Cell replacement therapy for intracerebral hemorrhage

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✓ Intracerebral hemorrhage (ICH), for which no effective treatment strategy is currently available, constitutes one of the most devastating forms of stroke. As a result, developing therapeutic options for ICH is of great interest to the medical community. The 3 potential therapies that have the most promise are cell replacement therapy, enhancing endogenous repair mechanisms, and utilizing various neuroprotective drugs. Replacement of damaged cells and restoration of function can be accomplished by transplantation of cells derived from different sources, such as embryonic or somatic stem cells, umbilical cord blood, and genetically modified cell lines. Early experimental data showing the benefits of cell transplantation on functional recovery after ICH have been promising. Nevertheless, several studies have focused on another therapeutic avenue, investigating novel ways to activate and direct endogenous repair mechanisms in the central nervous system, through exposure to specific neuronal growth factors or by inactivating inhibitory molecules. Lastly, neuroprotective drugs may offer an additional tool for improving neuronal survival in the perihematomal area. However, a number of scientific issues must be addressed before these experimental techniques can be translated into clinical therapy. In this review, the authors outline the recent advances in the basic science of treatment strategies for ICH.

Abbreviations used in this paper:ASC = adipose-derived stem cell; BMSC = bone marrow–derived stem cell; BrdU = 5-bromo-2-deoxyuridine; CNS = central nervous system; ESC = embryonic stem cell; ICH = intracerebral hemorrhage; MMP = matrix metalloproteinase; MSC = mesenchymal stem cell; NSC = neural stem cell; UCB = umbilical cord blood; VEGF = vascular endothelial growth factor; SGL = subgranular layer; SVZ = subventricular zone.

Abstract

✓ Intracerebral hemorrhage (ICH), for which no effective treatment strategy is currently available, constitutes one of the most devastating forms of stroke. As a result, developing therapeutic options for ICH is of great interest to the medical community. The 3 potential therapies that have the most promise are cell replacement therapy, enhancing endogenous repair mechanisms, and utilizing various neuroprotective drugs. Replacement of damaged cells and restoration of function can be accomplished by transplantation of cells derived from different sources, such as embryonic or somatic stem cells, umbilical cord blood, and genetically modified cell lines. Early experimental data showing the benefits of cell transplantation on functional recovery after ICH have been promising. Nevertheless, several studies have focused on another therapeutic avenue, investigating novel ways to activate and direct endogenous repair mechanisms in the central nervous system, through exposure to specific neuronal growth factors or by inactivating inhibitory molecules. Lastly, neuroprotective drugs may offer an additional tool for improving neuronal survival in the perihematomal area. However, a number of scientific issues must be addressed before these experimental techniques can be translated into clinical therapy. In this review, the authors outline the recent advances in the basic science of treatment strategies for ICH.

Intracerebral hemorrhage, or hemorrhagic stroke, constitutes one of the most devastating forms of cerebrovascular disease and is responsible for ~ 10–15% of stroke cases.59 The incidence of ICH in Western countries is 10–20 cases per 100,000 people, and even higher incidences have been reported in Black and Asian populations.15,28 In the elderly, the incidence of ICH doubles with each decade of life after the age of 50 years.14 As the elderly segment of our population continues to rapidly grow, the prevalence of ICH is expected to continue to increase. This will place a heavy burden on national health care systems and demands the development of novel therapeutic strategies.

There are several risk factors associated with ICH, including amyloid angiopathy, impaired coagulation, vasculitis, cocaine or alcohol abuse, and genetic predisposition.5,6,30 However, the major risk factor for ICH is arterial hypertension, particularly if it is untreated. Arterial hypertension accounts for about 60% of cases.16 The prognosis of ICH is poor, with an overall mortality rate of about 40% at 1 month; most of the survivors suffer from persistent, severe neurological deficits. It is estimated that 90% of surviving patients are dependent on a caregiver at 1 month, and 80% are dependent on a caregiver at 6 months after the insult.7,8,19

The available therapy is mainly supportive, including maintenance of homeostasis and treatment of brain edema. Therapies that prevent hematoma expansion and continuous bleeding through the administration of hemostatic agents, such as recombinant activated factor VII,79 are currently under investigation, but the results of a Phase III study (Factor Seven for Acute Hemorrhagic Stroke [FAST] trial) have failed to demonstrate efficacy at the primary end point in patients suffering from ICH.40 In selected patients with space-occupying hematomas, surgery may relieve the mass effect.54 However, the indications for surgical evacuation are a matter of ongoing debate.59,71

Once the bleeding has occurred, damage to the brain parenchyma is inevitable, and no effective treatment for improving the outcome, other than neurological rehabilitation, is currently available. However, potential therapies are arousing a great deal of interest. Neuroprotective strategies might prevent additional cell loss in the perihematomal area and therefore improve the outcome after ICH. Additionally, newly developed techniques, including transplantation of stem or neural progenitor cells, might not only contribute to neuroprotection, but also lead to the integration of the transplanted cells into the host brain. Once in the brain, these transplanted cells could differentiate into the appropriate neuronal and glial phenotypes, replace the functions of the lost cells, and restore disrupted neuronal circuitry. Finally, enhancing endogenous neurogenesis could allow damaged brain areas to regenerate without administration of exogenous cells.

Despite the progress made in understanding the nature of ICH over the last few years, the development of therapeutic options remains an underinvestigated area of research. In this review, we provide an overview of the current knowledge regarding neuroprotective and regenerative strategies for the treatment of this debilitating disease.

Experimental Models of Intracerebral Hemorrhage

Intracerebral hemorrhage is a type of stroke with its own specific mechanisms of injury. The pathogenesis is complex and includes initial rupture of a blood vessel, hematoma expansion with mechanical trauma, local disruption of the blood–brain barrier, brain edema formation, excitotoxic injury to the surrounding cells, induction of a sustained perihematomal inflammatory reaction, and finally apoptotic and necrotic neuronal and glial cell death in the perihematomal area.52 Recent publications have shown that thrombin as well as hemoglobin and its degradation products, may have additional detrimental effects on the surrounding brain tissue that was not primarily affected by ICH. Infusion of thrombin and iron into the brain parenchyma is known to result in inflammatory reaction, edema formation, and death of neurons and astrocytes.34,82 Expression of MMPs has been shown to be upregulated in astrocytes in response to hemoglobin exposure, and this might constitute an important step in the pathogenesis of hemorrhagic brain edema.70 Accordingly, it was found in an in vitro model of hemoglobin neurotoxicity that exposure of cortical neurons to hemoglobin resulted in oxidative stress and upregulation of upstream and downstream caspases.77 An increase of perihematomal tumor necrosis factor–α levels contributes to the pathogenesis of brain edema after ICH.35 Concurrently, a cascade of biochemical events initiates and maintains an inflammatory reaction, which is characterized by production of proinflammatory cytokines, activation of resident microglia, and migration of immune cells into the brain parenchyma surrounding the lesion.82

Experimental animal models of ICH should reproduce these pathophysiological features of the human disease as closely as possible. Currently, 2 different rodent models are used for investigating ICH: collagenase and autologous blood injection. The more widely used technique is based on the injection of bacterial collagenase into the brain parenchyma, mostly the striatum, resulting in disruption of the basal lamina of cerebral blood vessels and subsequent bleeding.60 The other well-described model is based on stereotactically guided injection of autologous blood aspirated from the femoral or jugular vein into the striatum using a microsyringe.17 MacLellan and colleagues48 recently investigated the differences between these 2 models. Although both techniques initially result in similar hematoma volumes, collagenase infusion induces an ongoing tissue loss for longer than 4 weeks after the insult, while with blood infusion there is only a slight increase in the lesion volume from 1 to 6 weeks. The collagenase model also results in more severe damage to remote areas of the infusion site, such as the substantia nigra, white matter, and cortex, and in a greater breakdown of the blood–brain barrier. Spontaneous functional recovery is faster and sometimes complete in the autologous blood infusion model compared with the collagenase injection model.48 There are advantages and disadvantages to both methodologies, but neither closely replicates the pathogenic mechanisms and the clinical situation in humans.

