Cell Transplant. 2015 Oct 5. [Epub ahead of print]

Optimal timing of mesenchymal stem cells therapy for neonatal intraventricular hemorrhage.

Park WS, Sung SI, Ahn SY, Sung DK, Im GH, Yoo HS, