Similar results in rat neonatal HI model are reported by Takeshi Hayashi et al.(Hayashi et al., 2005). Hypoxic-ischemic injury increases cell proliferation in both ipsilateral cortex and striatum, and phenotype study indicates these dividing cells are not only doublecortin (DCX) positive neuroblasts but also GFAP/Neural/glial antigen 2 (NG2) positive glial cells (Hayashi et al., 2005). These studies suggest that HI injury-induced proliferation of SVZ NSCs participate in both neural replacement and gliosis. Furthermore, tissues isolated from ipsilateral SVZ suffered a moderate HI injury can generate more tripotential neurospheres in vitro, which prefer to differentiate into neurons and oligodendrocytes (Felling et al., 2006; Yang and Levison, 2006). A more recent study, using novel multimarker flow cytometry, analyzed the population change of SVZ NSCs after HI injury in vivo (Buono et al., 2015). Interestingly, multipotential progenitors (MPs) and glia-restricted progenitors (GRPs), instead of NSCs, remarkably increase 48 h after HI. This finding may partly explain the reason for gliogenesis after neonatal HI injury. However, some fundamental questions remain unanswered, such as the relationship between migrated neuroblasts and dividing glial progenitors on brain recovery after neonatal HI injury.
At present, it is clear that neuroblasts migrate to the striatum/cortex, and some glial progenitor cells surround the HI-affected brain. The next question is whether the migrated neuroblasts or newly born neurons survive in the HI-affected area. So far, it is still a controversy about the fate of newly born neurons. Jennifer Plane et al. have shown that newly generated striatum neurons cannot survive for two weeks (Plane et al., 2004). While, others reported that such neurons, with 5-bromo-2′-deoxyuridine (BrdU)+ and Rbfox3(NeuN)+, still exist in striatum or cortex five weeks after the injury (Felling et al., 2006; Yang et al., 2007). However, most of the newly formed neurons (about 85%) induced by injury die before maturation, even though some of them could survive for five weeks (Yang et al., 2007). Thus, understanding the reasons for the death of newly born neurons will be necessary for future studies.
One serious issue that needs to pay attention to in animal HI study or translational clinical study is the severity of HI injury. The disparate observations on NSC response to injury and cell survival between studies could be due to the differences in the severity of HI injury. For example, 45 mins 10% oxygen treatment was used to induce hypoxia in P10 CD-1 mice in Jennifer Plane et al. study, while 90 mins 8% oxygen was reported to apply on P6 rats in the study of Ryan Felling et al. Therefore, the relationship between the severity of HI and NSC response remains to be explored. And how to quantify the severity and to predict the NSC response based on the level of severity are the important questions that warrant the further investigation.
Beside NSCs in SVZ, NSCs within dentate gyrus subgranular zone (SGZ) also respond to neonatal HI injury. Similar to the studies of SVZ, committed type 2b and type 3 (DCX positive) neural progenitors in SGZ are vulnerable to HI injury, leading to cell apoptosis at 24 h after HI (Kwak et al., 2015; Miles and Kernie, 2008). However, nestin-positive type 1 and type 2a neural stem/progenitors not only resist acute injury but also actively proliferate, following by long-term neuronal restore (Miles and Kernie, 2008).
3.2 Neurogenesis after adult ischemic stroke
Stroke is still the leading cause of adult chronic disability, and the fifth leading cause of death in the United States (U.S.), which kills more than 130,000 Americans each year (Benjamin et al., 2017). Of the 6 million Americans who are stroke survivors, 71% are unable to return to work. About $36.5 billion are spent due to stroke every year (Benjamin et al., 2017; Howard and Goff, 2012). Currently, the treatments for stroke are insufficient. Tissue plasminogen activator (tPA) is still the only FDA-approved drug for acute ischemic stroke. In addition to tPA, emerging evidence has shown that endovascular therapy is beneficial and promising (Cougo-Pinto et al., 2015). However, only a small portion of stroke patients can benefit from these treatments due to the narrow therapeutic time window and the strict therapeutic criteria that are uneasy to fulfill (Cougo-Pinto et al., 2015). Meanwhile, most of the survivors cannot fully complete neurological and functional recovery and have to face several obstacles to normal life, even after the utility of long-term rehabilitation (Qureshi et al., 2013).
Like neonatal HI injury, lack of blood supply triggers a serial of pathophysiological events leading to neural cell death after ischemic stroke. The mechanism includes excitotoxicity, mitochondrial dysfunction, protein misfolding, oxidative stress and inflammatory response (George and Steinberg, 2015). Although these pathways are first recognized as the detrimental effects in the development of neural injury, some of the pathways have also been proven beneficial for brain recovery, such as neurogenesis (George and Steinberg, 2015; Hao et al., 2014). Next, we will discuss the response of endogenous NSCs to ischemic stroke.
From early 2000s, the increasing evidence indicates the existing of post-stroke cell proliferation in SVZ (Jin et al., 2001; Parent et al., 2002; Zhang et al., 2001), SGZ(Jin et al., 2001; Yagita et al., 2001), heavily relied on the technique of 5 -bromo-2′-deoxyuridine (BrdU) staining. Moreover, this cell proliferation in SVZ and SGZ starts from 2–5 days after stroke and lasts for about 30 days, with a peak on day7–8 post-ischemia (Yagita et al., 2001; Zhang et al., 2001). Stroke also causes the changes of NSC dividing pattern from asymmetric to symmetric (Zhang et al., 2004). Most of the BrdU-positive proliferating cells in SVZ are DCX-positive neuroblasts, none or few of them are mature neurons. Interestingly, DCX positive cells are also observed in the ipsilateral striatum (Arvidsson et al., 2002; Jin et al., 2003) and cortex (Jin et al., 2003) after stroke. This phenomenon raises a new question about the resource of neuroblasts outside the neurogenic area. Do they generate locally or migrate from the existing neurogenic niche after stroke? Proof of evidence has been demonstrated that the dividing neuroblasts migrate out from SVZ to the ipsilateral striatum and peri-infarct area (Arvidsson et al., 2002; Parent et al., 2002, Yamashita et al., 2006). More interestingly, the SVZ-derived neuroblasts could further differentiate into neurons and form synapses (Yamashita et al., 2006). Taking advantage of in vivo tracking and transgenic mouse, we now know that DCX-positive cells can move at an incredible speed of 17.98 ± 0.57 μm/h out of SVZ following ischemia (Zhang et al., 2009). Such migration mainly follows existed Rostral Migratory Stream (RMS) and is close to microvasculature (Thored et al., 2007). And some of the migrating neuroblasts change their direction to ipsilateral striatum or cortex, rather than chain migration to the olfactory bulb in the normal brain. It is still debated whether such migration to stroke-affected area expenses the cells whose original target of movement is OB. Studies have also shown that stromal cell-derived factor-1 (SDF-1) is the main regulator for neuroblast migration, through the chemokine(C-X-C motif) receptor 4 (CXCR4) (Kokovay et al., 2010; Thored et al., 2006). Even though dividing neuroblasts migrate to the stroke-affected area and try to replace the lost neurons, most of them die in about two weeks. The reason remains elusive and may be due to the un-health post-ischemic environment. Brain ischemia initiates an inflammatory cascade, such as microglial activation, immune cells infiltration and the release of toxic proinflammatory molecules (Tobin et al., 2014). Inflammation not only leads to neuron death but also affects the neurogenesis and survival of newly born neurons. Several lines of evidence indicate that microglial activation associated with inflammation disrupts the neurogenesis in the hippocampus (Monje et al., 2003), and proinflammatory factor interferon-γ (IFN-γ) increases apoptosis of cultured NSCs (Ben-Hur et al., 2003). Moreover, a recent study demonstrates that deletion of circulating monocytes after stroke improves the short-term survival of newly formed neuroblasts in SVZ (Laterza et al., 2017). Besides neuroblast, some studies indicate that many of the migrated neural progenitor cells give rise to reactive astrocytes and participate into the astrogliosis after stroke (Li et al., 2010). It may be a good way to prevent the extension of inflammatory factors from infarction in the acute phase of stroke. While, the role of gliosis after stroke, especially its long-term effect, is still elusive and needs further investigation.