Due to the high variability in hematoma size combined with an irregular delineation of the obtained lesions, these models have drawbacks for studying neuroregenerative strategies and the effects of ICH on remote brain areas. To induce a lesion with a more reproducible size and location, we have developed an experimental model of ICH in rats by combining a striatal microtrauma with a slow infusion of autologous blood (Fig. 1). Because it produces a quantifiable neurological deficit, correlating to a lesion that has a clearly defined volume, morphology, and location in the brain, this model is particularly well-adapted to studying regenerative strategies after an acute focal hemorrhagic brain lesion.10 Magnetic resonance imaging has turned out to be a powerful tool that allows the repetitive, noninvasive assessment of the lesion with high spatial resolution (Fig. 2). In addition, labeling of transplanted cells with paramagnetic nanoparticles allows the noninvasive magnetic resonance imaging–based monitoring of their migration and survival in the host brain.31 However, it must be taken into consideration that all currently available experimental animal models poorly reflect the complex pathophysiology of ICH, and the data obtained from these models should be extrapolated to the human disease with caution.

Fig. 1.
Fig. 1.

Photograph of a right striatal hematoma (arrow) in the brain of an adult rat 2 days posthemorrhage. Due to the circumscribed hematoma borders and preservation of the surrounding brain parenchyma, this lesion is well-suited for studies of restorative strategies after the insult.

Fig. 2.
Fig. 2.

Magnetic resonance images at 3T of rats with ICH obtained 30 days posthemorrhage. A: Fast low angle shot sequence showing susceptibility artifacts of hemosiderin deposits (arrow). B–D: On triplanar T2-weighted turbo spin-echo images, the location and configuration of the lesion in the right striatum is demonstrated (arrows).

Neuroprotection

Neuroprotection aims at rescuing cells after excitotoxic, inflammatory, oxidative, metabolic, or free radical–induced stress after a cerebral insult. Although some concepts of neuroprotection have shown promising effects in experimental models of ischemic stroke as well as traumatic brain and spinal cord injury (see Faden and Stoica24 for a review), only a small number of such studies have been performed in the paradigm of ICH.

Recent studies have shown beneficial effects in animal models of ICH using a variety of drugs, such as memantine, an n-methyl-d-aspartate receptor antagonist;44 celecoxib, a selective cyclooxygenase-2 inhibitor,18 GM001, a broad-spectrum MMP inhibitor;76 minocycline, a tetracycline antibiotic;80 atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor;66 and valproic acid, an antiepileptic drug.67 A number of compounds that have shown promising neuroprotective effects in other types of brain injury, such as creatine,2–4 have not been investigated yet for the treatment of ICH.

Hypothermia, which has been reported to mediate its effects through activation of the Akt pathway and inhibition of apoptosis,84 is known to protect brain tissue in a variety of insults, including trauma and ischemic stroke.50 In a rat model of ICH, mild hypothermia (33–35°C) started 12 hours after hemorrhage resulted in a significantly smaller lesion volume. However, earlier hypothermia treatment caused adverse effects including increased cerebral bleeding, probably due to induction of increased blood pressure.47 Interestingly, local hypothermia induced by implantation of an epidural cooling device in a swine model of ICH (14°C) or by implanting a cooling coil into the striatum of rats (32°C) resulted in significantly reduced brain edema.26,73 Although local hypothermia seems more promising for the treatment of ICH because it causes fewer systemic side effects, further research is necessary to determine the potential of this technique in the treatment of patients.

In the first clinical study investigating a neuroprotective compound in patients with ICH, gavestinel (GV150526), an antagonist at the glycine site of the n-methyl-d-aspartate receptor, was administered to 571 patients within 6 hours of hemorrhage. This collectively represented the patients diagnosed with ICH in the glycine antagonist in neuroprotection study, in which stroke patients were included regardless of stroke type. Unfortunately, gavestinel had no effect on functional recovery measured 3 months after ICH.32 These results do not differ from the previously reported futility of gavestinel treatment in patients suffering from ischemic stroke.61 It must be taken into consideration that the results from the translation of promising findings in basic research into clinical trials of neuroprotection in ischemic stroke have been disappointing.24 Based on the limited preliminary data obtained in experimental models of ICH, further research is warranted to determine whether this strategy could be effective in treating patients with ICH.

Stem Cell Therapy

Stem cells are undifferentiated cells that retain the capacity to proliferate and produce generations of progenitor cells, which can differentiate into virtually all cell types of the body in response to the proper stimuli. Knowledge about stem cells is rapidly growing and has recently opened new avenues for brain repair strategies in acute diseases, such as ischemic stroke (for review see Bliss et al.12) and trauma (for review see Schouten et al.64), as well as in chronic neurodegenerative conditions, including Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and multiple sclerosis (for review see Ormerod et al.58) Progress in research gives hope that new therapeutic options using stem cell transplantation could be used against brain tissue damage from ICH.

Different types of stem cells are generated throughout mammalian development, and consequently, there are several sources of stem cells that may be useful in ICH. Embryonic stem cells derived from the inner cell mass of pre-implantation embryos can be maintained and expanded in specialized cell culture media where they can proliferate indefinitely.23 By altering their culture conditions and exposure to specific growth factors, pluripotent ESCs can differentiate into any type of cell in the body, which offers a huge potential for cell replacement therapies.

Neural stem cells are found in specific regions of the developing and the adult mammalian brain, such as the fore-brain SVZ of the lateral ventricles, the SGL of the hippocampal dentate gyrus, cortex, cerebellum, and spinal cord (for review see Kornblum39). These cells have the potential to renew themselves (immortality) and give rise to cell populations restricted to the neuronal and glial lineage. Isolated NSCs can proliferate and differentiate into specific neuronal and glial phenotypes in response to different growth factors and changes in culture conditions.

Bone marrow, UCB, and adipose tissue constitute an easily available source of MSCs. In addition to hematopoietic stem cells, bone marrow contains MSCs that can not only differentiate into mesodermal cells, but also adopt the fate of endodermal and ectodermal cell types (for review see Kassem et al.37). In response to the proper environmental stimuli, MSCs can differentiate into cells of the neuronal and glial lineage. Adult mammalian adipose tissue contains multipotent mesenchymal stem cells (ASCs) that have many similarities to BMSCs and can proliferate and give rise to neural cells in vitro after exposure to appropriate differentiation factors (for review see Safford and Rice62). Umbilical cord blood contains a population of stem cells that also have the potential to become neural cells (for review see Sanberg et al.63). Umbilical cord blood–derived stem cells have the added advantage of being less immunogenic than MSCs derived from the bone marrow.

