Murine model: maternal administration of stem cells for prevention of prematurity

Abstract

OBJECTIVE Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu. STUDY DESIGN A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide + intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5. RESULTS Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P < .01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P < .05), decreased microglial activation (P < .05), and decreased fetal neurotoxicity (P < .05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P < .05). Injected MSCs were localized to placenta. CONCLUSION Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice.

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep

“…This change in organ weight was not seen in the LPS + UCB group, thereby demonstrating that UCB moderates the peripheral response to such stimuli, which may in turn contribute to the neuroprotective benefits of the cells. This finding is supported by previously published work showing that maternally administered mesenchymal stromal cells are neuroprotective for the fetus in response to LPS exposure in pregnant mice, principally via actions at the placenta [40]. Combined, these results suggest that UCB/mesenchymal stromal cells target inflammation-regulatory sites, rather than the brain, to exert a neuroprotective benefit on the fetus.…”

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

“…CD1 pregnant dams Charles River were used for this study. Pregnant dams were subjected to a well‐established model of IUI as per a previously described protocol on embryonic day 17 (E17) . Mice were anesthetized with isoflurane (Baxter # NDC 10019‐360‐60) before undergoing a mini‐laparotomy.…”

Potential neuroprotective strategies for perinatal infection and inflammation

“…Supporting this concept, maternal administration of human adipose tissue‐derived mesenchymal stem cells at 15 h before intrauterine LPS (50 μg) at E17 reduced neural microglia reactivity and IL‐6 expression and attenuation of deficits in the cliff aversion test at P5, suggesting a modulatory role on fetal immune responses (Lei et al, 2014). Consistent with an anti‐inflammatory effect, human amnion epithelial cells given intravenously to late‐preterm fetal sheep (117 days) starting at the same time as an intra‐amniotic injection of LPS (20 mg) was associated with reduced microglial induction in white and gray matter regions and reduced cell death after seven days recovery (Yawno et al, 2013).…”