Abstract
BackgroundNeonatal 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.MethodsSurgery 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.ResultsFGR (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.ConclusionsUmbilical 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.
Highlights
Fetal growth restriction (FGR), due to placental insufficiency, leads to progressive reduction of oxygen and nutrient supply to the developing fetus
fetal growth restriction (FGR) lambs (FGR and FGR+umbilical cord blood stem cell (UCBC)) weighed 23% less than appropriate for gestational age (AGA) lambs at birth (AGA and AGA+UCBC) (2.3 ± 0.4 kg vs. 3.0 ± 0.3 kg; p = 0.0002). Both FGR and FGR+UCBC lambs demonstrated an increase in brain/body weight ratio compared to AGA, indicative of brain sparing
We observed a significant increase in cellular oxidative stress within the periventricular white matter (PVWM) and subcortical white matter (SCWM) of FGR brains compared to AGA (p < 0.05)
Summary
Fetal growth restriction (FGR), due to placental insufficiency, leads to progressive reduction of oxygen and nutrient supply to the developing fetus. The neurological outcomes associated with FGR depend on the gestation at onset of FGR, severity of growth restriction, degree of fetal cardiovascular adaptation, and gestation at birth [1, 2]. In preterm FGR offspring, neonatal ventilation leads to increased risk of brain injury [5, 6], contributed by a greater susceptibility to neuroinflammation and blood-brain barrier (BBB) breakdown in FGR offspring [6]. 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
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