Finally, immortalized neuronal precursor cell lines constitute an alternative source of cells suitable for transplantation (for review see Fisher27). The advantages of cell lines include unlimited availability, better characterization, tighter lineage-restriction, and easier genetic programming of the cells before transplantation. The cells appear to be neurally restricted in vitro and differentiate mostly into neurons when transplanted (Fig. 3).

Fig. 3.
Fig. 3.

Photomicrographs of green fluorescent protein–transfected neuronal progenitor cells transplanted into the striatum of an adult rat with ICH. A: Implanted cells were visualized by immunohistochemistry for p75 nerve growth factor receptor. B: Enlarged view (boxed area in A) of the p75 nerve growth factor receptor–positive cells (arrows). C: Green fluorescent protein expression was detected in transplanted cells in the graft (arrow). LV = lateral ventricle, St = striatum, T = transplant. Bars = 50 μm

Despite extensive cell replacement studies in neurodegenerative disorders and ischemic stroke, studies on cell replacement therapies after ICH have emerged only during the last few years. In the limited number of studies available so far, various types of the above-mentioned cells have been transplanted in different experimental paradigms of ICH, with varying degrees of success (Table 1). In the first experimental study of stem cell–based therapy for ICH, survival and differentiation of human NSCs intravenously administered into neurons and astrocytes was observed, and animals showed a significantly improved behavioral recovery, as assessed with the rotarod and limb placing tests, compared with the control group.36 In a later study, mouse ESCs were intraventricularly transplanted after induction of differentiation into nestinpositive NSCs by retinoic acid exposure. Again, these cells were found to differentiate into neurons and astrocytes. However, no behavioral analysis was done in this study.57 In anothr study, intracerebral transplantation of rat NSCs resulted in differentiation into neuronal and glial phenotypes.1

TABLE 1

Summary of preclinical studies addressing cell transplantation after ICH*

Authors & YearICH modelCell Type Transplanted, RouteNo. of Cells InjectedTiming Post-ICHNo. of AnimalsImmunosuppressive TherapyUsedDifferentiationBehavioral RecoveryEffects After
Jeong et al., 2003rat collagenasehuman NSCs, intravenous5 × 10624 hrs12noneneurons & astrocytesrotarod & limb placing2–8 wks
Nonaka et al., 2004rat collagenasemouse ESCs, intraventricular (contralateral side)1057 days10CsAneurons, astrocytes, & tumor formation (in 1)N/AN/A
An et al., 2004rat blood infusionrat NSCs, intracerebral3 × 1063 days1noneneurons, astrocytes, & oligodendrocytesN/AN/A
Nan et al., 2005rat collagenasehuman UCB, intravenous2.4–3.2 × 10624 hrs16CsAastrocyteslimb placement & elevated body swing7–14 days
Seyfried et al., 2006rat blood infusionhuman BMSCs, intravenous3, 5, or 8 × 10624 hrs27noneneurons & synaptogenesisNSS & corner turn test improved7–14 days
Zhang et al., 2006rat collagenaserat BMSCs; intravenous, intraarterial, intraventricular2 × 1061, 3, 5, & 7 days40noneneurons, astrocytes, & oligodendrocytesbeam walking1–7 days
Lee et al., 200742mouse collagenasehuman NSCs, intracerebral2 × 1057 days31noneneurons & astrocytesrotarod & limb placing2–8 wks
Wan et al., 2007rat blood infusionrat Schwann cells, intracerebral1063 days1noneremyelinationN/AN/A
Kim et al., 2007rat collagenasehumanASCs, intravenous3 × 10624 hrs16noneendothelial cellslimb placing4–5 wks
Li et al., 2007rat collagenaserat NSCs, intraarterial4 × 1062, 7, 14, 21, or 27 days40noneneurons & astrocytesrotarod, beam walking, limb placing, & spontaneous cycling4–9 wks
Lee et al., 200743mouse collagenasehuman NSCs, intracerebral2 × 1057 days50noneneurons, astrocytes, & angiogenesisrotarod & limb placing1–9 wks

* Abbreviations: CsA: cyclosporine A; N/A: not addressed; NSS – Neurological Severity Score.

† No improvement was seen in the animals that received intravenous injections.

In a study by Lee et al.,42 cells derived from the v-myc immortalized human NSC line HB1.F3 transplanted into the brain of mice after ICH gave rise to both neurons and astrocytes and induced behavioral recovery in the rotarod and limb placing tests. Because combined administration of human NSCs and VEGF resulted in neuroprotection and improved functional recovery after cerebral ischemia,33,68 In a second study, Lee and coauthors43 investigated the effects of human NSCs overexpressing VEGF from the HB1.F3 VEGF NSC line. The cells were found to produce 4-fold higher levels of VEGF in vitro compared with parental HB1.F3 cells. Transplantation into the ipsilateral striatum in a mouse model of ICH resulted in improved cell survival, increased neuronal and astrocytic differentiation, and significantly enhanced recovery of neurological deficits compared with controls. In addition, a marked induction of angiogenesis around the lesion site was observed after transplantation of VEGF-overexpressing cells. Li and colleagues45 tried to determine the optimal time point for intraarterial transplantation of rat NSCs after the insult. In rats subjected to ICH, BrdU-labeled NSCs transplanted 2, 7, 14, 21, or 27 days after injury were found to migrate into the perihematomal area and express neuronal or astrocytic markers. Interestingly early transplantation predominantly gave rise to astrocytes, while later transplantation favored neuronal differentiation. The rate of cell survival was highest when transplantation was performed at 7 and 14 days after ICH, and corresponding results were obtained by assessing behavioral recovery.

Other studies have concentrated on the role of MSCs in ICH therapy. Human BMSCs were found to migrate towards the perihematomal area in rats after ICH, where they differentiate into neuronal phenotypes. Upregulation of synaptophysin levels, indicating increased synaptogenesis or the formation of new neuronal connections and significantly improved neurological function, were found 1 week after transplantation.65 Different modes of administration of BMSCs were compared in a study by Zhang and coauthors,83 who used cells of rat origin. Intravenous, intraarterial, and intraventricular infusions of 2 × 106 cells resulted in migration of the cells into the brain, where they were found in the perihematomal area, hippocampus, and cortex. Dependent on their location, the BMSCs differentiated into neurons, astrocytes, and oligodendrocytes. Behavioral recovery in the beam-walking test was only observed in the groups that received intraarterial and intraventricular delivery of stem cells, and not in those that received intravenous injections. Intravenous infusion of human UCB 24 hours after ICH in rats resulted in cell migration into the injured brain area, differentiation into astrocytes, and significantly better functional recovery, as shown on limb placement and elevated body swing tests.55 In a recent study, ASCs isolated from human fat tissue obtained by liposuction were intravenously administered in rats at 24 hours after ICH. Cells were found to migrate towards the perihematomal area and reduce the neurological deficits, as assessed using the limb-placing test. A trend towards behavioral recovery was already seen 10 days after ICH and reached significance after 28 days. Interestingly, the transplanted ASCs differentiated into endothelial cells, expressing von Wille-brand factor as a specific marker. In addition, ASC transplantation successfully reduced brain edema, inflammatory reaction, and glial scar formation after ICH.38

Finally, Schwann cells derived from newborn rats were expanded in vitro and transplanted into the lesioned area after induction of ICH in a rat, where they were found to integrate into the host brain and induce remyelination.74

In summary, in all of the published studies regardless of the cell type, migration of the transplanted cells into the perihematomal region and robust survival after transplantation were reported. Using immunolabeling colocalization studies, most of the reported studies showed differentiation of the transplanted cells into neuronal and glial phenotypes. Surprisingly, Kim and coworkers38 found differentiation into endothelial cells after intravenous administration of human ASCs, but the effects on behavioral recovery were comparable to those found in studies in which neural differentiation of the grafted cells was observed.