A clear conclusion about endogenous post-stroke neurogenesis is that although the period of SVZ cell proliferation seems short, this process is critical for stroke recovery. Transgenic ablation of SVZ neuroblasts increases brain infarction and worsens the stroke-caused behavioral deficits (Jin et al., 2010b). In addition, conditional delete of neural progenitor cells impedes the cognitive function and reduces synaptic connectivity after stroke (Sun et al., 2013a). Furthermore, it should be noted that most of the studies mentioned above used young adult animals. However, over 80% of strokes occur in the elderly. Thus, age should be an important factor to be considered when studying neurogenesis after stroke. Indeed, aging reduces SVZ cell proliferation and migration of neuroblasts after stroke, even though neurogenesis is still observed (Moraga et al., 2015).
Post-stroke neurogenesis was also proved in human brains through the study of immunostaining on the brain specimens of stroke patients (Jin et al., 2006; Nakayama et al., 2010). Proliferated neuroblasts or newly-born neurons were found in the ischemic penumbra area of cortex, and some of them seem under migration 30 days after stroke (Jin et al., 2006). In addition, Nakayama et al. (2010) have shown that nestin-positive cells exist in the post-stroke cortex from as early as one day after stroke, and disappear after three months. Nonetheless, many questions remain to be verified on human post-stroke neurogenesis, due to the limitation of patient samples and a shortage of available in vivo technologies. For example, the duration and location of post-stroke NSC proliferation remain unclear, as well as the resource of newly generated neurons in the cortex.
4. NSC-based therapy for hypoxic-ischemic brain injury
4.1 Exogenous NSC transplantation
4.1.1 NSC transplantation in neonatal HI brain injury
Although endogenous NSCs have the self-repair ability after brain injury, it is usually insufficient and needs time to proliferate and migrate to the lesion area. Therefore, transplantation of exogenous NSCs is probably a more efficient way to improve the brain restore after injury. Moreover, in vitro cultured NSCs have the potential of self-renewal and differentiation to neuronal or glial cells. No matter the neural stem cells are derived from embryonic stem cells or isolated from fetal brains, substantial pre-clinical evidence has indicated that neural stem cell transplantation is efficient and effective for treating neonatal hypoxic-ischemic brain injury (Table 1).
Table 1.
Neural stem cell transplantation in neonatal H/I injury model
| Route | Timing of transplantation | Cell Type/Modification Human NSCs | Dose | Species | Model | Major finding | Reference |
|---|---|---|---|---|---|---|---|
| Intracerebral | 24h | 3.0×105 | SD rat (P7) | RVM (8%O2) 90mins | Improving motor function recovery; Axonal sprouting enhancement | (Daadi et al., 2010) | |
| 48h | NPC(from ESC) | 2.5×105 | ICR mouse (P2) | RVM (8%O2) 20mins | Improving motor function recovery; Enhancing axonal outgrowth | (Shinoyama et al., 2013) | |
| 72h | Mouse NSCs | 5.0×105 | SD rat (P10) | RVM (8%O2) 90mins | NSC migration to lesion; Survived for 58weeks after HI | (Obenaus et al., 2011) | |
| 72h | Rat NSCs (from fetal brain) +enhanced VEGF expression | 1.0×105 | SD rat (P7) | RVM (8%O2) 120mins | Reducing neuronal apoptosis; Increasing angiogenesis | (Zheng et al., 2012) | |
| 7 d | Human NSCs (fetal brain) +enhanced Neurog2 expression | 9.6×105 | ICR mouse (P7) | RVM (8%O2) 90mins | Improving sensorimotor function recovery; Increasing neural plasticity | (Lee et al., 2017) | |
| 10 d | Mouse NSCs (from fetal brain) | 1.0×105 | C57Bl/6 mouse (P9) | RVM (10%O2) 45mins | Reducing infarct volume; Improving motor function recovery | (Braccioli et al., 2017) | |
| Intracerebro- ventricular (i.c.v.) | 2h | Mouse OPCs (Derived from mESCs) | 2.5×105 | Rat (P3) | RVM (6%O2) 150mins | Improving motor function recovery; | (Chen et al., 2015) |
| 24h | Rat NSC (from fetal brain)/+ChABC | 2.5×105 | SD rat (P7) | RVM (8%O2) 120mins | Reducing infarct volume | (Sato et al., 2008) | |
| Intranasal | 24h | Human NSCs | 3.0×105 | SD rat (P7) | RVM (7.8%O2) 120mins | Reducing infarct volume; Improving sensorimotor function recovery; Suppressing inflammation | (Ji et al., 2015) |
Abbreviation in the Table: RVM: Rice-Vannucci model; NSCs: Neural Stem Cells; ESCs: Embryonic Stem Cells; OPCs: Oligodendrocyte progenitor cells
4.1.1.1 Effect of NSC transplantation
The first question that all the studies of stem cell transplantation is whether stem cell therapy can reduce brain infarction and behavioral deficits. Indeed, several studies have shown that NSC transplantation significantly reduces HI-induced lesion volume in the acute and subacute phase (Sato et al., 2008) and the brain loss in the chronic phase of brain HI injury (Braccioli et al., 2017). However, the change in brain lesion volume is not always correlated with the improvement of behavioral functions. For example, although there is no significant difference on the change of infarct size after NSC treatment, an apparent improvement in sensorimotor functions have been observed in the NSC treated group compared to the vehicle group (Daadi et al., 2010). Thus, another important factor to evaluate the impact of NSC transplantation is the recovery of behavioral functions, such as sensorimotor, cognitive functions. The improvement of sensorimotor functions evaluated by cylinder test, beam walking test, and rotorad test has been shown 30 days after NSC transplantation treatment (Daadi et al., 2010; Shinoyama et al., 2013). Similarly, a delayed NSC treatment study has reported that this behavioral improvement can even last for about two months after NSC transplantation (Braccioli et al., 2017). Using T-maze and Morris water maze tests, NSC transplantation has also indicated the better recovery in the capability of spatial memory in a neonatal cerebral HI model one month after the cell treatment (Ji et al., 2015; Zheng et al., 2012). In addition to the reduction of infarction and improvement of behavioral functions, NSC treatment also attenuates neuroinflammation after HI injury. The HI-induced activation of microglia (Braccioli et al., 2017) and upregulation of pro-inflammatory factors (e.g., interleukin-1β (IL-1β) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)) (Ji et al., 2015) are reduced after NSC transplantation. Furthermore, engrafted NSCs participate into the remodeling of neuroplasticity, as the evidence of axonal growth has been noticed after NSC transplantation (Daadi et al., 2010; Shinoyama et al., 2013).
4.1.1.2 Methodologies of NSC transplantation
Source of NSCs
Both human and animal NSCs have been evaluated in pre-clinical studies (Daadi et al., 2010; Ji et al., 2015; Lee et al., 2010; Zheng et al., 2012), aimed to test the efficacy of NSC therapy for neonatal brain HI injury. Mouse and rat NSCs can be generated from fetal brain tissues (E14-16) (Sato et al., 2008) and grow as neurosphere. Another way to obtain animal NSCs is to derive them from animal embryonic stem cell (ESC) line with or without genetic modification (Shinoyama et al., 2013). Similarly, human NSCs can be derived from human ESC line (Daadi et al., 2010). More importantly, these ESC-derived NSCs have been proved safe for transplantation, as they do not form tumors after transplanted into normal nude animals (Daadi et al., 2008). Meanwhile, brain tissues of human fetal cadaver that involved neurogenic area (like SVZ) are another resource for acquiring hNSCs (Ashwal et al., 2014). Although all of these NSCs have been reported the neuroprotective role for neonatal HI treatment, there is no direct comparison between the efficacies of NSCs generated from different sources yet. Therefore, it is still difficult to conclude which type (s) of NSCs are the most efficient for the NSC therapy. For better translating NSC therapy to clinical studies, many variables need to be compared with the two kinds of human NSCs, like the safety, the immune response in the host environment, the accessibility and the operability.
