Human umbilical cord blood–derived mesenchymal stem cell transplantation attenuates severe brain injury by permanent middle cerebral artery occlusion in newborn rats

Kim, Eun Sun; Ahn, So Yoon; Im, Geun Ho; Sung, Dong Kyung; Park, Ye Rim; Choi, Seok Keun; Choi, Soo Jin; Chang, Yun Sil; Oh, Wonil; Lee, Jun Young; Park, Won Soon

doi:10.1038/pr.2012.71

Cited by 110 publications

(140 citation statements)

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“…Recently, we also reported that transplanting of human umbilical cord blood (UCB)-derived MSCs significantly attenuated several disorders, such as bronchopulmonary dysplasia, 14,15 acute respiratory distress syndrome, 16 and middle cerebral arterial occlusion, 17 through paracrine effects. These findings suggest that transplanting MSCs could be a novel therapy to prevent PHH after severe IVH.…”

Section: -13mentioning

confidence: 99%

“…[18][19][20] Human fetal lung fibroblasts (MRC-5; Korean Cell Line Bank No.10171) were obtained from the Korean Cell Line Bank (Seoul, Korea). Human UCB-derived MSCs from a single donor were cultured with super paramagnetic iron oxide particles (Feridex I. V., Taejon Pharmaceutical Co Ltd, Seoul, Korea) in culture medium to induce endocytosis 17,20 and were dual-labeled with PKH26GL Red Fluorescent Cell Membrane Labeling Kit (Sigma-Aldrich, St. Louis, MO) for transplantation according to the manufacturer protocol, as previously reported. 14,15,17 The localization of transplanted donor cells was confirmed as described in the online-only Data Supplement.…”

Section: Cell Preparationmentioning

confidence: 99%

“…17 Volume estimates were then made according to Cavalieri's principal, 17 and the ventricle to whole brain volume ratio was calculated to determine the extent of PHH after severe IVH. …”

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Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

Ahn

Chang²,

Sung³

et al. 2013

Stroke

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146

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I ntraventricular hemorrhage (IVH) is a serious complication of preterm birth, and the number of infants at high risk for developing IVH is increasing as a result of the rise in the absolute number and improved survival of very premature infants with recent advances in neonatal intensive care medicine. 1,2 Over half of infants with severe IVH (grade ≥3) die or develop posthemorrhagic hydrocephalus (PHH), which requires shunt surgery in up to 70% of cases.3 IVH is associated with brain damage, especially to the periventricular white matter, which is exacerbated by PHH, and finally results in increased mortality and long-term neurological morbidity, such as seizure, cerebral palsy, and developmental retardation in survivors. [4][5][6] Until now, however, there has not been any effective treatment to prevent PHH or ameliorate brain damage after severe IVH in preterm infants, so it remains a major problem of neonatal intensive care.Although the precise mechanism has not been completely delineated, the pathogenesis of communicating progressive posthemorrhagic ventricular dilatation has been explained by inflammation within subarachnoid spaces attributable to blood contact and deposition of blood products. 7,8 This obliterative arachnoiditis leads to dysfunction of arachnoid granulations, which reduces cerebrospinal fluid (CSF) resorption and increases intracranial pressure, resulting in venous infarction with decreased cerebral perfusion. 8 Moreover, inflammatory cytokines originating from blood products in the cerebral ventricles may injure the periventricular white matter. 9,10 Therefore, new therapeutic modalities with anti-inflammatory capabilities to treat PHH and brain damage after severe IVH would be of great value.Recent preclinical research reported that an anti-inflammatory agent, a cycloxygenase-2 inhibitor, noticeably reduced reactive gliosis and improved neurological impairment after IVH in a newborn rabbit model. This finding indicates that modulating inflammation could be a key factor in IVH therapy for preterm Background and Purpose-Severe intraventricular hemorrhage (IVH) in premature infants and the ensuing posthemorrhagic hydrocephalus cause significant mortality and neurological disabilities, and there are currently no effective therapies. This study determined whether intraventricular transplantation of human umbilical cord blood-derived mesenchymal stem cells prevents posthemorrhagic hydrocephalus development and attenuates brain damage after severe IVH in newborn rats. Methods-To induce severe IVH, 100 μL of blood was injected into each lateral ventricle of postnatal day 4 (P4) SpragueDawley rats. Human umbilical cord blood-derived mesenchymal stem cells or fibroblasts (1×10 5 ) were transplanted intraventricularly under stereotaxic guidance at P6. Serial brain MRI and behavioral function tests, such as the negative geotaxis test and rotarod test, were performed. At P32, brain tissue and cerebrospinal fluid were obtained for histological and biochemical analyses. Results-Intraventricular tran...