In most available reports, the first signs of beneficial effects of transplanted cells on behavioral recovery were seen 2–4 weeks after transplantation. However, there are a number of studies that found significant effects on behavioral recovery after only 1–7 days (Table 1). Because migration to the lesion, integration, neuronal differentiation, and establishment of functional connections with the host cells are unlikely to be accomplished in such a short time period, it is probable that the reported effects on functional recovery are mediated by mechanisms other than direct electrophysiological graft–host interactions. On the other hand, the formation of synapses, establishment of functional electrophysiological connections, and functional integration into host cortical circuitry are well-documented after stem cell transplantation.21 Changes in protein expression profiles consistent with increased synaptogenesis have also been found after cell transplantation for ICH, although this might also be caused by increased neuronal plasticity.65 Perhaps these mechanisms at least partially account for functional improvement at later time points.

Further questions concerning the underlying mechanisms of stem cell–mediated actions arise from the surprising fact that the number of transplanted cells found in the brains of graft recipients does not necessarily correlate with the degree of neurological improvement. Nan et al.55 reported that only a scant number of transplanted UCB-derived cells were found in the area around the hematoma despite the functional recovery of the treated animals. In line with this finding is a report of similar results in a model of is-chemic stroke,72 and Borlongan and colleagues13 suggested that UCB cells do not have to enter the brain to induce neuroprotective effects. It is known that UCB-derived cells are able to secrete neurotrophic factors, such as brain-derived neurotrophic factor, nerve growth factor, and neurotrophins, which are potent neuroprotective agents and have significant effects on neuronal plasticity.55 In addition, ASCs are known to have the potential to produce multiple growth factors, which might be responsible for the neuroprotective effects seen after endothelial differentiation of transplanted ASCs.38,41 In sum, these findings suggest that mechanisms other than cell replacement might significantly contribute to the effects of cell transplantation in ICH.

Many technical problems with the optimization of the transplantation process have not yet been solved, and new questions have arisen from the published studies. Most important, the optimal time window for transplantation after ICH has yet to be determined. Although the upregulation of chemoattractants and cytokines that promote migration of stem cells and precursors towards the lesion site peaks at 24–72 hours after the insult in ischemic stroke,56 no such data exist in the context of ICH. Neuroprotective mechanisms, as postulated above, might be most effective if the cells are transplanted early after the insult. Thus, the authors of most studies have used early transplantation (Table 1). On the other hand, the environment of an acute inflammatory reaction and brain edema is hostile to the transplanted cells and impairs their survival. With these factors in mind, it was shown that the optimal time point for transplantation of NSCs leading to the best recovery of neurological deficits after ICH might be 7–14 days after bleeding.45 In addition, the timing of transplantation was found to be crucial for determining cell fate towards the neuronal or glial lineage, with an increasing percentage of cells showing neuronal differentiation as they are transplanted at later time points. It might be suggested that the microenvironment of ICH favors the differentiation of transplanted cells into astrocytes during the acute phase of the inflammatory reaction and facilitates the development of neurons during a period of increased neuronal plasticity later on. Because optimal functional effects were found at time points after ICH when astrocytic differentiation prevailed, it can be hypothesized that astrocytes play an even more important role in functional recovery than neurons.45

The value of systemic immunosuppression for CNS cell replacement strategies is still controversial (for review see Barker and Widner9). This is of particular interest in ICH because transplantation of cells to a microenvironment in which astrocytes and microglia have already been activated is known to result in enhanced graft survival, a finding that is probably dependent on local production of neurotrophic factors.20 In the majority of reported studies in ICH, no immunosuppressive therapy was used after transplantation (Table 1). Two groups used a cyclosporine regimen when cells were transplanted across the species barrier.55,57 Other studies in which immunosuppressive therapy was not used in this context did not show inferior results, however. Finally, because the formation of a rapidly growing glial tumor was reported in 1 case after intraventricular transplantation of mouse ESCs, important safety issues must be resolved.57

In sum, there is accumulating evidence supporting the potential benefit of stem cell therapy for the treatment of experimental ICH. Although the results of the first studies are encouraging, further investigations are necessary to shed light on the pathological microenvironment after ICH. The field of stem cell research has the potential to lead to effective new therapeutic interventions for this severe form of stroke in the future.

Endogenous Neurogenesis

Over the past decades, the dogma established in the late 19th century by Santiago Ramón y Cajal regarding the lack of regeneration in the adult CNS has been overcome by evidence of ongoing neuronal birth in the mammalian brain (for review see Gage29). Endogenous neurogenesis is now known to occur throughout life in the adult CNS by proliferation of NSCs in specific brain areas, including the SVZ and the SGL.22,46,53 From the SVZ newborn neuroblasts, which express doublecortin as a characteristic marker, migrate along the rostral migratory stream to the olfactory bulb, while developing cells in the SGL give rise to granule cells in the hippocampus. Moreover, endogenous neurogenesis has been found in the cerebral cortex.49

Different types of brain injuries, including ischemic stroke, have been shown to stimulate the recruitment of endogenous neural precursor cells, including in ischemic stroke.81 Stem cells in the SVZ are able to respond to damage in remote brain regions by increased proliferation and migration of neuroblasts toward the lesion. Molecular signals originating from degenerating cells in the lesion or cells in the vicinity of the lesion, such as growth factors, seem to be responsible for this neurogenic response.78 However, the underlying mechanisms are still poorly understood.25 The brain seems to have a latent capacity for self-repair, even if its regenerative potential is limited. It is possible that interfering with these processes could offer new ways for neuroregenerative strategies.11

The effects of experimental ICH on endogenous stem cell proliferation have recently been investigated by several groups, and the results of 2 studies have been published so far.51,69 Proliferating cells in the brain parenchyma can be identified by labeling them with BrdU, a thymidine base analog that can be systemically administered and is incorporated into the DNA formed during replication in dividing cells.