Route of NSC transplantation
Up to now, intracerebroventricular (i.c.v), intracerebral (cortex or hippocampus) and intranasal deliveries of NSCs have been reported in the pre-clinical studies (Ashwal et al., 2014; Ji et al., 2015; Sato et al., 2008; Zheng et al., 2012). Engrafted NSCs distribute around the lateral ventricle and are close to the lesion area 7 days after i.c.v transplantation (Sato et al., 2008). Although such cell treatment reduces the lesion volume, it remains unclear that how many engrafted cells migrate to the lesion and the long-term effect of this therapy. Four weeks after intracerebral injection of NSCs, engrafted cells survive, and about 40% of them differentiate into mature neurons (Daadi et al., 2010). Moreover, NSCs successfully distribute to the ipsilateral hemisphere and survive for 42 days after being intranasal administrated (Ji et al., 2015). Due to lack of system comparison on the efficiency of delivery routes, we still do not know which method(s) is ideal for the clinical application. However, intranasal administration is less invasive than intracerebral and i.c.v injection. Comparing to the latter ones, if the intranasal treatment has proved the similar therapeutic effect, it will be a more acceptable and practical way to perform the cell therapy in the clinical study.
Timing of NSC transplantation
Timing is a critical factor in designing and performing stem cell therapy, as HI-induced brain injury is dynamically changed. However, it is never straightforward to find the optimized time point for cell transplantation, due to the complexity of the pathogenic process of the disease. Most reported pre-clinical studies selected 24 hours after HI injury as the time point to transplant NSCs (Daadi et al., 2010; Ji et al., 2015; Sato et al., 2008). The possible reason is to avoid the acute excitotoxicity and inflammatory reaction after brain injury. However, human NSC transplantation 24 hours after HI increased microglial accumulation around the injection site in the previous study (Daadi et al., 2010). But it is unclear whether or not these increased microglia cause death of engrafts. A recent study indicates that delayed transplantation of NSCs (10 days after HI) still improves long-term functional recovery and reduces brain loss (Braccioli et al., 2017). This suggests that the therapeutic time window for NSC transplant may be wider than previously thought, probably due to the high plasticity of the neonatal brain. Further studies are needed to explore the optimized timing for NSC transplantation for neonatal HI brain injury.
Dosage of NSC transplantation
Dosage is another factor that should be considered to perform the cell transplantation. A low dose may be not effective to rescue the brain damage, whereas a too high dose may cause side effects, such as forming cell clots. Unfortunately, there is no study yet to test the dose-dependent effect of NSC transplantation on neonatal HI injury. The dosage selected in the reported pre-clinical studies probably based on their pilot studies, ranging from a total of 1 ×105 to 3 ×105 cells. Even though these dosages have been reported effective for neuroprotection, it is difficult to get an ideal dosage based on previous studies. Because various transplantation parameters, e.g., timing, delivery route, and animal model, will impact the effective dosage, it is necessary to optimize the dosage in certain scenario of cell transplantation.
4.1.2 NSC transplantation in adult ischemic stroke
NSC therapy for the treatment of stroke in the adult has been much more widely investigated, compared to NSC therapy in neonatal HI injury. More than two hundred publications were published in the past decades. NSC transplantation is no doubt beneficial for reducing infarct volume and behavioral deficits caused by stroke. Indeed, a recent meta-analysis and systematic review analyzes the effect of preclinical NSC transplantation on stroke and indicates favorable outcomes of NSC therapy in the stroke treatment (Chen et al., 2016). In the following section, we will discuss the methodology and underlying mechanisms of NSC therapy for stroke (Table 2), providing a rationale for future translational studies.
Table 2.
Representative experimental studies of neural stem cell transplantation for adult ischemic stroke
| Route | Timing of transplantation | Cell Type/Modification NSCs derived from human iPSCs | Dose | Species | Model | Major finding | Reference |
|---|---|---|---|---|---|---|---|
| Intracerebral | 0h | 1.0×106 | SD rat | tMCAO 120mins | Improving motor function recovery; | (Yuan et al., 2013) | |
| 24h | Mouse NSCs (from fetal brain) | 1.0×106 | SD rat | tMCAO 120mins | Improving motor function recovery; Increasing neurogenesis and angiogenesis | (Tang et al., 2014) | |
| 24h | Human CTX0E03 cell line | 8.0×105 | SD rat | tMCAO 70mins | Improving sensorimotor function; engrafts are not tumorigenic | (Pollock et al., 2006) | |
| 24h | Human NSCs (derived from ESCs) | 1.0×106 | C57BL6 Mouse | tMCAO 60mins | Engrafted NSC rapidly migrate to infarct area, reducing inflammation | (Huang et al., 2014) | |
| 7d | NSC derived from human iPSCs | 1.0×105 | C57BL6 Mouse | tMCAO 30mins | Improving function recovery; generating mature neuron | (Oki et al., 2012) | |
| 7d | Human NSCs (derived from ESCs) | 1.0×105 | SD rat | tMCAO 90mins | Grafts differentiate into neuron, oligodendrocytes, and form neural connectivity | (Daadi et al., 2009) | |
| 7d | Human NSCs (Isolated from fetal brain tissue) | 1.0×105 | SD rat | dMCAO | Engrafts survive, migrate to the lesion, and express the immature neuronal marker | (Kelly et al., 2004) | |
| Intracerebro ventricular (i.c.v.) | 24h | mouse NPCs (Isolated from fetal brain tissue) | 3.6×105 | SD rat | tMCAO 60mins | Engrafts migrate towards the lesion tissue and express the immature neuronal marker | (Jin et al., 2005) |
| Intraarterial | 6h, 24h, 72h, | Mouse NSCs (from fetal brain) | 5.0×105 | C57BL6 mouse | Hypoxia-ischemia stroke (8%O2) 20mins | Transplantation at 72h yield highest cell survival | (Rosenblum et al., 2012) |
| 24h | Mouse NSCs (from fetal brain) | 5.0×105 | Nude mouse | Hypoxia-ischemia stroke (8%O2) 30mins | IA is a superior delivery route vs. IV infusion. | (Pendharkar et al., 2010) | |
| Intravenous | 72h | Mouse NPCs | 1.0×106 | C57B L6 mouse | tMCAO 45mins | NPC engrafts modulating axonal rewiring and dendritic plasticity; and improving long-term functional recovery. | (Bacigaluppi et al., 2016) |
| 24h, 28d | Mouse NPCs (Isolated from adult SVZ) | 1.0×106 | C57B L6 mouse | tMCAO 30mins | Cell delivery at acute phage stabilizes BBB and modulate immune response; at chronic phage stimulates neurogenesis | (Doeppner et al., 2014) |
Abbreviation in the Table: NSCs: Neural Stem Cells; NPCs: neural progenitor cells; ESCs: Embryonic Stem Cells; iPSCs: induced pluripotent stem cells; tMCAO: transient middle cerebral artery occlusion; IA: intra-arterial; IV: intravenous; SD: Sprague Dawley; SVZ: subventricular zone
4.1.2.1 Transplantation methodologies
Source of NSCs
Four primary sources of NSCs can be used in the treatment of stroke: 1) NSCs generated from fetal brains; 2) NSCs derived from ESCs (ESC-NSC); 3) immortalized neural precursor cells; 4) induced pluripotent stem cell-derived NSCs (iPSC-NSC). NSCs generated from fetal brains, and ESCs are the most widely used for pre-clinical studies. These NSCs have the potential for proliferation and neuronal differentiation in vitro. After being transplanted, they rapidly migrate to the infarcted area, leading to a reduction of neuronal apoptosis and improvement of behavioral function (Huang et al., 2014; Jin et al., 2010a). About 40 – 60% of engrafted NSCs differentiate into neurons (Takagi et al., 2005). Immortalized neural precursor cells, like CTX0E03 (Pollock et al., 2006) and HB2.F3 cells (Chang et al., 2013), are neural precursor cells with an incorporated immortalizing oncogenes. Preclinical studies have shown the neuroprotective effect by transplanting these cells, and they have been used in ongoing type I clinical trial (Irion et al., 2017). Compared to other types of NSCs, iPSC-NSCs have their unique advantage. Firstly, iPSC-NSC transplantation remarkably reduced behavioral deficits after stroke (Eckert et al., 2015; Oki et al., 2012). Moreover, these cells can be generated from stroke patients’ own skin fibroblasts, which eliminate the immune rejection and ethical concern. Human iPSC-NSCs can differentiate into mature neurons with electrophysiological activity and can survive for at least four months in the brain of animal stroke models. In addition, there is no tumor formation during this period (Oki et al., 2012). Although iPSC-NSCs are promising, one pitfall is that the process of iPSC-NSCs can be time-consuming. However, this could be overcome with the rapid technological development of iPSC culture.
