Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb

James D.S. Aridas, Courtney A. McDonald, Madison C.B. Paton, Tamara Yawno, Amy E. Sutherland, Ilias Nitsos, Yen Pham, Michael Ditchfield, Michael C. Fahey, Flora Wong, Atul Malhotra, Margie Castillo-Melendez, Kishore Bhakoo, Euan M Wallace, Graham Jenkin, Suzanne Lee Miller

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, however 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 euthanasia at 72 h. Cord blood was collected once the cord was clamped, mononuclear cells 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 versus 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 versus asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetyl aspartate (P <0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)1421 - 1435
Number of pages15
JournalThe Journal of Physiology
Volume594
Issue number5
DOIs
Publication statusPublished - 2016

Cite this

@article{1259500ffae1465d9b4f9d21b7857345,
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, however 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 euthanasia at 72 h. Cord blood was collected once the cord was clamped, mononuclear cells 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 versus 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 versus asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetyl aspartate (P <0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia. This article is protected by copyright. All rights reserved.",
author = "Aridas, {James D.S.} and McDonald, {Courtney A.} and Paton, {Madison C.B.} and Tamara Yawno and Sutherland, {Amy E.} and Ilias Nitsos and Yen Pham and Michael Ditchfield and Fahey, {Michael C.} and Flora Wong and Atul Malhotra and Margie Castillo-Melendez and Kishore Bhakoo and Wallace, {Euan M} and Graham Jenkin and Miller, {Suzanne Lee}",
year = "2016",
doi = "10.1113/JP271104",
language = "English",
volume = "594",
pages = "1421 -- 1435",
journal = "The Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "5",

}

Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb. / Aridas, James D.S.; McDonald, Courtney A.; Paton, Madison C.B.; Yawno, Tamara; Sutherland, Amy E.; Nitsos, Ilias; Pham, Yen; Ditchfield, Michael; Fahey, Michael C.; Wong, Flora; Malhotra, Atul; Castillo-Melendez, Margie; Bhakoo, Kishore; Wallace, Euan M; Jenkin, Graham; Miller, Suzanne Lee.

In: The Journal of Physiology, Vol. 594, No. 5, 2016, p. 1421 - 1435.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cord blood mononuclear cells prevent neuronal apoptosis in response to perinatal asphyxia in the newborn lamb

AU - Aridas, James D.S.

AU - McDonald, Courtney A.

AU - Paton, Madison C.B.

AU - Yawno, Tamara

AU - Sutherland, Amy E.

AU - Nitsos, Ilias

AU - Pham, Yen

AU - Ditchfield, Michael

AU - Fahey, Michael C.

AU - Wong, Flora

AU - Malhotra, Atul

AU - Castillo-Melendez, Margie

AU - Bhakoo, Kishore

AU - Wallace, Euan M

AU - Jenkin, Graham

AU - Miller, Suzanne Lee

PY - 2016

Y1 - 2016

N2 - Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, however 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 euthanasia at 72 h. Cord blood was collected once the cord was clamped, mononuclear cells 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 versus 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 versus asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetyl aspartate (P <0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia. This article is protected by copyright. All rights reserved.

AB - Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, however 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 euthanasia at 72 h. Cord blood was collected once the cord was clamped, mononuclear cells 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 versus 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 versus asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetyl aspartate (P <0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia. This article is protected by copyright. All rights reserved.

U2 - 10.1113/JP271104

DO - 10.1113/JP271104

M3 - Article

VL - 594

SP - 1421

EP - 1435

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 5

ER -