Using collagenase induced–ICH in rats, Masuda and coworkers51 were able to demonstrate a significant up-regulation of endogenous neurogenesis in both the ipsilateral and contralateral SVZ through BrdU postlabeling for 14 days after the insult. Bromodeoxyuridine prelabeling for 2 days prior to the insult was found to result in an increased number of BrdU-positive cells in the striatum ipsilateral to the lesion as compared to the other side, indicating migration of these cells towards the lesion. Accordingly, an increased number of doublecortin-expressing migrating neuroblasts was found in the striatum and the perihematomal area 14 days after ICH. Another group reported an increase in the number of BrdU-positive cells in the perihematomal area only 2 days after ICH; this peaked at 14 days and gradually declined at 28 days after the insult. In addition, abundant cells expressing nestin, a marker for neuronal and glial precursor cells, were found in the region around the hematoma.69

In line with these observations, we found a significant increase in the number of BrdU-positive cells in the SVZ and in the perihematomal area after induction of ICH in rats and BrdU postlabeling for 7 days in our own studies (unpublished data). Therefore, experimental ICH seems to stimulate neurogenesis from the endogenous stem cell pool and induces migration of neural precursors towards the lesioned area. Activation and amplification of this neurogenic response could become a powerful tool for brain repair in patients with ICH in the future.

Conclusions

Intracerebral hemorrhage comprises roughly 10–15% of all cerebrovascular insults and carries the highest risk of mortality, severe complications, and poor long-term outcome. Concurrently, ICH has long been regarded as the least treatable form of stroke, as compared with cerebral ischemia and subarachnoid hemorrhage. In most cases, no effective therapeutic options other than conventional rehabilitation measures are available to improve the recovery of patients after the insult.

In the past decade basic and clinical research has made considerable progress leading to a steady increase in our knowledge concerning the mechanisms underlying brain injury from ICH. An initial physical trauma, the mass effect of the hematoma, the resulting inflammatory reaction, oxidative stress, neurotoxicity mediated by excitatory neurotransmitters, thrombin, and hemoglobin breakdown products have all been identified as contributing factors to neuronal cell death after ICH. However, our current knowledge is still limited and a better understanding of the pathophysiological mechanisms after ICH will be needed to successfully develop new therapeutic options. The currently available animal models, which only poorly reflect the complex pathophysiology of ICH, must also be improved to achieve this goal.

Authors of studies in animals have suggested a role for neuroprotective strategies aimed at blocking glutamate excitotoxicity, inhibiting the inflammatory response, oxidative damage, MMP activity, and apoptosis. The induction of local or systemic hypothermia might also be beneficial for neuronal survival after ICH. However, the results of the first clinical trial investigating the neuroprotective effects in patients with ICH were disappointing, as were data from clinical studies investigating neuroprotection in ischemic stroke. Because there is only a limited body of preclinical studies on neuroprotection in ICH, there is a need for additional investigations to clarify its therapeutic potential.

Several strategies are currently under investigation aimed at transplanting a variety of different types of stem cells, including ESCs, NSCs, BMSCs, ASCs, and UCB-derived stem cells. The transplanted cells have the ability to survive in the host brain, migrate, and acquire a specific neuronal phenotype in response to local cellular signals. These cells are also capable of forming functional synapses with the surrounding neurons. One could argue that at least some of the beneficial effects on neurological recovery seen after cell transplantation rely on neuroprotection or stimulation of neuronal plasticity rather than on functional integration into the disrupted neuronal circuitry. These effects could be due to local modulation of the immune response or to the secretion of trophic factors. Unsolved problems in the field of stem cell therapy include the limited capacity of transplanted cells to survive, differentiate, and maintain an acquired phenotype in pathological environments, the molecular heterogeneity of outwardly lineage-restricted cell populations, and the uncertain physiological functions and effects of transplanted cells on the host brain. Although knowledge about the molecular mechanisms of stem cell development is accumulating, further research is needed into the identification, characterization, and preparation of stem cells before they can be used safely for brain repair.

The proliferation of endogenous NSCs observed in response to various types of CNS injury indicates that the brain has a limited capacity of self repair. There is evidence that experimental ICH enhances the proliferation of endogenous NSCs and promotes the migration of newly born neuroblasts toward the hemorrhage area in the rat brain. To use this neurogenic response for reconstructing the damaged neuronal circuitry, we must first understand the signals that guide the migration, differentiation, and integration of stem cells and neural progenitors. Until recently, ICH was considered an untreatable disease with a fatal outcome. However, basic and clinical research accomplished in the last few years offers great promise for developing novel and efficacious cell-based treatment strategies for patients who suffer from this debilitating disease. The next decade should bring us a better understanding of the mechanisms that regulate stem cell development, this understanding is necessary so that knowledge from basic research can be translated into clinical therapeutic applications in humans.

Disclaimer

None of the authors has any direct financial interest in the subject matter of this article.

References

  • 1

    An YHWang HYGao ZXWang ZC: Differentiation of rat neural stem cells and its relationship with environment. Biomed Environ Sci 17:172004

  • 2

    Andres RHDucray ADHuber AWPérez-Bouza AKrebs SHSchlattner U: Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue. J Neurochem 95:33452005

  • 3

    Andres RHDucray ADPerez-Bouza ASchlattner UHuber AWKrebs SH: Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system. Cell Transplant 14:5375502005

  • 4

    Andres RHHuber AWSchlattner UPérez-Bouza AKrebs SHSeiler RW: Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience 133:7017132005

  • 5

    Ariesen MJClaus SPRinkel GJAlgra A: Risk factors for intra-cerebral hemorrhage in the general population: a systematic review. Stroke 34:206020652003

  • 6

    Badjatia NRosand J: Intracerebral hemorrhage. Neurologist 11:3113242005

  • 7

    Bamford JDennis MSandercock PBurn JWarlow C: The frequency, causes and timing of death within 30 days of a first stroke: the Oxfordshire Community Stroke Project. J Neurol Neurosurg Psychiatry 53:8248291990

  • 8

    Bamford JSandercock PDennis MBurn JWarlow C: A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981–86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 53:16221990

  • 9

    Barker RAWidner H: Immune problems in central nervous system cell therapy. NeuroRx 1:4724812004

  • 10

    Barth AGuzman RAndres RHMordasini PBarth LWidmer HR: Experimental intracerebral hematoma in the rat. Restor Neurol Neurosci 25:172007

  • 11

    Björklund ALindvall O: Self-repair in the brain. Nature 405:8928938952000

  • 12

    Bliss TGuzman RDaadi MSteinberg GK: Cell transplantation therapy for stroke. Stroke 38:2 Suppl8178262007

  • 13

    Borlongan CVHadman MSanberg CDSanberg PR: Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 35:238523892004

  • 14

    Broderick JBrott TTomsick TLeach A: Lobar hemorrhage in the elderly. The undiminishing importance of hypertension. Stroke 24:49511993

  • 15

    Broderick JPBrott TTomsick THuster GMiller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med 326:7337361992

  • 16

    Brott TThalinger KHertzberg V: Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke 17:107810831986

  • 17

    Bullock RMendelow ADTeasdale GMGraham DI: Intracranial haemorrhage induced at arterial pressure in the rat. Part 1: Description of technique, ICP changes and neuropathological findings. Neurol Res 6:1841881984

  • 18

    Chu KJeong SWJung KHHan SYLee STKim M: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 24:9269332004

  • 19

    Dennis MS: Outcome after brain haemorrhage. Cerebrovasc Dis 16:1 Suppl9132003

  • 20

    Duan WMWidner HCameron RMBrundin P: Quinolinic acid-induced inflammation in the striatum does not impair the survival of neural allografts in the rat. Eur J Neurosci 10:259526061998

