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a Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden;
b Laboratory of Neural Stem Cell Biology, Section of Restorative Neurology, Stem Cell Institute, University Hospital, Lund, Sweden;
c Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden
Key Words. Stem cells • Neurogenesis • Striatum • Stroke
Correspondence: Olle Lindvall, M.D., Ph.D., Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, SE-221 84 Lund, Sweden. Telephone: 46-46-222 0543; Fax: 46-46-222 0560; e-mail: olle.lindvall{at}med.lu.se
Received June 23, 2005;
accepted for publication September 27, 2005.
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ABSTRACT |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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and its receptor CXCR4. These results show that endogenous neural stem cells continuously supply the injured adult brain with new neurons, which suggests novel self-repair strategies to improve recovery after stroke.
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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We show herein that stroke-induced neurogenesis is extensive and long-lasting, with continuous production of mature striatal neurons for several months after the insult. We also find that stromal cell– derived factor-1 (SDF-1)/CXCR4 signaling regulates the directed migration of new neurons to the injured area.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Caspase Inhibitor and CXCR4 Antagonist Treatments
Daily intraventricular infusions of a caspase inhibitor cocktail, comprising equal portions of a multicaspase, a caspase 3, and a caspase 9 inhibitor, were given over 12 days, starting on day 3 after MCAO [11]. Mini-osmotic pumps (model 2002, flow rate, 0.5 µl/hour; Alzet, Palo Alto, CA, http://www.alzet.com) were implanted 4 weeks after 2-hour MCAO, infusing either the CXCR4 antagonist AMD3100 (Sigma-Aldrich, 5 mg/ml in phosphate-buffered saline [PBS]) or PBS for 2 weeks into the lateral ventricle.
In Vitro Assays
Neurospheres were grown in Dulbecco’s modified Eagle’s medium(DMEM)/F12(Gibco-BRL,Gaithersburg,MD,http://www.gibcobrl.com) supplemented with B27 containing 20 ng/ml epidermal growth factor and 10 ng/ml basic fibroblast growth factor (R&D Systems Inc., Minneapolis, http://www.rndsystems.com) [12]. After trituration of SVZ tissue or primary neurospheres, cells were plated in 24-well plates for 7 days, and the number and diameter of spheres were quantified.
For studies of phosphorylation, adult rat SVZ cells were plated in 96-well plates. After 5 days in vitro, serum and growth factors were withdrawn for 18 hours. Cells were treated with the basal medium either alone or containing 500 ng/ml SDF-1 (R&D Systems) for 10 minutes. Phosphorylation of extracellular signal-related kinase (ERK)-1/2 was assessed using FACE enzyme-linked immunosorbent assay kits (Active Motif, Rixensart, Belgium, http://www.activemotif.com).
For the migration assay, neurospheres from the SVZ were distributed on a poly-L-lysine coated polyvinylpyrrolidine-free polycarbonate filter in the upper section of a 96-well microchemotaxis chamber (Neuro Probe, Gaithersburg, MD, http://www.neuroprobe.com). SDF-1 (100 or 500 ng/ml) was added to either the lower wells, upper wells, or both. Basal medium without SDF-1 served as control. Neurospheres were allowed to migrate for 12 hours. The filter was fixed in 4% phosphate-buffered paraformaldehyde (PFA) and stained with Hoechst 33342 (Molecular Probes Inc., Eugene, OR, http://probes.invitrogen.com), and migrated cells were counted using an epifluorescence microscope.
