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Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat.

ABSTRACT: Perinatal hypoxic-ischemic (HI) brain injury occurs in 1 in 1,000 live births and remains the main cause of neurological disability and death in term infants. Cytotherapy has recently emerged as a novel treatment for tissue injury. In particular, mesenchymal stem cells (MSCs) are thought to have therapeutic potential, but little is known about the differences according to their origin. In the current study, we investigated the therapeutic effects and safety of intravenous injection of allogeneic bone marrow-derived MSCs (BM-MSCs) and adipose-derived stem cells (ADSCs) in a rat model of HI brain injury. HI models were generated by ligating the left carotid artery of postnatal day 7 Wistar/ST rats and exposing them to 8% hypoxia for 60 min. Bone marrow and adipose tissue were harvested from adult green fluorescent protein transgenic Wistar rats, and cells were isolated and cultured to develop BM-MSCs and ADSCs. At passaging stages 2-3, 1 × 105 cells were intravenously injected into the external right jugular vein of the HI rats at 4 or 24 h after hypoxia. Brain damage was evaluated by counting the number of cells positive for active caspase-3 in the entire dentate gyrus. Microglial isotypes and serum cytokines/chemokines were also evaluated. Distribution of each cell type after intravenous injection was investigated pathologically and bio-optically by ex vivo imaging (IVIS®) with a fluorescent lipophilic tracer DiR. The mortality rate was higher in the ADSC group compared to the BM-MSC group, in pups injected with cells 4 h after hypoxia. The number of active caspase-3-positive cells significantly decreased in the BM-MSC group, and the percentage of M1 microglia (a proinflammatory isotype) was also lower in the BM-MSC vs control group in the penumbra of the cortex. Moreover, BM-MSC administration increased anti-inflammatory cytokine and growth factor levels, while ADSCs did not. Each injected cell type was mainly distributed in the lungs and liver, but ADSCs remained in the lungs longer. Pathologically, pulmonary embolisms and diffuse alveolar hemorrhages were seen in the ADSC group. These results indicated that injection of allogeneic BM-MSCs ameliorated neonatal HI brain injury, whereas ADSCs induced severe lung hemorrhage and higher mortality.

SUBMITTER: Sugiyama Y

PROVIDER: S-EPMC6141968 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat.

Sugiyama Yuichiro Y Sato Yoshiaki Y Kitase Yuma Y Suzuki Toshihiko T Kondo Taiki T Mikrogeorgiou Alkisti A Horinouchi Asuka A Maruyama Shoichi S Shimoyama Yoshie Y Tsuji Masahiro M Suzuki Satoshi S Yamamoto Tokunori T Hayakawa Masahiro M

Frontiers in neurology 20180911

Perinatal hypoxic-ischemic (HI) brain injury occurs in 1 in 1,000 live births and remains the main cause of neurological disability and death in term infants. Cytotherapy has recently emerged as a novel treatment for tissue injury. In particular, mesenchymal stem cells (MSCs) are thought to have therapeutic potential, but little is known about the differences according to their origin. In the current study, we investigated the therapeutic effects and safety of intravenous injection of allogeneic ...[more]

PMID: 30254603

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Project description:Background/Objective: Perinatal hypoxic-ischemia (HI) causes neonatal death and permanent neurological deficits. Cell therapy using various cell sources has been recently identified as a novel therapy for perinatal HI. Among the available types of cell sources, bone marrow-derived mononuclear cells (BMMNCs) have unique features for clinical application. For example, stem cells can be collected after admission, thus enabling us to perform autologous transplantation. This study aimed to investigate whether the administration of BMMNCs ameliorated HI brain injury in a neonatal rat model. Methods: Seven-day-old rats underwent left carotid artery ligation and were exposed to 8% oxygen for 60 min. BMMNCs were collected from the femurs and tibias of juvenile rats using the Ficoll-Hypaque technique and injected intravenously 24 h after the insult (1 × 105 cells). Active caspase-3, as an apoptosis marker, and ED1, as an activated microglia/macrophage marker, were evaluated immunohistochemically 48 h after the insult (vehicle, n = 9; BMMNC, n = 10). Behavioral assessments using the rotarod treadmill, gait analysis, and active avoidance tests were initiated 3 weeks after the insult (sham, n = 9, vehicle, n = 8; BMMNC, n = 8). After these behavioral tests (6 weeks after the insult), we evaluated the volumes of their hippocampi, cortices, thalami, striata, and globus pallidus. Results: The mean cell densities of the sum of four parts that were positive for active caspase-3 significantly decreased in the BMMNC group (p < 0.05), whereas in the hippocampi, cortices, thalami, and striata cell densities decreased by 42, 60, 56, and 47%, respectively, although statistical significance was not attained. The number of ED1 positive cells for the sum of the four parts also significantly decreased in the BMMNC group compared to the vehicle group (p < 0.05), whereas in each of the four parts the decrease was 35, 39, 47, and 36%, respectively, although statistical significance was not attained. In gait analysis, the BMMNC normalized the contact area of the affected hind paw widened by HI. The volumes of the affected striata and globus pallidus were significantly larger in the BMMNC group than in the control group. Conclusion: These results indicated that the injection of BMMNCs ameliorated HI brain injury in a neonatal rat model.

Project description:Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex.

Dataset Information

Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat.

Publications

Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat.

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