Route of NSC transplantation
Intracerebral, intravascular and intracerebroventricular transplantation of NSCs have all been investigated and confirmed the positive functional improvement after stroke. However, it remains unclear which one is the optimal route for NSC transplantation. It may depend on the situation of stroke, like topology of brain lesion and stroke subtype. More NSCs are generally distributed into the infarcted area by intracerebral delivery, compared to intravascular injection. This is the reason why most of the pre-clinical studies have selected this delivery route. However, caution should be observed when translating this to clinical study because intracerebral delivery is invasive and raises the risk of several adverse events, e.g., seizure (Savitz et al., 2005). Considering intravascular delivery, intra-arterial has been proven more efficient than intravenous administration. A systematic comparison of intra-arterial and intravenous delivery has demonstrated that most of the NSCs are trapped in the lung after intravenous injection. In contrast, about 93% NSCs are distributed into the brain following intra-arterial injection (Pendharkar et al., 2010). However, a safety issue of intra-arterial cell delivery is the possibility of forming microemboli, which could cause micro-strokes. But this issue could be avoided by optimizing injection paradigms, like speed of cell infusion and appropriate blood flow. For example, micro-stroke has not been observed with a microneedle injection technique without slowing down the anterograde blood flow (Chua et al., 2011).
Timing of NSC transplantation
Selecting a reasonable time point is another essential step to design cell therapy. The timing chose in preclinical studies vary widely from 6 hours to 6 weeks. However, few studies have directly addressed the question of optimal transplantation timing with cell survival. Intra-arterial NSC transplantation 72 hours after stroke results in highest cell brain distribution and less host immune response, compared to the transplantation 7 or 14 days after stroke (Rosenblum et al., 2012). Similarly, NSCs survive better with early (48 hours post stroke) intrastriatal transplantation than late (6 weeks) transplantation (Darsalia et al., 2011). Thus, it appears that 2–3 days after stroke would be optimal for the NSC treatment, which should avoid post-stroke abundance of excitotoxic molecules and acute inflammatory response in the host environment. Moreover, timing of NSC transplantation has the distinct effects on the fate of engrafted NSCs. NSCs prefer to differentiate into glial cells if they are intravenously delivered in the acute phase (less than 24 hours after stroke); conversely, delayed transplantation enhances the neuronal differentiation (Doeppner et al., 2014; Rosenblum et al., 2012).
4.1.2.2 Potential mechanisms of brain repair
Cell replacement
The initial goal of NSC therapy for stroke was to replace the dying neurons. Although the engrafted NSCs can differentiate into mature neurons and some of them have electrophysiological property (Daadi et al., 2009; Oki et al., 2012), the overall number of survived engrafts are far less than the number of lost neurons caused by stroke. Mounting evidence indicates that host immune response and inflammation status influence the survival of grafts. In vitro studies have shown that exposure of NPC to IFN-γ upregulates its expression of major histocompatibility complex (MHC) antigen (Hori et al., 2003; Kim et al., 2006). In addition, inflammatory cells (e.g., macrophage, microglia) cluster around the implantation site of exogenous NSCs in mouse brain (Buhnemann et al., 2006; Kim et al., 2006), while such cluster is not observed in the brain of immunocompromised nude mouse (Kim et al., 2006). Beside immune response, there are probably other mechanisms that cause apoptosis/cell death of grafts, as the application of immunosuppression agents could not completely reverse the death of grafts (Buhnemann et al., 2006). For example, the abundance of reactive oxygen species after stroke may be another threaten, as genetically modifying NSC to overexpress antioxidant enzyme, Cu/Zn-superoxide dismutase(SOD1), increases graft survival in the ischemic brain (Sakata et al., 2012a). Another possible reason is the loss of cell-cell connection, as single cells are usually prepared for transplantation. A recent study demonstrates that cell-cell contact enhances survival and neuronal differentiation of cultured NSCs (Jiao et al., 2017). Such interaction increases the expression of gap junction and, more importantly, enhances the support of neurotrophic factors from each other (Jiao et al., 2017). However, NSC treatment induced beneficial impact of behavioral function lasts for an extended period, even when the engrafted NSCs were insufficient to replace cell loss or most of them disappeared (Rosenblum et al., 2015). This suggests that cell replacement only takes a small part of the therapeutic mechanism of NSC transplantation. Indeed, the previous study by Borlogan et al. provided a new notion that neuroprotective effect of stem cell therapy does not require the engrafted cells to physically pass the blood-brain-barrier and enter the brain (Borlongan et al., 2004). Consistent with this concept, a recent study has shown that only conditioned medium from cultured neural progenitor cells is sufficient to reduce the infarct volume and improve behavioral recovery after stroke (Doeppner et al., 2017).
Moreover, the neuronal differentiation rate of engrafted NSC after stroke varies from 10% to 60% (Buhnemann et al., 2006; Daadi et al., 2009; Sakata et al., 2012a). In addition to neurons, grafts are able to differentiate into glial cells, including astrocyte, microglia, oligodendrocytes in vivo (Rosenblum et al., 2012; Sakata et al., 2012b). Both cell-intrinsic factors and extrinsic factors (e.g., host environment, transplantation strategy, cell-cell interaction) could affect the fate of grafts. For example, early transplantation of NSC is prone to astrocytic differentiation but later transplantation is prone to neuronal differentiation (Rosenblum et al., 2012). Furthermore, evidence shows that astrocytes negatively regulate hippocampus neurogenesis in an entorhinal cortex injury model (Wilhelmsson et al., 2012). Thus, it is highly possible that the neuronal differentiation of grafts is hindered by reactive astrocytes after stroke. However, the underlying mechanism of grafted NSC differentiation in ischemic brain and how to precisely guide the differentiation are still elusive, which warrant further investigation.
Immunomodulation
We have shown that post-stroke inflammatory response is significantly reduced after NSC transplantation, and the activation of microglia is also suppressed by engrafted NSCs (Huang et al., 2014). In line with our findings, several studies have confirmed the role of NSCs in immunomodulation after stroke, with downregulation of pro-inflammatory factors and activity of immune cells (Doeppner et al., 2013; Doeppner et al., 2014).
Bystander effect
The bystander effect is a currently well-accepted concept for explaining the neuroprotective effect of stem cell transplantation. It means that engrafted NSCs can either release growth and neurotrophic factors by themselves or stimulate host cells upregulating expression of such factors. There is substantial evidence that cultured NSCs can secrete multiple trophic factors, such as BDNF, VEGF, and EGF (Hicks et al., 2013). Moreover, human iPSC-NSCs increase VEGF expression of host astrocytes and promote angiogenesis after being transplanted into striatum of stroke mouse (Oki et al., 2012).
Accelerating endogenous recovery
Although the spontaneous post-stroke neurogenesis is inadequate to repair the injured brain, the natural self-repair activity occurs as early as few days after stroke. The possibility of enhancing endogenous neurogenesis has been the focus of pre-clinical stroke studies. Expectedly, several NSC translational studies observed that exogenous cell administration has a consistent impact on the endogenous neurogenesis (Jin et al., 2011; Park et al., 2010; Zhang et al., 2011). One possible explanation for the effect of stimulating endogenous neurogenesis is the bystander effect of cell treatment. However, it seems that the delivery route also has an effect. Intracerebral, instead of intravascular, injection of NSCs promote host cell proliferation in the SVZ (Minnerup et al., 2011). Except for neurogenesis, NSC transplantation has been proven to secrete angiogenic factors, thereby promoting host angiogenesis or vasculogenesis (Hicks et al., 2013; Zhang et al., 2011). Meanwhile, stroke mostly occurs in the elderly, so the effect of NSC treatment in aged stroke animals may be more clinically relevant. Some studies have shown that NSC transplantation greatly enhances the neurogenesis and angiogenesis in both young and aged animals (24-month old) (Jin et al., 2011; Tang et al., 2014). Moreover, equal survived engrafted cells distribute in the host post-stroke environment, regardless of host’s age (Tang et al., 2014). This suggests that the age may not be a concern affecting the therapeutic effect of engrafted NSCs.
