Term vs. preterm cord blood cells for the prevention of preterm brain injury

Abstract

BACKGROUNDWhite matter brain injury in preterm infants can induce neurodevelopmental deficits. Umbilical cord blood (UCB) cells demonstrate neuroprotective properties, but it is unknown whether cells obtained from preterm cord blood (PCB) vs. term cord blood (TCB) have similar efficacy. This study compared the ability of TCB vs. PCB cells to reduce white matter injury in preterm fetal sheep.METHODSHypoxia-ischemia (HI) was induced in fetal sheep (0.7 gestation) by 25 min umbilical cord occlusion. Allogeneic UCB cells from term or preterm sheep, or saline, were administered to the fetus at 12 h after HI. The fetal brain was collected at 10-day post HI for assessment of white matter neuropathology.RESULTSHI (n=7) induced cell death and microglial activation and reduced total oligodendrocytes and CNPase+myelin protein in the periventricular white matter and internal capsule when compared with control (n=10). Administration of TCB or PCB cells normalized white matter density and reduced cell death and microgliosis (P<0.05). PCB prevented upregulation of plasma tumor necrosis factor (TNF)-a, whereas TCB increased anti-inflammatory interleukin (IL)-10 (P<0.05). TCB, but not PCB, reduced circulating oxidative stress.CONCLUSIONSTCB and PCB cells reduced preterm HI-induced white matter injury, primarily via anti-inflammatory actions. The secondary mechanisms of neuroprotection appear different following TCB vs. PCB administration.

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

“…Microglial cell activation was decreased across all white matter brain regions examined in FGR+UCBC lambs. The cerebral and systemic anti-inflammatory benefits of UCBC therapy have been reported previously in a preclinical model of preterm brain injury induced via acute hypoxia-ischemia [10]. Li et al also showed a significant correlation between increasing density of activated microglia and loss of oligodendrocytes at 10 days after insult, indicative that neuroinflammation is strongly associated with oligodendrocyte development.…”

“…Umbilical cord blood collected at birth has a high cell yield and a wide variety of stem and progenitor cells, which are shown to mediate positive benefits on glial cells, neurons, and cells that maintain the BBB [7,[14][15][16]. These and other studies show that the neuroprotective or neuroreparative benefits of UCBC for the immature brain acts through anti-apoptotic, anti-inflammatory, pro-angiogenic, neurogenic, anti-oxidant, and BBB protective mechanisms [9][10][11][12].…”

“…Preclinical studies support that umbilical cord blood cell (UCBC) therapy decreases the progression of perinatal brain injury. UCBCs are neuroprotective for the preterm brain when administered in ovine models of hypoxia and inflammation-induced preterm brain injury [10][11][12]. More recently, it has been shown that a single administration of UCBC therapy resulted in improvement in long-term behavioral outcomes in a rat model of neonatal hypoxic ischemic injury [13].…”

Umbilical Cord Blood Cells Do Not Reduce Ventilation-Induced Lung Injury in Preterm Lambs

“…The UCB cells used in this study were from sheep UCB, due to the limited availability of sheep-specific antibodies, we were unable to identify the proportion of various cell types within the UCB samples. However, previous studies have shown UCB cells from autologous and allogeneic sheep to be efficacious in a sheep model of preterm brain injury (Li et al, 2017).…”

“…UCB cells were cryopreserved in dimethyl sulfoxide (10% DMSO, Sigma in FBS) and stored in liquid nitrogen for subsequent administration to lambs. UCB cells were thawed as previously described and have shown that administration of immediately thawed cells is effective at reducing inflammation and cell death (Aridas et al, 2016;Li et al, 2017;Paton et al, 2018;Paton et al, 2019). Briefly, cells were rapidly thawed in a 37 • C water bath with 10 ml media, centrifuged for 5 min at 300 × g and then supernatant was removed and cells resuspended in media and counted using a hemocytometer and trypan blue.…”