Immunohistochemistry
After transcardial perfusion with 4% ice-cold PFA, brains were postfixed overnight in PFA and sectioned coronally at 30 µm on dry ice. Prior to staining using diaminobenzidine (DAB), free-floating sections were quenched for 20 minutes in 3% hydrogen peroxide and 10% methanol, and prior to staining for BrdU, sections were incubated in 1 M HCl at 65°C for 10 minutes and at 37°C for 20 minutes. Following preincubation with the appropriate normal sera, sections were incubated for 36 hours at 4°C with either two of the following antibodies—rat anti-BrdU (1:100; Harlan Sera-Lab, Loughborough, U.K., http://www.harlaneurope.com), goat anti-doublecortin (Dcx) antibody (1:400; Santa Cruz Biotechnology Inc., Santa Cruz, CA, http://www.scbt.com), guinea-pig anti-Dcx (1:3,000; Abcam, Cambridge, U.K., http://www.abcam.com), mouse anti-neuronal nuclei (NeuN; 1:100; Chemicon, Temecula, CA, http://www.chemicon.com), goat anti-CXCR4 (recognizes SDF-1 and SDF-1ß, 1:100; Santa Cruz Biotechnology), goat anti-SDF-1 (recognizes SDF-1 and SDF-1ß, 1:100; Santa Cruz Biotechnology), mouse anti-ED1 (1:200; SeroTec, Ltd., Oslo, Norway, http://www.serotec.com), or mouse glial fibrillary acidic protein (GFAP; 1:1,000; Sigma-Aldrich)—or overnight with mouse anti-NeuN only, in normal sera. Stainings were visualized by incubation for 2 hours with Cy3-conjugated (1:200; Jackson ImmunoResearch Laboratories, West Grove, PA, http://www.jacksonimmuno.com) and biotinylated secondary antibodies (1:200; Vector Laboratories, Burlingame, CA, http://www.vectorlabs.com) followed by Alexa 488-conjugated streptavidin (1:200; Molecular Probes) for 2 hours for double stainings, or avidin-biotin-peroxidase complex for 1 hour followed by treatment with DAB (0.5 mg/ml) and hydrogen peroxide for single staining. Sections were then mounted on glass slides and coverslipped. For caspase-cleaved poly(ADP-ribose) polymerase (cPARP)/Dcx double staining, sections were stained for Dcx as above and mounted on glass slides before incubation overnight with rabbit anti-rat cPARP antibody (1:20; Cell Signaling Technology, Beverly, MA, http://www.cellsignal.com) in 3% bovine serum albumin at 4°C. For in vitro stainings, neurospheres were plated on poly-L-lysine-coated four-well chamber slides and differentiated for 7 days in basal medium containing 1% fetal bovine serum (differentiation medium). Cells were fixed in 4% PFA at room temperature and stained using mouse anti-ßIII-tubulin antibody (1:350; Sigma-Aldrich). For CXCR4 staining, SVZ-derived neurospheres or primary cells were plated overnight in expansion medium, fixed, and stained with goat anti-CXCR4 antibody (1:100). Both stainings were counterstained with Hoechst 33342.
Microscopical Analysis
Cells double-labeled with BrdU and Dcx or NeuN were counted using an epifluorescence microscope with 40x objective (Olympus A/S, Glostrup, Denmark, http://www2.olympus.dk). The accuracy of double labeling was validated using a confocal laser-scanning microscope (Leica, Heerbrugg, Switzerland, http://www.leica.com). Dcx+, Dcx+/BrdU+, and NeuN+/BrdU+ cells were counted, using a 0.25-mm-wide quadratic grid, in the entire striatum in four sections, at +1.60, +1.00, +0.48, and –0.26 mm from bregma, the most medial column lining the SVZ. Striatal volumes were measured using stereological equipment in the same sections. The size of the SVZ was measured in sections from the same rostrocaudal levels stained with NeuN and cresyl violet. The SVZ was delineated by cells stained with cresyl violet only. BrdU+ cells in the SVZ were counted in three sections (+1.60, +0.70, and –0.26 mm from bregma) with the optical fractionator method on stereological equipment.
Behavioral Tests
Behavioral tests were performed 24 hours before (control) and 48 hours, 4 weeks, and 16 weeks after 30-minute MCAO. In the modified horizontal ladder walking test [13], rats were allowed to walk on the ladder for 5 minutes. The degree of behavioral deficit was calculated for each animal using a formula that takes into account the total number of steps and falls, as well as the time and speed of active walking. The stepping test, for evaluation of forelimb akinesia [14], and the cylinder test of forelimb asymmetry [15] were performed as described previously [16].
