Optimal timing of mesenchymal stem cell therapy for neonatal intraventricular hemorrhage

Abstract

We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated posthemorrhagic hydrocephalus (PHH) and brain injury after severe intraventricular hemorrhage (IVH) in newborn rat pups. The purpose of this study was to optimize the timing of MSC transplantation for severe IVH. Severe IVH was induced by injecting 100 µl of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human UCB-derived MSCs (1 × 105 cells in 10 µl of normal saline) were transplanted intraventricularly under stereotaxic guidance either early at P6 or late at P11. Serial brain MRIs and behavioral function tests, such as negative geotaxis and rotarod tests, were performed. At P32, brain tissue samples were obtained for histological and biochemical analyses. Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, behavioral impairment, increased apoptosis and astrogliosis, reduced corpus callosum thickness and brain myelination, and upregulated inflammatory cytokines including interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) at P6 but not at P11 after induction of severe IVH. Intracerebroventricular transplantation of human UCB-derived MSCs attenuated PHH and brain injury after severe IVH in newborn rats in a time-dependent manner. Significant neuroprotection was only demonstrated when administered early at 2 days after induction but not late at 7 days after induction of severe IVH.