Administration of Umbilical Cord Blood Cells Transiently Decreased Hypoxic-Ischemic Brain Injury in Neonatal Rats

Hattori, Tetsuo; Sato, Yoshiaki; Kondo, Teruyoshi; Ichinohashi, Yuko; Sugiyama, Yasuo; Yamamoto, Masayuki; Kotani, Tomomi; Hirata, Hitoshi; Hirakawa, Akihiro; Suzuki, Satoshi; Tsuji, Masahiro; Ikeda, Tomoaki; Nakanishi, Kazuyoshi; Kojima, Seiji; Blomgren, Klas; Hayakawa, Masahiro

doi:10.1159/000368396

Cited by 51 publications

(59 citation statements)

References 42 publications

(60 reference statements)

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“…This finding agrees with a previous study by our group [16] which showed that the intraperitoneal administration of hUCBCs as a single dose also decreased the number of cells immunopositive for various injury markers immediately after the insult, although there was no long-lasting effect on brain volume.…”

Section: Discussionsupporting

confidence: 93%

“…The Rice-Vannucci [25] neonatal adaptation of the Levine procedure [26] was used to produce HIE in 7-day-old (P7) male rat pups (weight = 12-17 g) with minor modifications, as described previously [16] (for details, please refer to the online suppl. information; for all online suppl.…”

Section: Hi Insultmentioning

confidence: 99%

“…For instance, human umbilical cord blood cells (hUCBCs) can be obtained at birth and transplanted as an autologous source [15] . Recently, our group provided evidence for the benefit of hUCBCs in a neonatal rat model [16,17] , and clinical trials are currently under way (ClinicalTrials.gov: NCT02256618). However, it is conceivable that we might often encounter difficulties collecting hUCBCs in emergency situations, such as precipitous delivery.…”

Section: Introductionmentioning

confidence: 99%

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Dedifferentiated Fat Cells as a Novel Source for Cell Therapy to Target Neonatal Hypoxic-Ischemic Encephalopathy

Mikrogeorgiou¹,

Sato²,

Kondo³

et al. 2017

Dev Neurosci

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Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) remains a major cause of mortality and persistent neurological disabilities in affected individuals. At present, hypothermia is considered to be the only applicable treatment option, although growing evidence suggests that cell-based therapy might achieve better outcomes. Dedifferentiated fat (DFAT) cells are derived from mature adipocytes via a dedifferentiation strategy called ceiling culture. Their abundance and ready availability might make them an ideal therapeutic tool for the treatment of HIE. In the present study, we aimed to determine whether the outcome of HIE can be improved by DFAT cell treatment. HI injury was achieved by ligating the left common carotid artery in 7-day-old rat pups, followed by 1-h exposure to 8% O₂. Subsequently, the severity of damage was assessed by diffusion-weighted magnetic resonance imaging to assign animals to equivalent groups. 24 h after hypoxia, DFAT cells were injected at 10⁵ cells/pup into the right external jugular vein. To evaluate brain damage in the acute phase, a group of animals was sacrificed 48 h after the insult, and paraffin sections of the brain were stained to assess several acute injury markers. In the chronic phase, the behavioral outcome was measured by performing a series of behavioral tests. From the 24th day of age, the sensorimotor function was examined by evaluating the initial forepaw placement on a cylinder wall and the latency to falling from a rotarod treadmill. The cognitive function was tested with the novel object recognition (NOR) test. In vitro conditioned medium (CM) prepared from cultured DFAT cells was added at various concentrations to neuronal cell cultures, which were then exposed to oxygen-glucose deprivation (OGD). The number of cells that stained positive for the apoptosis marker active caspase-3 decreased by 73 and 52% in the hippocampus and temporal cortex areas of the brain, respectively, in the DFAT-treated pups. Similarly, the numbers of ED-1-positive cells (activated microglia) decreased by 66 and 44%, respectively, in the same areas in the DFAT-treated group. The number of cells positive for the oxidative stress marker 4-hydroxyl-2-nonenal decreased by 68 and 50% in the hippocampus and the parietal cortex areas, respectively, in the DFAT-treated group. The HI insult led to a motor deficit according to the rotarod treadmill and cylinder test, where it significantly affected the vehicle group, whereas no difference was confirmed between the DFAT and sham groups. However, the NOR test indicated no significant differences between any of the groups. DFAT treatment did not reduce the infarct volume, which was confirmed immunohistochemically. According to in vitro experiments, the cell death rates in the DFAT-CM-treated cells were significantly lower than those in the controls when DFAT-CM was added 48 h prior to OGD. The treatment effect of adding DFAT-CM 24 h prior to OGD was also significant. Our results indicate that intravenous injection with DFAT cells i...