Animal Groups and Statistical Analysis
Quantification of the number of Dcx+, Dcx+/BrdU+, and NeuN+/BrdU+ cells 2, 6, and 16 weeks after stroke, and cell migration and SVZ volume, was performed on the same groups of animals, whereas cell numbers at 8 and 12 weeks were taken from the vehicle-treated animals in the AMD 3100 experiment. Data in the caspase inhibitor and AMD3100 experiments, following BrdU pulses 4 days and 6 weeks after stroke as well as in all behavioral tests, were obtained from separate animal groups. Values are reported as mean ± standard error of the mean. Group differences were assessed with unpaired t tests and side differences were assessed with paired t tests. A one-way analysis of variance with Fischer’s post hoc test was used to assess differences in the number of migrated cells and level of phosphorylation in vitro. For studies of correlation, Pearson’s correlation coefficients were generated and analyzed for significance using Fisher’s r to z transformation.
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RESULTS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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). In contrast, in the damaged striatum, the number of Dcx+ cells was already elevated at 1 week, and was stable thereafter for up to 16 weeks following the insult (Fig. 1A). The majority of the Dcx+ cells had an immature neuronal morphology. At all time points, Dcx+ cells had similar distributions within the striatum (Fig. 1B, 1C) and appeared to migrate from the SVZ into the damaged area. Stroke in humans varies in severity, influencing both the magnitude and time course of functional recovery [17]. We, therefore, determined whether the long-lasting increase in Dcx+ neuroblasts after the 2-hour MCAO also occurred in response to a less severe insult. We analyzed rats subjected to a 30-minute MCAO, which gave rise to a lesion restricted to the striatum (Fig. 2A). Following 2-hour MCAO, there was more extensive striatal damage and, in addition, injury to the overlying parietal cortex (Fig. 2A, 2B). Dcx+ cells were markedly fewer in the damaged striatum in the 30-minute than in the 2-hour MCAO group both 2 and 6 weeks after the insults (Fig. 2C). The number of Dcx+ cells correlated significantly with the volume of striatal injury (Fig 2E). Thus, the extent of the ischemic lesion influences the degree of activation of the molecular and cellular mechanisms that promote recruitment of new striatal neurons after stroke.
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). Virtually no Dcx+/BrdU+ double-labeled cells were detected in animals that survived for 6 or 16 weeks after stroke, despite the total number of Dcx+ cells at these time points being similar to that at 2 weeks (Fig. 1D). These findings indicated that the production of new striatal neuroblasts continued beyond the first 2 weeks, and we therefore injected BrdU during weeks 7 and 8 after MCAO. Supporting the occurrence of neurogenesis late after stroke, the majority of Dcx+ cells (about 71%) in the damaged striatum were BrdU+ at 8 weeks (Fig. 1D, 1E), but at 12 weeks hardly any Dcx+/BrdU+ cells remained.
We asked whether the dramatic difference between ischemic and nonischemic striatum in the number of neuroblasts produced at late time points after stroke could depend on a corresponding difference in SVZ cell proliferation. Consistent with increased proliferation early after stroke [3, 7], we found a higher number of BrdU+ cells in the ipsilateral, compared with the contralateral, SVZ in animals given BrdU pulses just prior to sacrifice 4 days following 2-hour MCAO (Fig. 3A). When pulses of BrdU were given 6 weeks after stroke and animals killed directly thereafter, the number of BrdU+ cells did not differ between sides. Thus, stroke only transiently increased overall cell proliferation in the SVZ. However, the ipsilateral SVZ was larger both 2 and 6 weeks after 2-hour MCAO (Fig. 3B). Moreover, the number and diameter of primary neurospheres were greater when generated from ipsilateral than from contralateral SVZ at 6 weeks (Fig. 3C, 3D). These findings indicate that stroke induced a long-term increase in the number of neural stem/progenitor cells in the ipsilateral SVZ [18, 19].