4.2 Enhancing neurogenic potential of endogenous NSCs
In this section, we will cover most of the main factors that are known to be involved in post-injury neurogenesis following the neonatal HI injury and adult ischemic stroke. We will not undertake a detailed review of factors that regulating neurogenesis in the normal adult brain or during central nervous system development, as several comprehensive reviews are discussing these topics (Faigle and Song, 2013; Semple et al., 2013). Neurogenesis and involved factors within the ipsilateral brain after HI injury are illustrated in Figure 2.
Figure 2. Endogenous neurogenesis after stroke and regulating factors.
Neurogenesis in the SVZ is stimulated after stroke, leading to NSCs proliferation and migration of dividing neuroblasts. Neuroblasts move to the infarcted area following chain migration and along the vasculature. A small part of neuroblasts survive and become mature neurons to replace dying neurons. Many factors (Morphogens, Growth factors, Neurotrophic factors, EPO, MicroRNAs) regulate the process of neurogenesis, including proliferation, migration, and differentiation. Red dots indicate the stroke-affected area. BDNF, brain-derived neurotrophic factor; CC, corpus callosum; EGF, epidermal growth factor; EPO, erythropoietin; LV, lateral ventricle; miR, microRNA; Shh, Sonic hedgehog; Wnt, Wingless-type MMTV integration site family; VEGF, vascular endothelial growth factor.
4.2.1 Factors involved in the regulation of neurogenesis after neonatal HI brain injury
Erythropoietin (EPO)
EPO, a hypoxia-inducible factor, is critical for erythropoiesis (Beleslin-Cokic et al., 2004). Interestingly, studies also indicate that EPO can stimulate proliferation of NSCs through its specific membrane receptor – EPOR (Chen et al., 2007; Shingo et al., 2001). Consistent evidence has shown that EPO treatment not only reduces acute brain damage and behavioral deficits (Iwai et al., 2007; Iwai et al., 2010), but also increases SVZ neurogenesis and migration of neural progenitors after neonatal HI brain injury (Iwai et al., 2007). Moreover, EPO administration attenuates white matter injury (Iwai et al., 2010), which is a detrimental pathophysiology of neonatal HI injury and leads to dysfunction of the brain. In addition, oligodendrogenesis is significantly improved after a delayed EPO treatment (Iwai et al., 2010). However, like every coin has two sides, long-term EPO administration could increase the risk of polycythemia and vascular thrombosis (Coleman et al., 2006). Fortunately, a recent study using asialo-EPO (AEPO) that is a non-erythropoietic derivative of EPO, demonstrates the similar beneficial effect on proliferation of oligodendrocyte progenitor cells (OPCs) without side effect of EPO injection (Kako et al., 2012). Consecutive two weeks AEPO treatment increases mature of OPCs in corpus callosum (CC) of HI-insulted neonatal mice and improves myelin formation in the CC area two months after HI insult (Kako et al., 2012).
Neurotrophic factors and growth factors
Brain-derived neurotrophic factor (BDNF) is a key element to keep neuronal survival. A delayed chronic combination treatment of BDNF and epidermal growth factor (EGF) significantly increases cell proliferation in the SVZ and ipsilateral striatum after HI insult in mouse (Im et al., 2010), leading to improvement of behavioral functions. Meanwhile, the proliferation of newly generated neurons in the striatum is increased by the BDNF+EGF treatment (Im et al., 2010). Even though the therapeutic effect of BDNF treatment is promising, the delivery of BDNF is a concern for clinical study, as BDNF may be difficult to pass the blood-brain-barrier (BBB). Vascular endothelial growth factor (VEGF) promotes angiogenesis, which is an important event to maintain the neurogenic niche. There are seven members of the VEGF family and the function of VEGF isoforms on neurogenesis is different. VEGF-A and VEGF-C at the SVZ are transiently induced after neonatal HI injury (Bain et al., 2013). VEGF-A has been shown to enhance the differentiation of SVZ glial progenitors to astrocytes, and VEGF-C prefers to stimulate proliferation and differentiation of late oligodendrocyte progenitors through its receptor – VEFGR-3 (Bain et al., 2013).
Leukemia inhibitory factor (LIF)
LIF, a cytokine from the family of interleukin-6 (IL-6), is an important factor for maintenance of NSCs (Pitman et al., 2004; Shimazaki et al., 2001). HI injury transiently upregulates the mRNA levels of LIF in the SVZ, with a peak at 24 hours after injury (Buono et al., 2015; Covey and Levison, 2007). In addition, LIF treatment increases proliferation of neurosphere generated from the SVZ in vitro (Covey and Levison, 2007). This effect of LIF is through the Notch signal pathway (Covey and Levison, 2007; Felling et al., 2016). In a LIF heterozygotes transgenic mouse, HI-induced expansion of neural progenitors in the SVZ is inhibited, suggesting that LIF signal is required for NSCs responding to HI injury (Buono et al., 2015). Furthermore, study by Ryan Felling et al. shows for the first time that LIF is released by the SVZ astrocytes responding to HI injury (Felling et al., 2016). These studies have shed light on the potential of LIF as a treatment avenue to boost NSC neurogenesis after neonatal HI injury.
Hyperbaric oxygen (HBO)
HBO therapy, using 100% oxygen at 2.4–3.0 absolute atmosphere (ATA), has been reported neuroprotective for many neurological diseases (Deng et al., 2014). Surprisingly, brief application of HBO during reperfusion of HI injury causes cell death of oligodendrocyte glial progenitors in the cortex and leads to deficit of motor function 2–4 weeks after injury (Koch et al., 2008). In contrast, consecutive perform HBO treatment for one week, starting from 3 hours after HI injury, significantly increases NSC proliferation in the SVZ, and improves behavioral recovery (Wang et al., 2008). The paradigm of HBO treatment may explain the difference between these two studies. HBO cannot be administrated in the hyperacute phase of HI injury, as it could cause more severe ischemic-reperfusion damage. The treatment time window is 3 hours to 24 hours after HI injury, based on the previous report (Wang et al., 2008). Daily HBO treatment for one week may compensate the adverse aspect of toxic oxygen. Moreover, many other key parameters, like the severity of injury and dose of HBO treatment, also need to be considered in performing HBO therapy for clinical studies in the future.
Hypothermia
Growing evidence indicates that mild hypothermia (33–35 °C) is an effective management for neonatal HI encephalopathy. However, it is still uncertain that hypothermia is beneficial for neurogenesis after HI insult. The previous study has shown that a severe hypothermia (30 °C for 24 hours) reduces cell proliferation in the SGZ, but not in the SVZ (Kanagawa et al., 2006). In contrast, a short period of hypothermia (28.5 °C for 4 hours) partially rescues the SGZ cells from apoptosis and increases the proliferation of neural progenitors in the SGZ (Kwak et al., 2015). Consistent with this report, hypothermia (32–33 °C for 24 hours) attenuates HI-induced white matter damage and elevates proliferation of early oligodendrocyte progenitors in the hippocampus (Xiong et al., 2013). A possible explanation for the controversial reports is the differences in the parameter of hypothermia. It appears that mild hypothermia with short period is neuroprotective and beneficial for neurogenesis after neonatal HI injury, while severe hypothermia may be not. To make future hypothermia studies more comparable, parameters used for hypothermia should be standardized. For instance, rectal temperature should be reported in all the studies, instead of only report water bath temperature. Besides, the severity of injury should always be considered, as it affects the evaluation of the efficacy of hypothermia therapy.
