Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

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Abstract

Background: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs. Methods: Surgery was performed in twin-bearing pregnant ewes at 88 days' gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 106 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized. Results: FGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs. Conclusions: Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.

Original languageEnglish
Article number17
Number of pages14
JournalStem Cell Research and Therapy
Volume11
Issue number1
DOIs
Publication statusPublished - 8 Jan 2020

Keywords

  • Brain injury
  • FGR
  • Intrauterine growth restriction
  • IUGR
  • Preterm
  • Ventilation

Cite this

@article{166ca1386d9f4639be7eac520436d67a,
title = "Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs",
abstract = "Background: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs. Methods: Surgery was performed in twin-bearing pregnant ewes at 88 days' gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 106 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized. Results: FGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs. Conclusions: Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.",
keywords = "Brain injury, FGR, Intrauterine growth restriction, IUGR, Preterm, Ventilation",
author = "Atul Malhotra and Margie Castillo-Melendez and Allison, {Beth J.} and Sutherland, {Amy E.} and Ilias Nitsos and Yen Pham and McDonald, {Courtney A.} and Fahey, {Michael C.} and Polglase, {Graeme R.} and Graham Jenkin and Miller, {Suzanne L.}",
year = "2020",
month = "1",
day = "8",
doi = "10.1186/s13287-019-1526-0",
language = "English",
volume = "11",
journal = "Stem Cell Research and Therapy",
issn = "1757-6512",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Neurovascular effects of umbilical cord blood-derived stem cells in growth-restricted newborn lambs

AU - Malhotra, Atul

AU - Castillo-Melendez, Margie

AU - Allison, Beth J.

AU - Sutherland, Amy E.

AU - Nitsos, Ilias

AU - Pham, Yen

AU - McDonald, Courtney A.

AU - Fahey, Michael C.

AU - Polglase, Graeme R.

AU - Jenkin, Graham

AU - Miller, Suzanne L.

PY - 2020/1/8

Y1 - 2020/1/8

N2 - Background: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs. Methods: Surgery was performed in twin-bearing pregnant ewes at 88 days' gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 106 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized. Results: FGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs. Conclusions: Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.

AB - Background: Neonatal ventilation exacerbates brain injury in lambs with fetal growth restriction (FGR), characterized by neuroinflammation and reduced blood-brain barrier integrity, which is normally maintained by the neurovascular unit. We examined whether umbilical cord blood stem cell (UCBC) treatment stabilized the neurovascular unit and reduced brain injury in preterm ventilated FGR lambs. Methods: Surgery was performed in twin-bearing pregnant ewes at 88 days' gestation to induce FGR in one fetus. At 127 days, FGR and appropriate for gestational age (AGA) lambs were delivered, carotid artery flow probes and umbilical lines inserted, lambs intubated and commenced on gentle ventilation. Allogeneic ovine UCBCs (25 × 106 cells/kg) were administered intravenously to lambs at 1 h of life. Lambs were ventilated for 24 h and then euthanized. Results: FGR (n = 6) and FGR+UCBC (n = 6) lambs were growth restricted compared to AGA (n = 6) and AGA+UCBC (n = 6) lambs (combined weight, FGR 2.3 ± 0.4 vs. AGA 3.0 ± 0.3 kg; p = 0.0002). UCBC therapy did not alter mean arterial blood pressure or carotid blood flow but decreased cerebrovascular resistance in FGR+UCBC lambs. Circulating TNF-α cytokine levels were lower in FGR+UCBC vs. FGR lambs (p < 0.05). Brain histopathology showed decreased neuroinflammation and oxidative stress, increased endothelial cell proliferation, pericyte stability, and greater integrity of the neurovascular unit in FGR+UCBC vs. FGR lambs. Conclusions: Umbilical cord blood stem cell therapy mitigates perinatal brain injury due to FGR and ventilation, and the neuroprotective benefits may be mediated by stabilization of the neurovascular unit.

KW - Brain injury

KW - FGR

KW - Intrauterine growth restriction

KW - IUGR

KW - Preterm

KW - Ventilation

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U2 - 10.1186/s13287-019-1526-0

DO - 10.1186/s13287-019-1526-0

M3 - Article

C2 - 31915068

AN - SCOPUS:85077692864

VL - 11

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

SN - 1757-6512

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M1 - 17

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