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Section: -13mentioning

confidence: 99%

Section: Cell Preparationmentioning

confidence: 99%

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Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

Ahn

Chang²,

Sung³

et al. 2013

Stroke

Self Cite

146

219

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“…However, most preclinical and all clinical studies have been performed on adult animals or humans, and only a few reports have studied stem cell therapy in neonatal stroke models (52,56,59,61). Those laboratories show great promise for cellular therapy using core blood stem cells or BMSCs to provide enhanced trophic support and an enriched microenvironment in the damaged developing brain (11,32,57).…”

Section: Discussionmentioning

confidence: 99%

Intranasal Delivery of Bone Marrow Mesenchymal Stem Cells Improved Neurovascular Regeneration and Rescued Neuropsychiatric Deficits after Neonatal Stroke in Rats

Wei

Ferdinand

et al. 2015

Cell Transplant

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Neonatal stroke is a major cause of mortality and long-term morbidity in infants and children. Currently, very limited therapeutic strategies are available to protect the developing brain against ischemic damage and promote brain repairs for pediatric patients. Moreover, children who experienced neonatal stroke often have developmental social behavior problems. Cellular therapy using bone marrow mesenchymal stem cells (BMSCs) has emerged as a regenerative therapy after stroke. In the present investigation, neonatal stroke of postnatal day 7 (P7) rat pups was treated with noninvasive and brain-specific intranasal delivery of BMSCs at 6 h and 3 days after stroke (1 × 10 6 cells/animal). Prior to transplantation, BMSCs were subjected to hypoxic preconditioning to enhance their tolerance and regenerative properties. The effects on regenerative activities and stroke-induced sensorimotor and social behavioral deficits were specifically examined at P24 of juvenile age. The BMSC treatment significantly reduced infarct size and blood-brain barrier disruption, promoted angiogenesis, neurogenesis, neurovascular repair, and improved local cerebral blood flow in the ischemic cortex. BMSC-treated rats showed better sensorimotor and olfactory functional recovery than saline-treated animals, measured by the adhesive removal test and buried food finding test. In social behavioral tests, we observed functional and social behavioral deficits in P24 rats subjected to stroke at P7, while the BMSC treatment significantly improved the performance of stroke animals. Overall, intranasal BMSC transplantation after neonatal stroke shows neuroprotection and great potential as a regenerative therapy to enhance neurovascular regeneration and improve functional recovery observed at the juvenile stage of development.

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“…They also possess multipotent differentiation potential and thus can be induced to differentiate into cells of multiple lineages such as adipocytes, osteocytes, chondrocytes, myocytes, hepatocytes, neurons, astrocytes and oligodendrocytes [1][2][3][4][5][6][7][8]. Treatment with HUCBMSCs significantly reduced the infarct size, improved survival and offered neurological recovery in animals subjected to ischemic stroke [9][10][11]. In addition, HUCB-MSCs treatment after focal cerebral ischemia prevented the upregulation of apoptotic signaling pathway molecules and thereby attenuated the extent of apoptosis [12,13].…”

Section: Introductionmentioning

confidence: 99%

Stem Cell Treatment after Ischemic Stroke Alters the Expression of DNA Damage Signaling Molecules

Chelluboina

Nalamolu

Klopfenstein

et al. 2016

JSRT

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Accumulating evidence suggests that oxidative DNA damage plays a critical role in cell death associated with ischemic stroke. Endogenous oxidative DNA damage can be detected in the ischemic brain during the stages that precedes the manifestation of cell death and is believed to trigger cell death via various intracellular signaling pathways. Inhibiting the signaling associated with DNA damage induction or facilitating the signaling associated with the DNA repair process can be neuroprotective against brain injury after ischemic stroke. Recent reports demonstrated that human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) prevented the upregulation of apoptotic signaling pathway molecules and thereby attenuated the extent of apoptosis after focal cerebral ischemia as well as improved the neurological recovery. Therefore, we hypothesized that HUCB-MSCs treatment after focal cerebral ischemia prevents the overexpression of molecules associated with DNA damage induction as well as augments the expression of molecules associated with DNA repair process. In order to test our hypothesis, we administered HUCB-MSCs (0.25x10 6 cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a two-hour middle cerebral artery occlusion followed by one-day reperfusion. Ischemic brain tissues obtained from various groups seven days' post reperfusion were subjected to DNA damage signaling pathway PCR microarray. Our results demonstrated the induction of both DNA damage inducing and repair genes after focal cerebral ischemia and reperfusion. HUCB-MSCs treatment downregulated the DNA damage inducing genes and upregulated the DNA repair genes without disturbing the endogenous defense mechanisms.

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Human umbilical cord blood–derived mesenchymal stem cell transplantation attenuates severe brain injury by permanent middle cerebral artery occlusion in newborn rats

Cited by 110 publications

References 32 publications

Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

Intranasal Delivery of Bone Marrow Mesenchymal Stem Cells Improved Neurovascular Regeneration and Rescued Neuropsychiatric Deficits after Neonatal Stroke in Rats

Stem Cell Treatment after Ischemic Stroke Alters the Expression of DNA Damage Signaling Molecules

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