  • 21

    Englund UBjorklund AWictorin KLindvall OKokaia M: Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry. Proc Natl Acad Sci USA 99:17089170942002

  • 22

    Eriksson PSPerfilieva EBjörk-Eriksson TAlborn AMNordborg CPeterson DA: Neurogenesis in the adult human hippocampus. Nat Med 4:131313171998

  • 23

    Evans MJKaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature 292:1541561981

  • 24

    Faden AIStoica B: Neuroprotection: challenges and opportunities. Arch Neurol 64:7948002007

  • 25

    Ferretti P: Neural stem cell plasticity: recruitment of endogenous populations for regeneration. Curr Neurovasc Res 1:2152292004

  • 26

    Fingas MClark DLColbourne F: The effects of selective brain hypothermia on intracerebral hemorrhage in rats. Exp Neurol 208:2772842007

  • 27

    Fisher LJ: Neural precursor cells: applications for the study and repair of the central nervous system. Neurobiol Dis 4:1221997

  • 28

    Furlan AJWhisnant JPElveback LR: The decreasing incidence of primary intracerebral hemorrhage: a population study. Ann Neurol 5:3673731979

  • 29

    Gage FH: Neurogenesis in the adult brain. J Neurosci 22:6126132002

  • 30

    Greenberg SM: Genetics of primary intracerebral hemorrhage. J Stroke Cerebrovasc Dis 11:2652712002

  • 31

    Guzman RUchida NBliss TMHe DChristopherson KKStellwagen D: Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci USA 104:10211102162007

  • 32

    Haley EC JrThompson JLLevin BDavis SLees KRPittman JG: Gavestinel does not improve outcome after acute intra-cerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke 36:100610102005

  • 33

    Hayashi TAbe KItoyama Y: Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 18:8878951998

  • 34

    Hua YKeep RFHoff JTXi G: Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38:2 Suppl7597622007

  • 35

    Hua YWu JKeep RFNakamura THoff JTXi G: Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 58:5425502006

  • 36

    Jeong SWChu KJung KHKim SUKim MRoh JK: Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage. Stroke 34:225822632003

  • 37

    Kassem MKristiansen MAbdallah BM: Mesenchymal stem cells: cell biology and potential use in therapy. Basic Clin Pharmacol Toxicol 95:2092142004

  • 38

    Kim JMLee STChu KJung KHSong ECKim SJ: Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res 1183C:43502007

  • 39

    Kornblum HI: Introduction to neural stem cells. Stroke 38:2 Suppl8108162007

  • 40

    Lapchak PAAraujo DM: Advances in hemorrhagic stroke therapy: conventional and novel approaches. Expert Opin Emerg Drugs 12:3894062007

  • 41

    Lapergue BMohammad AShuaib A: Endothelial progenitor cells and cerebrovascular diseases. Prog Neurobiol 83:3493622007

  • 42

    Lee HJKim KSKim EJChoi HBLee KHPark IH: Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 25:120412122007

  • 43

    Lee HJKim KSPark IHKim SU: Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2:e1562007

  • 44

    Lee STChu KJung KHKim JKim EHKim SJ: Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 26:5365442006

  • 45

    Li FLiu YZhu SWang XYang HLiu C: Therapeutic time window and effect of intracarotid neural stem cells transplantation for intracerebral hemorrhage. Neuroreport 18:101910232007

  • 46

    Lois CAlvarez-Buylla A: Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 90:207420771993

  • 47

    MacLellan CLGirgis JColbourne F: Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 24:4324402004

  • 48

    MacLellan CLSilasi GPoon CCEdmundson CLBuist RPeeling J: Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab [epub ahead of print]2007

  • 49

    Magavi SSLeavitt BRMacklis JD: Induction of neurogenesis in the neocortex of adult mice. Nature 405:9519552000

  • 50

    Maier CMAhern KCheng MLLee JEYenari MASteinberg GK: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 29:217121801998

  • 51

    Masuda TIsobe YAihara NFuruyama FMisumi SKim TS: Increase in neurogenesis and neuroblast migration after a small intracerebral hemorrhage in rats. Neurosci Lett 425:1141192007

  • 52

    Mayer SARincon F: Treatment of intracerebral haemorrhage. Lancet Neurol 4:6626722005

  • 53

    McKay R: Stem cells in the central nervous system. Science 276:66711997

  • 54

    Mendelow ADGregson BAFernandes HMMurray GDTeasdale GMHope DT: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:3873972005

  • 55

    Nan ZGrande ASanberg CDSanberg PRLow WC: Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann N Y Acad Sci 1049:84962005

  • 56

    Newman MBWilling AEManresa JJDavis-Sanberg CSanberg PR: Stroke-induced migration of human umbilical cord blood cells: time course and cytokines. Stem Cells Dev 14:5765862005

  • 57

    Nonaka MYoshikawa MNishimura FYokota HKimura HHirabayashi H: Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats. Neurol Res 26:2652722004

  • 58

    Ormerod BKPalmer TDCaldwell MA: Neurodegeneration and cell replacement. Philos Trans R Soc Lond B Biol Sci 363:1531702008

  • 59

    Qureshi AITuhrim SBroderick JPBatjer HHHondo HHanley DF: Spontaneous intracerebral hemorrhage. N Engl J Med 344:145014602001

  • 60

    Rosenberg GAMun-Bryce SWesley MKornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 21:8018071990

  • 61

    Sacco RLDeRosa JTHaley EC JrLevin BOrdronneau PPhillips SJ: Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 285:171917282001

  • 62

    Safford KMRice HE: Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Curr Drug Targets 6:57622005

  • 63

    Sanberg PRWilling AEGarbuzova-Davis SSaporta SLiu GSanberg CD: Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad Sci 1049:67832005

  • 64

    Schouten JWFulp CTRoyo NCSaatman KEWatson DJSnyder EY: A review and rationale for the use of cellular transplantation as a therapeutic strategy for traumatic brain injury. J Neurotrauma 21:150115382004

  • 65

    Seyfried DDing JHan YLi YChen JChopp M: Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg 104:3133182006

  • 66

    Seyfried DHan YLu DChen JBydon AChopp M: Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 101:1041072004

  • 67

    Sinn DIKim SJChu KJung KHLee STSong EC: Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:4644722007

  • 68

    Sun YJin KXie LChilds JMao XOLogvinova A: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:184318512003

  • 69

    Tang TLi XQWu HLuo JKZhang HXLuo TL: Activation of endogenous neural stem cells in experimental intracerebral hemorrhagic rat brains. Chin Med J (Engl) 117:134213472004

  • 70

    Tejima EZhao BQTsuji KRosell Avan Leyen KGonzalez RG: Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 27:4604682007

  • 71

    Thompson KMGerlach SYJorn HKLarson JMBrott TGFiles JA: Advances in the care of patients with intracerebral hemorrhage. Mayo Clin Proc 82:9879902007

  • 72

    Vendrame MCassady JNewcomb JButler TPennypacker KRZigova T: Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 35:239023952004

  • 73

    Wagner KRBeiler SBeiler CKirkman JCasey KRobinson T: Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir (Wien) Suppl 96:1771822006

