title: Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb.
abstract: Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, but new therapeutic strategies are required. Umbilical cord blood (UCB) mononuclear cells have potent anti-inflammatory properties and may reduce neuropathology. This study examined whether autologous UCB mononuclear cells were neuroprotective when administered to newborn lambs at 12 h after birth asphyxia. At caesarean section, birth asphyxia was induced by clamping the umbilical cord until mean arterial blood pressure decreased to 18-20 mmHg. Asphyxia (n = 20) or control (n = 11) lambs were resuscitated and maintained, with magnetic resonance spectroscropy (MRS) performed at 12 and 72 h, and were then killed at 72 h. Cord blood was collected once the cord was clamped, and mononuclear cells were isolated and labelled fluorescently and administered to control (n = 3) or asphyxia (n = 8) lambs. Asphyxia induced a significant increase in cellular apoptosis (caspase-3 immunopositive) within all brain regions examined, including cortex, hippocampus, thalamus, striatum and subcortical white matter (P < 0.01 vs. control). Additionally, asphyxia induced significant and widespread astrogliosis and increased inflammatory cells (activated microglia and macrophages). The administration of UCB mononuclear cells (asphyxia+UCB) significantly decreased neuronal apoptosis, astrogliosis and inflammation (P < 0.05 vs. asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetylaspartate (P < 0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, and reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia.
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: James D S
authors.initials: JD
authors.lastname: Aridas
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: McDonald
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Madison C B
authors.initials: MC
authors.lastname: Paton
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Yawno
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Sutherland
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors.forename: Ilias
authors.initials: I
authors.lastname: Nitsos
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Yen
authors.initials: Y
authors.lastname: Pham
authors.affiliation: Monash Children's, Monash Health, and Department of Paediatrics, Monash University, Clayton, Victoria, Australia.|Diagnostic Imaging, Monash Health, Clayton, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Ditchfield
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Monash Children's, Monash Health, and Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fahey
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Monash Children's, Monash Health, and Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Flora
authors.initials: F
authors.lastname: Wong
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Monash Children's, Monash Health, and Department of Paediatrics, Monash University, Clayton, Victoria, Australia.
authors.forename: Atul
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors.forename: Margie
authors.initials: M
authors.lastname: Castillo-Melendez
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Biopolis Way, Singapore.
authors.forename: Kishore
authors.initials: K
authors.lastname: Bhakoo
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors.forename: Euan M
authors.initials: EM
authors.lastname: Wallace
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Jenkin
authors.affiliation: The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.|Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Miller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005311:Fetal Hypoxia / Q000473:pathology* / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012756:Sheep; D014182:Transplantation, Autologous