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, and Fig. 2). One third of the NeuN+/BrdU+ cells 6 weeks after 2-hour MCAO survived 4 months postischemia (Fig. 4A). When we injected BrdU during weeks 7 and 8, the number of NeuN+/BrdU+ neurons at 12 weeks constituted 23% of the number of Dcx+/BrdU+ neuroblasts at 8 weeks. Thus, similar to neuroblasts produced early after stroke, those produced a long time after the insult developed into mature neurons. In accordance, neurosphere cultures from ipsilateral and contralateral SVZ 6 weeks following MCAO generated similar numbers of mature neurons (Fig. 4C).
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We wanted to confirm the involvement of caspases in compromising the survival of the newly formed striatal neurons, and to explore whether the inhibition of caspases could rescue these neurons. Caspase inhibitors were infused from day 3–14 after 2-hour MCAO, and striatal neurogenesis was analyzed directly thereafter. Infusions began when striatal neuronal death was virtually complete [22] and, in accordance, no difference in ischemic damage was observed compared with the control group (data not shown). Caspase inhibitor-treated rats showed a markedly higher number of Dcx+ cells in the damaged striatum (Fig. 4E).
Migration of Neuroblasts Generated from SVZ Precursors to the Damaged Striatum Is Regulated by SDF-1/CXCR4 Signaling
We hypothesized that the long-lasting directed migration of the new neurons toward the ischemic injury was dependent on the interaction between the chemokine SDF-1 and its receptor CXCR4. We first demonstrated SDF-1 immunoreactivity in the periphery of the damaged striatal area, extending toward the SVZ 2, 6, and 16 weeks after 2-hour MCAO (Fig. 5A, 5B). The majority of SDF-1+ cells and processes coexpressed GFAP and were probably reactive astrocytes (Fig. 5B). In addition, large ED1+/SDF-1+ cells, presumably activated microglia, were found in the core of the damage. The 30-minute MCAO induced a similar pattern of SDF-1 expression, but the number of processes and staining intensity were lower than after 2-hour MCAO (Fig. 5A). No specific SDF-1 staining was detected in the intact striatum (Fig. 5A).
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/CXCR4 signaling influenced the migration of cells derived from adult rat SVZ in vitro. Cells in neurospheres (Fig. 5C), as well as in primary SVZ cultures, expressed the CXCR4 receptor. In a chemotactic chamber assay, neurosphere cells migrated toward a gradient of SDF-1 (Fig. 5D). SDF-1 also increased phosphorylation of ERK-1/2 in primary SVZ cultures (Fig. 5E). Both effects were blocked by the CXCR4 receptor antagonist AMD3100 [23].
Finally, we explored if SDF-1/CXCR4 signaling is involved in the in vivo migration of striatal neuroblasts after stroke. We infused AMD3100 during weeks 5 and 6 after 2-hour MCAO, and rats were killed directly thereafter. The AMD3100 infusion did not change the total number of striatal Dcx+ cells, but suppressed the migration of the new neurons in the striatal parenchyma (Fig. 5F). In the vehicle-treated rats, about 50% of the Dcx+ and Dcx+/BrdU+ neuroblasts were localized within 0.25 mm from the border of the SVZ. Following administration of the CXCR4-receptor blocker, about 70% of the cells remained in this area (Fig. 5F).