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Section: Discussionsupporting

confidence: 93%

Section: Hi Insultmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dedifferentiated Fat Cells as a Novel Source for Cell Therapy to Target Neonatal Hypoxic-Ischemic Encephalopathy

Mikrogeorgiou¹,

Sato²,

Kondo³

et al. 2017

Dev Neurosci

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“…The intranasal cavity provides a direct passage to the intracerebral compartment along olfactory pathways and has been used to directly deliver the drugs to the CNS, bypassing the blood-brain barrier and minimizing systemic exposure [2, 36]. Several studies have demonstrated that intranasal stem cells treatment improves sensorimotor and cognitive function, and decreases gray or white matter damage after HI [37-39].…”

Section: Discussionmentioning

confidence: 99%

Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

et al. 2017

Cell Physiol Biochem

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Background/Aims: Neonatal hypoxia-ischemia (HI) causes severe brain damage and significantly increases neonatal morbidity and mortality. Increasing evidences have verified that stem cell-based therapy has the potential to rescue the ischemic tissue and restore function via secreting growth factors after HI. Here, we had investigated whether intranasal neural stem cells (NSCs) treatment improves the recovery of neonatal HI, and NSCs overexpressing basic fibroblast growth factor (bFGF) has a better therapeutic effect for recovery than NSCs treatment only. Methods: We performed permanent occlusion of the right common carotid artery in 9-day old ICR mice as animal model of neonatal hypoxia-ischemia. At 3 days post-HI, NSC, NSC-GFP, NSC-bFGF and vehicle were delivered intranasally. To determine the effect of intranasal NSC, NSC-GFP and NSC-bFGF treatment on recovery after HI, we analyzed brain damage, sensor-motor function and cell differentiation. Results: It was observed that intranasal NSC, NSC-GFP and NSC-bFGF treatment decreased gray and white matter loss area in comparison with vehicle-treated mouse. NSC, NSC-GFP and NSC-bFGF treatment also significantly improved sensor motor function in cylinder rearing test and adhesive removal test, however, NSC-bFGF-treatment was more effective than NSC-treatment in the improvement of somatosensory function. Furthermore, compared with NSC and NSC-GFP, NSC-bFGF treatment group appeared to differentiate into more neurons. Conclusion: Taken together, intranasal administration of NSCs is a promising therapy for treatment of neonatal HI, but NSCs overexpressing bFGF promotes the survival and differentiation of NSCs, and consequently achieves a better therapeutic effect in improving recovery after neonatal HI.

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“…Enhancing endogenous NO production by enhanced blood flow has been shown to protect the integrity of the blood-brain barrier and guards against neuroinflammation [59]. Reducing neuroinflammation through a reduction in activated microglia and proinflammatory chemokines is described as an effective strategy in reducing brain damage in rodent models of neonatal HI [60,61]. Other specific mechanisms may be at play in the neonatal brain, since it is still maturating at the time of birth with ongoing normal neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups

et al. 2016

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Term asphyxiated newborns remain at risk of developing brain injury despite available neuropreventive therapies such as hypothermia. Neurorestorative treatments may be an alternative. This study investigated the effect of sildenafil on brain injury induced by neonatal hypoxia-ischemia (HI) at term-equivalent age. Neonatal HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by left common carotid ligation followed by a 2-hour exposure to 8% oxygen; sham-operated rat pups served as the control. Both groups were randomized to oral sildenafil or vehicle twice daily for 7 consecutive days. Gait analysis was performed on P27. At P30, the rats were sacrificed, and their brains were extracted. The surfaces of both hemispheres were measured on hematoxylin and eosin-stained brain sections. Mature neurons and endothelial cells were quantified near the infarct boundary zone using immunohistochemistry. HI caused significant gait impairment and a reduction in the size of the left hemisphere. Treatment with sildenafil led to an improvement in the neurological deficits as measured by gait analysis, as well as an improvement in the size of the left hemisphere. Sildenafil, especially at higher doses, also caused a significant increase in the number of neurons near the infarct boundary zone. In conclusion, sildenafil administered after neonatal HI may improve brain injury recovery by promoting neuronal populations.

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Administration of Umbilical Cord Blood Cells Transiently Decreased Hypoxic-Ischemic Brain Injury in Neonatal Rats

Cited by 51 publications

References 42 publications

Dedifferentiated Fat Cells as a Novel Source for Cell Therapy to Target Neonatal Hypoxic-Ischemic Encephalopathy

Dedifferentiated Fat Cells as a Novel Source for Cell Therapy to Target Neonatal Hypoxic-Ischemic Encephalopathy

Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups

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