4.2.2 Factors involved in the regulation of neurogenesis after adult stroke
Growth factors
Epidermal growth factor (EGF)
EGF is a critical mitogen to regulate NSC growth and maintenance in vivo and in vitro (Kuhn et al., 1997; Reynolds et al., 1992). The receptor of EGF, EGFR, is widely expressed on the SVZ NSCs (Seroogy et al., 1995). The expression of EGFR in the SVZ area responds to cerebral ischemia (Ninomiya et al., 2006). Elevated SVZ EGFR positive staining is observed from 7 days after stroke (Ninomiya et al., 2006), which is coincident with the pattern of proliferation of SVZ NSCs. In addition, lateral ventricular infusion of Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) increases cell proliferation in the SVZ and DG in normal animals (Jin et al., 2002). The neurogenesis effect of EGF has also been confirmed by in vitro neurospheres study under the normoxic condition, and this effect takes place through EGFR (Jin et al., 2002). In stroke animals, intraventricular administration of EGF not only stimulates proliferation of DCX positive neuroblasts in the SVZ (Ninomiya et al., 2006), but also increases neuroblast migration out of the SVZ (Teramoto et al., 2003). Furthermore, EGF treatment enhances the neuronal differentiation in the striatum after stroke, and newly generated neurons are spiny projection interneurons (parvalbumin+) (Teramoto et al., 2003), which is the type of subpopulation affected by stroke. It is worthy of noting that EGF treatment can replace the lost neuronal cells caused by stroke, and enhance self-repair ability of brain post injury.
Fibroblast growth factor (FGF) + EGF
Like EGF, FGF-2 also can stimulate proliferation of cultured NSCs in vitro. However, the function of FGF-2 is distinct with EGF on the proliferation and migration of neural progenitor cells in vivo. FGF-2 increases newly born neurons in the olfactory bulb, while EGF increases striatum newly born cells through stimulating SVZ cell migration or proliferation of local neural progenitor cells (Kuhn et al., 1997). In addition, expression of FGF-2 in the cortex is upregulated after stroke (Kumon et al., 1993; Lin et al., 1997). Endogenous FGF-2 is an essential regulator of cell proliferation after brain injury, as dividing cells in DG after stroke are significantly reduced in FGF-2 knockout mice compared to wild-type mice (Yoshimura et al., 2001). In order to maximize the effect of growth factors on neurogenesis, many studies combine EGF with FGF-2 (Baldauf and Reymann, 2005; Oya et al., 2008; Tureyen et al., 2005). Three days infusion of EGF + FGF-2 increases cell proliferation in the SVZ and DG 7 days after stroke and improves the survival of newly born neurons at 21 days (Tureyen et al., 2005). Also, the mix of EGF with FGF-2 has been reported the most efficient way of growth factor combination for boosting neurogenesis after stroke (Oya et al., 2008). However, study by Baldauf et al. reemphasizes the importance of time frame for such combination therapy. A two weeks treatment with EGF + bFGF unexpectedly enlarges the size of stroke-induced brain injury, even though cell proliferation is increased in the SVZ two weeks after stroke (Baldauf and Reymann, 2005). It seems that long-term application of growth factor combination therapy may have detrimental effects on neuronal death.
Vascular endothelial growth factor (VEGF)
In addition to the angiogenetic function, VEGF has been demonstrated a powerful neurogenic effect after stroke (Greenberg and Jin, 2013), including both VEGF-A and VEGF-B. A short period of VEGF-A intracerebroventricular administration increases cell proliferation in the SVZ and DG 28 days after stroke (Sun et al., 2003). This neurogenesis effect is also accompanied with angiogenesis and acute neuroprotection (Sun et al., 2003). Furthermore, SVZ neurogenesis is markedly enhanced in VEGF-overexpress transgenic mice after cerebral ischemia, as well as migration of neuroblasts and generation of newly born neurons in the cortex (Wang et al., 2007). Similarly, VEGF-B knockout reduces the spontaneous post-stroke cell proliferation in the SVZ and DG (Sun et al., 2006). Moreover, exogenous administration of VEGF-B successfully restores such proliferation (Sun et al., 2006). This suggests that the VEGF treatment has therapeutic implications for stroke recovery by increasing angiogenesis and neurogenesis. However, the dosage should be considered carefully when applying VEGF therapy for the neurological disease. A study has shown that a high dose (500 ng/ml) and a low dose (50 ng/ml) of VEGF have distinct effects on proliferation and differentiation of neural progenitors in the SVZ (Meng et al., 2006). The high dose significantly inhibits the proliferation and enhances neuronal differentiation, whereas the low dose does not have these effects (Meng et al., 2006). A recent study indicates that the neurogenesis effect of VEGF after stroke is partly due to reactive astrocyte transdifferentiation into newly generated neurons (Shen et al., 2016).
Neurotrophic factors
Neurotrophic factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), are crucial for maintaining neural stem cell/neuronal survival and promoting neuronal differentiation during brain development or after injury (Barde, 1989). Ischemic stroke elevates mRNA levels of both BDNF and NGF in stroke-affected cortex area (Dmitrieva et al., 2016). The brain appears to initiate endogenous neuroprotective mechanisms against the brain injury after stroke. However, intranasal administration of NGF does not further increase SVZ cell proliferation after stroke (Zhu et al., 2011). Instead, it improves the survival of newly born neurons in the striatum (Zhu et al., 2011). Different from NGF, intravenous BDNF injection for five days increases neurogenesis and neural progenitor cell migration from the SVZ, leading to long-term improvement of sensorimotor functional recovery after stroke (Schabitz et al., 2007). Interestingly, it has been reported that upregulation of BDNF via recombinant adeno-associated virus (rAAV) inhibits the formation of newborn dentate granule cells in a global ischemia rat model (Larsson et al., 2002). The reason may lay on the methodology, as the rAAV-transducted cells may not release or secrete BDNF into the surrounding environment.
Erythropoietin (EPO)
In addition to regulating hematopoiesis, EPO has been reported various other essential functions, including angiogenesis and neuroprotection (Ribatti et al., 1999; Wang et al., 2004). EPO is also critical for neural development. EPO and EPO receptor (EPOR) express in the developing neural tube of embryo, and Epo or EpoR knockout mice cannot survive due to incomplete neural tube closure (Tsai et al., 2006). Intraperitoneal administration of EPO increases SVZ cell proliferation and angiogenesis around ischemic lesion after stroke (Wang et al., 2004). In line with this, the SVZ size and cell proliferation in the SVZ are reduced in EpoR conditional knockdown mice (Tsai et al., 2006). In addition, post-stroke neurogenesis is hindered in these transgenic mice (Tsai et al., 2006). Furthermore, EPO, administrated daily for seven days, augments the proliferation of oligodendrocyte progenitor cells and improves white matter remodeling after embolic cerebral ischemia (Zhang et al., 2010). Meanwhile, gene-expression profile study has shown that EPO treatment significantly upregulates neuronal plasticity-related genes (Egr1 and Egr2) after stroke (Mengozzi et al., 2012). Despite a possible adverse effect of increasing hematocrit and thrombosis, EPO has a high potential for further investigation of clinical application as a stroke management strategy.
Transcriptional factors
Notch pathway
The Notch signaling pathway is a conserved and fundamental pathway critical for maintaining NSC proliferation and differentiation during neural development. Function as a receptor, Notch is a transmembrane protein, including extracellular domain, transmembrane domain and internal cellular domain (NICD). Notch has many ligands, like jagged 1 (JAG1), JAG2 and delta-like (Dll) protein (Ables et al., 2011). Except for the developing brain, components of the notch signaling are cell-based throughout the adult brain, especially neurogenic area (Givogri et al., 2006; Mizutani et al., 2007; Stump et al., 2002). DCX positive neuroblasts in the SVZ highly express Notch and cerebral ischemia increases the expression of the Notch pathway components (NICD, and Notch downstream target-Hes1 and Sonic Hedgehog) in SVZ cells (Wang et al., 2009b). Importantly, SVZ cell proliferation is increased with Notch activation, whereas blocking the Notch signal with soluble Jagged1-Fc reduces the proliferation (Wang et al., 2009b). Moreover, knocking down Notch by RNAi reverses post-stroke proliferation of neural progenitor cells isolated from the SVZ of stroke rats (Wang et al., 2009a). Recent study also confirms the same phenomena in aged animals. Post-stroke neurogenesis in the SVZ is enhanced by Notch activation and reduced by blocking the Notch signal in aged (20–24 months old) rats (Sun et al., 2013b).