  • 74

    Wan HZhang SDLi JH: Action of Schwann cells implanted in cerebral hemorrhage lesion. Biomed Environ Sci 20:47512007

  • 75

    Wang JDoré S: Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 130:164316522007

  • 76

    Wang JTsirka SE: Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128:162216332005

  • 77

    Wang XMori TSumii TLo EH: Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33:188218882002

  • 78

    Wang YSheen VLMacklis JD: Cortical interneurons upregulate neurotrophins in vivo in response to targeted apoptotic degeneration of neighboring pyramidal neurons. Exp Neurol 154:3894021998

  • 79

    Wartenberg KEMayer SA: Reducing the risk of ICH enlargement. J Neurol Sci 261:991072007

  • 80

    Wasserman JKSchlichter LC: Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol 207:2272372007

  • 81

    Wiltrout CLang BYan YDempsey RJVemuganti R: Repairing brain after stroke: a review on post-ischemic neurogenesis. Neurochem Int 50:102810412007

  • 82

    Xi GKeep RFHoff JT: Mechanisms of brain injury after intra-cerebral haemorrhage. Lancet Neurol 5:53632006

  • 83

    Zhang HHuang ZXu YZhang S: Differentiation and neurological benefit of the mesenchymal stem cells transplanted into the rat brain following intracerebral hemorrhage. Neurol Res 28:1041122006

  • 84

    Zhao HShimohata TWang JQSun GSchaal DWSapolsky RM: Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci 25:979498062005

This work was supported in part by Russell and Elizabeth Siegelman, Bernard and Ronni Lacroute, the William Randolph Hearst Foundation, the Edward E. Hills Fund, the Swiss National Science Foundation (Grants No. 31-064975.1, 3100A0-112529 and PBBEB-117034), and the Department of Clinical Research, Medical Faculty, University of Berne, Switzerland

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Article Information

Address correspondence to: Gary K. Steinberg, M.D., Ph.D., Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive, R281, Stanford, California 94305–5327. email: gsteinberg@stanford.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Photograph of a right striatal hematoma (arrow) in the brain of an adult rat 2 days posthemorrhage. Due to the circumscribed hematoma borders and preservation of the surrounding brain parenchyma, this lesion is well-suited for studies of restorative strategies after the insult.

  • View in gallery

    Magnetic resonance images at 3T of rats with ICH obtained 30 days posthemorrhage. A: Fast low angle shot sequence showing susceptibility artifacts of hemosiderin deposits (arrow). B–D: On triplanar T2-weighted turbo spin-echo images, the location and configuration of the lesion in the right striatum is demonstrated (arrows).

  • View in gallery

    Photomicrographs of green fluorescent protein–transfected neuronal progenitor cells transplanted into the striatum of an adult rat with ICH. A: Implanted cells were visualized by immunohistochemistry for p75 nerve growth factor receptor. B: Enlarged view (boxed area in A) of the p75 nerve growth factor receptor–positive cells (arrows). C: Green fluorescent protein expression was detected in transplanted cells in the graft (arrow). LV = lateral ventricle, St = striatum, T = transplant. Bars = 50 μm

References

1

An YHWang HYGao ZXWang ZC: Differentiation of rat neural stem cells and its relationship with environment. Biomed Environ Sci 17:172004

2

Andres RHDucray ADHuber AWPérez-Bouza AKrebs SHSchlattner U: Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue. J Neurochem 95:33452005

3

Andres RHDucray ADPerez-Bouza ASchlattner UHuber AWKrebs SH: Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system. Cell Transplant 14:5375502005

4

Andres RHHuber AWSchlattner UPérez-Bouza AKrebs SHSeiler RW: Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience 133:7017132005

5

Ariesen MJClaus SPRinkel GJAlgra A: Risk factors for intra-cerebral hemorrhage in the general population: a systematic review. Stroke 34:206020652003

6

Badjatia NRosand J: Intracerebral hemorrhage. Neurologist 11:3113242005

7

Bamford JDennis MSandercock PBurn JWarlow C: The frequency, causes and timing of death within 30 days of a first stroke: the Oxfordshire Community Stroke Project. J Neurol Neurosurg Psychiatry 53:8248291990

8

Bamford JSandercock PDennis MBurn JWarlow C: A prospective study of acute cerebrovascular disease in the community: the Oxfordshire Community Stroke Project—1981–86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 53:16221990

9

Barker RAWidner H: Immune problems in central nervous system cell therapy. NeuroRx 1:4724812004

10

Barth AGuzman RAndres RHMordasini PBarth LWidmer HR: Experimental intracerebral hematoma in the rat. Restor Neurol Neurosci 25:172007

11

Björklund ALindvall O: Self-repair in the brain. Nature 405:8928938952000

12

Bliss TGuzman RDaadi MSteinberg GK: Cell transplantation therapy for stroke. Stroke 38:2 Suppl8178262007

13

Borlongan CVHadman MSanberg CDSanberg PR: Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 35:238523892004

14

Broderick JBrott TTomsick TLeach A: Lobar hemorrhage in the elderly. The undiminishing importance of hypertension. Stroke 24:49511993

15

Broderick JPBrott TTomsick THuster GMiller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med 326:7337361992

16

Brott TThalinger KHertzberg V: Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke 17:107810831986

17

Bullock RMendelow ADTeasdale GMGraham DI: Intracranial haemorrhage induced at arterial pressure in the rat. Part 1: Description of technique, ICP changes and neuropathological findings. Neurol Res 6:1841881984

18

Chu KJeong SWJung KHHan SYLee STKim M: Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J Cereb Blood Flow Metab 24:9269332004

19

Dennis MS: Outcome after brain haemorrhage. Cerebrovasc Dis 16:1 Suppl9132003

20

Duan WMWidner HCameron RMBrundin P: Quinolinic acid-induced inflammation in the striatum does not impair the survival of neural allografts in the rat. Eur J Neurosci 10:259526061998

21

Englund UBjorklund AWictorin KLindvall OKokaia M: Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry. Proc Natl Acad Sci USA 99:17089170942002

22

Eriksson PSPerfilieva EBjörk-Eriksson TAlborn AMNordborg CPeterson DA: Neurogenesis in the adult human hippocampus. Nat Med 4:131313171998

23

Evans MJKaufman MH: Establishment in culture of pluripotential cells from mouse embryos. Nature 292:1541561981

24

Faden AIStoica B: Neuroprotection: challenges and opportunities. Arch Neurol 64:7948002007

25

Ferretti P: Neural stem cell plasticity: recruitment of endogenous populations for regeneration. Curr Neurovasc Res 1:2152292004

26

Fingas MClark DLColbourne F: The effects of selective brain hypothermia on intracerebral hemorrhage in rats. Exp Neurol 208:2772842007

27

Fisher LJ: Neural precursor cells: applications for the study and repair of the central nervous system. Neurobiol Dis 4:1221997

28

Furlan AJWhisnant JPElveback LR: The decreasing incidence of primary intracerebral hemorrhage: a population study. Ann Neurol 5:3673731979

29

Gage FH: Neurogenesis in the adult brain. J Neurosci 22:6126132002

30

Greenberg SM: Genetics of primary intracerebral hemorrhage. J Stroke Cerebrovasc Dis 11:2652712002