Behavioral Recovery Continues for Several Months after Stroke-Induced Striatal Damage
We finally wanted to explore whether spontaneous functional recovery after stroke occurs concomitantly with the long-lasting production of new striatal neurons. We used 30-minute MCAO, which triggers continuous striatal neurogenesis, albeit of low magnitude, and, importantly, induces selective damage of the striatum. Thus, we avoided the confounding effects of the cortical lesion induced by the 2-hour insult. In in vivo behavioral tests, the stepping and cylinder tests, improvement had already plateaued within the first month. In contrast, there was a significant improvement between 1 and 4 months in the grid-walking test (Fig 6). Taken together, these findings indicate a progressive recovery of certain behavioral deficits that continues beyond 1 month after the stroke.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Maximum cell proliferation in the ipsilateral SVZ occurs 1 to 2 weeks after MCAO [1, 3–5, 7], and findings in neurosphere cultures indicate that the recruitment of NSCs is stimulated during the first week after stroke [7]. We found a greater number and size of neurospheres isolated from the ipsilateral SVZ 6 weeks post-MCAO, and expansion of the ipsilateral SVZ at both 2 and 6 weeks. BrdU labeling was greater in the ipsilateral SVZ 4 days but not 6 weeks after stroke, which argues against a long-term increase in the pool of rapidly dividing progenitors. Taken together, our findings provide evidence that stroke leads to long-term alterations in the stem cell niche in the SVZ.
Our data indicate that caspase-mediated apoptotic death caused the loss of the stroke-generated neuroblasts, and that caspase inhibitors can rescue these neuroblasts. Neurons formed in the dentate gyrus after an epileptic insult also undergo caspase-mediated apoptotic death [11, 25], probably via the mitochondrial pathway [25], similar to NSCs isolated from the adult SVZ [26]. It is conceivable that inflammatory changes accompanying the ischemic damage [27] contribute to the poor survival of the new striatal neurons [28, 29]. Also, the new striatal neurons will most likely die if they do not establish synaptic connections and receive trophic signals. Our finding that a population of new neurons survived for 4 months after stroke suggests that integration and trophic support can be achieved in the stroke-damaged striatum.
We provide the first evidence that SDF-1/CXCR4 signaling regulates the directed migration of new striatal neurons generated from endogenous NSCs toward the ischemic damage. Interaction between SDF-1 and CXCR4 mediates homing of transplanted bone marrow–derived cells to sites of brain injury [30, 31] and migration of transplanted NSCs to the infarcted area after stroke [32]. Upregulation of SDF-1 immunoreactivity was detected at all time points in reactive astrocytes in the penumbra area [30, 32]. Neurons formed after the 30-minute insult, which induced lower SDF-1 expression, exhibited less migration than those formed after 2-hour MCAO (Fig. 2). The specific CXCR4 blocker AMD3100 [23] inhibited the migration of the new neurons. The exact mechanism of how SDF-1/CXCR4 signaling regulates migration in damaged striatum is not known. We found that rat SVZ progenitors express the CXCR4 receptor in vitro [33]. A direct action on these cells is supported by our finding that SDF-1 activated mitogen-activated protein kinases and induced CXCR4-mediated chemotaxis in cells derived from adult rat SVZ. However, AMD3100 only partially suppressed migration in vivo, which suggests that other mechanisms also direct the new neurons to the damaged area.
Similar to observations after extensive ischemic lesions [34], we found that spontaneous motor recovery after stroke affecting only the striatum occurred over several months concomitantly with striatal neurogenesis (Fig. 6). Also in line with a possible functional role of the new neurons, administration of molecules that promote neural proliferation in the SVZ and striatal neurogenesis after stroke, for example, vascular endothelial growth factor [35] and erythropoietin [36], is associated with superior recovery. However, with available methods, it is not possible to prove a causal relationship between neurogenesis and behavioral improvement after stroke. Suppression or enhancement of stroke-induced neurogenesis through delivery of mitosis inhibitors or trophic factors, respectively, will also affect other processes. Generation of conditional transgenic mice, in which newly formed neuroblasts carry a gene for selective ablation, could solve this problem.
Our finding that stroke-induced neurogenesis is persistent has several implications. The number of new striatal neurons that potentially could replace the dead neurons is much larger than suggested by previous calculations [4]. Furthermore, experimental studies to explore mechanisms of neuronal replacement from endogenous NSCs in the damaged brain, as well as various interventions to promote neurogenesis, are not restricted to the acute postischemic phase but can be applied over an extended time period. Most importantly, we now know that adult NSCs continuously produce a cellular raw material that may be used for self-repair in the brain during the recovery phase after stroke.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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REFERENCES |
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