Sonic hedgehog (Shh)
Shh is another well-studied morphogen, and the Shh pathway is crucial for dorso-ventral patterning process of developing CNS (Marti and Bovolenta, 2002). Moreover, it has an important role in the adult brain for stem cell maintenance (Ahn and Joyner, 2005; Palma et al., 2005). Under the hypoxic condition, cultured neurons and neural progenitor cells increase Shh expression (Sims et al., 2009). In vivo studies also demonstrate that cerebral ischemia upregulates the expression of Shh signal in the ipsilateral hippocampus (Sims et al., 2009), cortex and striatum (Jin et al., 2015) after injury. These findings suggest that the Shh pathway plays an important role in the neuronal cell response to hypoxia. The further study has shown that inhibition of Shh pathway abolishes the post-stroke cell proliferation in the hippocampus (Sims et al., 2009). Shh-induced cell proliferation is vital for post-stroke behavioral recovery, as conditional knockout Shh gene in NSCs (Nestin positive) worsens the neurological function. Conversely, treatment with Shh signaling agonist (SAG) improves behavioral recovery after stroke (Jin et al., 2015). Consistently, intrathecal administration of Shh protein in stroke animals also has the beneficial effect of SVZ neurogenesis and functional improvement (Bambakidis et al., 2012).
Wingless-type MMTV integration site family (Wnt)
The Wnt pathway is a conserved signaling pathway, regulating multiple cellular processes during the development of CNS, including neuronal migration and synaptic differentiation (Fradkin et al., 2005). Accumulating evidence indicates that Wnt protein also participates in the adult neurogenesis under normal and pathophysiologic conditions (Hirota et al., 2016). One major Wnt signaling pathway is the β-caternin-dependent canonical pathway. In the absence of Wnt, β-caternin degrades under basal situation. On the opposite, this pathway is initiated, and transcription factor β-caternin is preserved when Wnt binds to its receptor (Hirota et al., 2016). Upregulation of Wnt via lentivirus intrastriatal injection increases the number of BrdU-positive cells in the striatum after endothelin-1-induced focal ischemic injury (Shruster et al., 2012). In addition, stroke increases symmetric division of SVZ NSCs accompanying with upregulated Wnt signal in the same area (Piccin and Morshead, 2011). Similarly, declining expression of β-caternin, a downstream transcriptional factor of Wnt, decreases SVZ expansion and striatal neurogenesis after stroke (Lei et al., 2008).
Epigenetic regulators
MicroRNAs
MicroRNAs (miRs) are a class of non-coding RNAs, participating in post-transcriptional gene regulation (Boyd, 2008). Mature miRs are single-stranded with ~21–22 nucleotides in length and can bind to 3′-untranslated region (3′UTR) of target mRNAs, which leads to translation repression and mRNA degradation (Boyd, 2008). MiRs have been shown to involve in the regulation of neural development and pathophysiology of various neurological disease including stroke. Studies about miRs and post-stroke neurogenesis are emerging. Four miRs related to neurogenesis have been widely investigated.
MiR-9
The expression of miR-9 starts during early neurosphere formation and promotes NSC proliferation (Delaloy et al., 2010). Moreover, miR-9 participates in the migration of NSCs under brain injury. For example, miR-9 inhibits the migration of engrafted NSCs after being transplanted into ipsilateral striatum of stroke mice (Delaloy et al., 2010). In addition, overexpression of miR-9 and miR-200 suppress the differentiation of oligodendrocyte precursor cells through downregulating the expression of serum response factor (SRF) (Buller et al., 2012).
MiR-124
MiR-124 is specifically expressed in DCX-positive neuroblasts in adult SVZ (Cheng et al., 2009). Knockdown of miR-124 enhances the division of SVZ neuroblasts. In contrast, overexpression of miR-124 increases the neuronal differentiation of SVZ cells in vivo, and this effect takes place through one of miR-124 direct target, Sox9 (Cheng et al., 2009). In line with these findings, focal cerebral ischemia substantially reduces the expression of miR-124a in SVZ cells (Liu et al., 2011), which may explain the post-stroke proliferation of SVZ cells. In addition, miR-124a transfection in neural progenitors promotes their differentiation to neurons. Furthermore, Jagged-1, a ligand of the Notch signal, has been demonstrated as a direct target of miR-124a (Liu et al., 2011). Thus, stroke downregulates miR-124a with an increase of JAG1, thereby enhances the activity of Notch signal and improves neurogenesis. However, the upstream mechanisms in regulating miR-124 after stroke remain to be explored. More excitingly, a recent study has shown that administration of synthesized exosomes carrying miR-124 promotes neuronal differentiation of cortical NSCs after stroke (Yang et al., 2017a). This suggests that miRs can be carried within exosomes and used as a therapeutic drug to treat neural diseases.
MiR-17-92 cluster
The miR-17-92 cluster includes six miRs (miR-17, miR-18a, miR-19a, miR-20a, miR19b, and miR-92) on human chromosome 13q31.3 (Xiao et al., 2008; Yang et al., 2017b). Stroke upregulates expression of miR-17-92 cluster in SVZ cells, especially miR-18a, miR-19a and miR-19b (Liu et al., 2013). Moreover, miR-18 and miR-19a mimics significantly increase the SCZ cell proliferation after stroke. A study has also shown that the phosphatase and tensin homolog (PTEN) is a direct target of miR-17-92 cluster, and a decrease in PTEN protein levels elevate cell proliferation (Liu et al., 2013). Furthermore, intravenous infusion of miR17-92 cluster-enriched exosomes enhances neurogenesis and oligodendrogenesis after stroke, as well as improvement of neurological behaviors (Xin et al., 2017).
MiR-210
MiR-210 is so far the only miR that has been reported robustly induced by hypoxia in all cell types studied (Chan and Loscalzo, 2010). Brain miR-210 levels increase 24 hours after ischemic stroke. However, the role of miR-210 in post-stroke neurogenesis is still elusive. Using lentiviral vector to overexpress miR-210 in normal mice brain for 28 days, Zeng et al. reported that cell proliferation in the SVZ was significantly increased (Zeng et al., 2014). A recent study by Voloboueva et al. found that reducing cellular miR-210 dramatically attenuated proliferation of cultured neural progenitor cells under inflammatory condition (Voloboueva et al., 2017). Currently, there is no solid evidence yet to show that miR-210 promotes post-stroke neurogenesis, thus whether it could be a potential neurogenic candidate remains to be determined.
DNA methylation and histone modification
Although little is known about the relationship between these two types of epigenetic regulation with post-stroke neurogenesis, DNA methylation and histone modifications are indeed involved in stroke development and neurogenesis under normal condition. For example, levels of DNA methylation are elevated in ischemic striatum and cortex 24 hours after cerebral ischemia (Endres et al., 2000), and the activity of DNA methyltransferase (DNMT) is negatively correlated with the stroke outcome. Inhibition of DNMT reduces ischemia-induced lesion volume (Endres et al., 2000). Furthermore, neuronal differentiation of NSCs is decreased after genetic deleting of Methyl-CpG binding protein 1 (MBD1), a protein participating in DNA methylation-mediated gene repression (Zhao et al., 2003). Recently, the epigenetic mechanisms on neuroplasticity after stroke has been reviewed (Felling and Song, 2015), providing further detailed discussion on this topic.
4.3 Direct neuronal reprogramming in vivo
Beside enhancing endogenous NSC to neurogenesis after injury, another emerging strategy is in vivo direct neuronal reprogramming. Although this technology is still in its infancy, it has already shed light and shown the promise on the brain repair after injury. The concept of direct reprogramming is partially inspired by the breakthrough of induced pluripotent stem cells technique, which demonstrates that pluripotent stem cells can be induced from skin fibroblast cells by only four transcription factors (Oct4, Sox2, Klf4, and c-Myc) (Takahashi and Yamanaka, 2006). Moreover, the induced pluripotent stem cells (iPSCs) are able to differentiate into various cell types, including neurons (Hu et al., 2010; Kim et al., 2011). The direct reprogramming could be regarded as a shortcut to directly acquire terminally differentiated cells from fibroblasts or other cell types bypassing the stage of PSC. Indeed, several pioneering studies have provided proof of evidence that cultured fibroblast and glial cells can be converted into neurons under neurogenetic transcription factors, like Achaete-scute complex homolog 1 (Ascl1) (Vierbuchen et al., 2010), paired box gene 6 (Pax6) (Heins et al., 2002), and neurogenin2 (Neurog2) (Berninger et al., 2007; Heinrich et al., 2010). Remarkably, the induced neuron not only is neural markers (e.g., MAP-2, Tuj-1) positive but also has the electrophysiological function (Berninger et al., 2007; Vierbuchen et al., 2010), as well as the synaptic connection with other cultured neurons (Vierbuchen et al., 2010).