31

Guzman RUchida NBliss TMHe DChristopherson KKStellwagen D: Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI. Proc Natl Acad Sci USA 104:10211102162007

32

Haley EC JrThompson JLLevin BDavis SLees KRPittman JG: Gavestinel does not improve outcome after acute intra-cerebral hemorrhage: an analysis from the GAIN International and GAIN Americas studies. Stroke 36:100610102005

33

Hayashi TAbe KItoyama Y: Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 18:8878951998

34

Hua YKeep RFHoff JTXi G: Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke 38:2 Suppl7597622007

35

Hua YWu JKeep RFNakamura THoff JTXi G: Tumor necrosis factor-alpha increases in the brain after intracerebral hemorrhage and thrombin stimulation. Neurosurgery 58:5425502006

36

Jeong SWChu KJung KHKim SUKim MRoh JK: Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage. Stroke 34:225822632003

37

Kassem MKristiansen MAbdallah BM: Mesenchymal stem cells: cell biology and potential use in therapy. Basic Clin Pharmacol Toxicol 95:2092142004

38

Kim JMLee STChu KJung KHSong ECKim SJ: Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res 1183C:43502007

39

Kornblum HI: Introduction to neural stem cells. Stroke 38:2 Suppl8108162007

40

Lapchak PAAraujo DM: Advances in hemorrhagic stroke therapy: conventional and novel approaches. Expert Opin Emerg Drugs 12:3894062007

41

Lapergue BMohammad AShuaib A: Endothelial progenitor cells and cerebrovascular diseases. Prog Neurobiol 83:3493622007

42

Lee HJKim KSKim EJChoi HBLee KHPark IH: Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model. Stem Cells 25:120412122007

43

Lee HJKim KSPark IHKim SU: Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model. PLoS ONE 2:e1562007

44

Lee STChu KJung KHKim JKim EHKim SJ: Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. J Cereb Blood Flow Metab 26:5365442006

45

Li FLiu YZhu SWang XYang HLiu C: Therapeutic time window and effect of intracarotid neural stem cells transplantation for intracerebral hemorrhage. Neuroreport 18:101910232007

46

Lois CAlvarez-Buylla A: Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 90:207420771993

47

MacLellan CLGirgis JColbourne F: Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats. J Cereb Blood Flow Metab 24:4324402004

48

MacLellan CLSilasi GPoon CCEdmundson CLBuist RPeeling J: Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab [epub ahead of print]2007

49

Magavi SSLeavitt BRMacklis JD: Induction of neurogenesis in the neocortex of adult mice. Nature 405:9519552000

50

Maier CMAhern KCheng MLLee JEYenari MASteinberg GK: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 29:217121801998

51

Masuda TIsobe YAihara NFuruyama FMisumi SKim TS: Increase in neurogenesis and neuroblast migration after a small intracerebral hemorrhage in rats. Neurosci Lett 425:1141192007

52

Mayer SARincon F: Treatment of intracerebral haemorrhage. Lancet Neurol 4:6626722005

53

McKay R: Stem cells in the central nervous system. Science 276:66711997

54

Mendelow ADGregson BAFernandes HMMurray GDTeasdale GMHope DT: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:3873972005

55

Nan ZGrande ASanberg CDSanberg PRLow WC: Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann N Y Acad Sci 1049:84962005

56

Newman MBWilling AEManresa JJDavis-Sanberg CSanberg PR: Stroke-induced migration of human umbilical cord blood cells: time course and cytokines. Stem Cells Dev 14:5765862005

57

Nonaka MYoshikawa MNishimura FYokota HKimura HHirabayashi H: Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats. Neurol Res 26:2652722004

58

Ormerod BKPalmer TDCaldwell MA: Neurodegeneration and cell replacement. Philos Trans R Soc Lond B Biol Sci 363:1531702008

59

Qureshi AITuhrim SBroderick JPBatjer HHHondo HHanley DF: Spontaneous intracerebral hemorrhage. N Engl J Med 344:145014602001

60

Rosenberg GAMun-Bryce SWesley MKornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 21:8018071990

61

Sacco RLDeRosa JTHaley EC JrLevin BOrdronneau PPhillips SJ: Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 285:171917282001

62

Safford KMRice HE: Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Curr Drug Targets 6:57622005

63

Sanberg PRWilling AEGarbuzova-Davis SSaporta SLiu GSanberg CD: Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad Sci 1049:67832005

64

Schouten JWFulp CTRoyo NCSaatman KEWatson DJSnyder EY: A review and rationale for the use of cellular transplantation as a therapeutic strategy for traumatic brain injury. J Neurotrauma 21:150115382004

65

Seyfried DDing JHan YLi YChen JChopp M: Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg 104:3133182006

66

Seyfried DHan YLu DChen JBydon AChopp M: Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg 101:1041072004

67

Sinn DIKim SJChu KJung KHLee STSong EC: Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation. Neurobiol Dis 26:4644722007

68

Sun YJin KXie LChilds JMao XOLogvinova A: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111:184318512003

69

Tang TLi XQWu HLuo JKZhang HXLuo TL: Activation of endogenous neural stem cells in experimental intracerebral hemorrhagic rat brains. Chin Med J (Engl) 117:134213472004

70

Tejima EZhao BQTsuji KRosell Avan Leyen KGonzalez RG: Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage. J Cereb Blood Flow Metab 27:4604682007

71

Thompson KMGerlach SYJorn HKLarson JMBrott TGFiles JA: Advances in the care of patients with intracerebral hemorrhage. Mayo Clin Proc 82:9879902007

72

Vendrame MCassady JNewcomb JButler TPennypacker KRZigova T: Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 35:239023952004

73

Wagner KRBeiler SBeiler CKirkman JCasey KRobinson T: Delayed profound local brain hypothermia markedly reduces interleukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir (Wien) Suppl 96:1771822006

74

Wan HZhang SDLi JH: Action of Schwann cells implanted in cerebral hemorrhage lesion. Biomed Environ Sci 20:47512007

75

Wang JDoré S: Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 130:164316522007

76

Wang JTsirka SE: Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128:162216332005

77

Wang XMori TSumii TLo EH: Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33:188218882002

78

Wang YSheen VLMacklis JD: Cortical interneurons upregulate neurotrophins in vivo in response to targeted apoptotic degeneration of neighboring pyramidal neurons. Exp Neurol 154:3894021998

79

Wartenberg KEMayer SA: Reducing the risk of ICH enlargement. J Neurol Sci 261:991072007

80

Wasserman JKSchlichter LC: Minocycline protects the blood-brain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol 207:2272372007

81

Wiltrout CLang BYan YDempsey RJVemuganti R: Repairing brain after stroke: a review on post-ischemic neurogenesis. Neurochem Int 50:102810412007

82

Xi GKeep RFHoff JT: Mechanisms of brain injury after intra-cerebral haemorrhage. Lancet Neurol 5:53632006

83

Zhang HHuang ZXu YZhang S: Differentiation and neurological benefit of the mesenchymal stem cells transplanted into the rat brain following intracerebral hemorrhage. Neurol Res 28:1041122006

84

Zhao HShimohata TWang JQSun GSchaal DWSapolsky RM: Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci 25:979498062005

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