The great success of in vitro direct neuronal reprogramming encourages the transfer of this technique to in vivo studies, as the in vivo direct reprogramming has several unique advantages for brain repair. Firstly, this method avoids the ethical and immune-rejection problem associated with exogenous cell transplantation. Secondly, endogenous glial cells provide abundant cells to target, unlike cell graft that are limited by the cell resource and inadequacy of available cell numbers. However, the transfer of in vitro reprogramming to in vivo application is not straightforward. The efficacy of same transcriptional factors for direct reprogramming is quite different in vitro and in vivo. For example, Pax6 sufficiently converts astrocytes into neurons in vitro (Heins et al., 2002), while very few induced neurons are observed after Pax6 is transduced into glial cells in mouse cortex and striatum (Grande et al., 2013). Moreover, the brain region is another factor to affect the reprogramming efficacy. Striatum and neocortex resident cells show distinct responses for the combination of growth factors (GFs) and Neurog2 transfection; more NeuN positive neurons are induced in the striatum after infection (Grande et al., 2013). Furthermore, the environment of the brain is also critical. It has been reported that the brain with ischemic injury promotes the generation of induced neurons, as compared to the normal brain under the same treatment with GFs and Neurog2 (Grande et al., 2013). Meanwhile, another big concern is the virus vector used for direct reprogramming. Currently, most of the studies, including both in vitro and in vivo experiments, rely on the virus vectors to express the neurogenic transcriptional factors. This may increase safety concerns when translating the technique into the clinical study. An alternate method is using small molecular compounds, which could avoid cerebral injection of the virus and easily offer widespread reprogramming in the injured brain. Substantial evidence indicates that sequentially applying a cocktail of chemical compounds, including nine small molecules (LDN193189, SB431542, TTNPB, Tzv, CHIR99021, VPA, DAPT, SAG, and Purmo), are able to reprogram the cultured astrocytes into neurons with fully electrophysiological function (Zhang et al., 2015). However, the combination of multiple molecules may increase the complexity of this technique and affect the feasibility to transfer it to the clinical application. Thus, several obstacles still need to overcome for using molecules to reprogram glia in vivo, like how to optimize the combination of chemical compounds, and how to efficiently deliver these molecules to the target brain area. Even though many technical questions still need to be answered, in vivo direct reprogramming glial cells into neurons open a novel and attractive avenue for brain repair, as emerging studies demonstrate that in vivo induced neurons functionally mature and form synaptic connection to other existing neurons (Pereira et al., 2017; Zhang et al., 2015).
Although applying in vivo glia-neuron reprogramming to repair brain damage after stroke is still in the early stage, other brain injury studies using the brain stab wound model have already demonstrated the feasibility of direct neuronal reprogramming for brain repair (Grande et al., 2013). Although direct neuronal reprogramming has made a significant progress in the last decade, some major challenges still lay ahead, in order to make this approach more efficient and practical for the future. Firstly, the average neuronal converting and survival rate is low under previously reported protocols. Surprisingly, less than 25% resident cortex cells have been reprogramed to neurons in the stab wound brain injury model 7 days after infection, and the estimated neuronal replacement rate is only 3.2% one month later (Grande et al., 2013). Recent studies provide the evidence that these challenges could be overcome by combining neurotrophic factors or anti-apoptotic factors with transfection of the neurogenic transcriptional factor. For example, co-expression of Bcl-2 facilitates the astrocyte-neuron conversation and increases the number of final survived neurons (Gascon et al., 2016). To mend the injured brain, we still need to figure out the approach that guides the endogenous glial cells to reprogram into specific neuron subtypes and to form functional neuronal circuits between different subtypes of neurons. This is especially important for the neurological disease like stroke, which affects a wide range of the brain and damages multiple kinds of neurons. Last but not least, the functional recovery is the final goal of neuronal replacement/regeneration therapy, including in vivo direct reprogramming. Without evidence of functional improvement, it will be difficult to translate this therapy to the clinical application.
5. Conclusion remarks
Considering the limited treatment option for both neonatal HI brain injury and stroke in the adult, there is an urgent need to explore new effective treatment strategies to protect the brain and promote the neurological recovery after injury. Although we have witnessed the failure in development of thousands neuroprotective drugs, we cannot simply conclude that neuroprotection is unattainable in stroke patients. The reality may suggest that regulating single treatment target could be insufficient to achieve clinical relevant neuroprotection. In contrast, the NSC therapy is multi-targeting, and NSCs have several unique beneficial characteristics, including migration to the brain lesion and secretion of angiogenic and neurotrophic factors. All of these cannot be achieved at the same time by traditional single drug administration. Furthermore, solid evidence from pre-clinical studies has proven that the NSC therapy holds the positive therapeutic potential, with both strategies - enhancing endogenous neurogenesis and transplanting NSCs. However, several basic questions remain to be elucidated, in order to better understand the NSC therapy. For example, it is unclear at present that why post-injury neurogenesis is a transient process. What are the factor(s) or mechanism(s) that inhibit the survival of most engrafted NSCs? How do we promote engrafted NSCs integrating into the host neural network? In addition, there are many other questions related to cell transplantation methodologies. The optimal route/dosage/timing merits further investigations in order to better translate the promising cell therapy to the clinical setting. Of importance, as the personalized treatment becomes the direction of modern medicine, understanding the strategy how to set up specific NSC therapy for individual stroke patient will be necessary for the future investigation.
Highlights.
This review provides a comprehensive overview of neural stem cell therapy for both neonatal and adult hypoxic-ischemic brain injury.
Endogenous neural stem cells rapidly react to the injury and initiate a limited self-repair process.
The strategies and mechanisms of exogenous neural stem cell transplantation for neonatal and adult hypoxic-ischemic brain are discussed.
The modulators that facilitate or enhance the endogenous repair process are summarized.
Direct in vivo neuronal reprogramming is promising for brain repair after ischemic stroke.
Acknowledgments
This work was supported in part by National Institutes of Health Grants HL083966 (LZ), HL118861 (LZ) and NS103017 (LZ). We apologize to those authors whose excellent studies covered by the scope of this review were unable to be cited due to space restriction.
Abbreviations
- NSCs
neural stem cells
- HI
hypoxic-ischemic
- SVZ
subventricular zone
- SGZ
subgranular zone
- NE
neuroepithelial
- RG
radial glial
- GLAST
glutamate transporter
- GFAP
glial fibrillary acidic protein
- VZ
ventricular zone
- nIPC
intermediate neural progenitor cell
- INM
interkinetic nuclear migration
- GSK-3
glycogen synthase kinase 3
- miRs
micro RNAs
- CSF-1
Colony Stimulating Factor-1
- FGF
fibroblast growth factor
- OB
olfactory bulb
- RMS
rostral migratory stream
- BNIP3
bcl-2/adenovirus E1B 19 kDa interacting protein-3
- MP2s
multipotential progenitors
- GRPs
glia-restricted progenitors
- tPA
tissue plasminogen activator
- SDF-1
stromal cell-derived factor-1
- ESC
embryonic stem cell
- iPSC-NSC
induced pluripotent stem cell-derived NSC
- HBO
hyperbaric oxygen
- EPO
erythropoietin
- AEPO
asialo-EPO
- OPCs
oligodendrocyte progenitor cells
- CC
corpus callosum
- BDNF
brain-derived neurotrophic factor
- EGF
epidermal growth factor
- BBB
blood-brain-barrier
- VEGF
vascular endothelial growth factor
- NGF
nerve growth factor
- rAAV
recombinant adeno-associated virus
- JAG1
jagged 1
- Dll
delta-like
- Shh
Sonic hedgehog
- SAG
Shh signaling agonist
- Wnt
Wingless-type
- SRF
serum response factor
- PTEN
phosphatase and tensin homolog
- DNMT
DNA methyltransferase
- MBD1
Methyl-CpG binding protein 1
Footnotes
Conflict of Interests
The authors declare no conflict of interests regarding the publication of this paper.
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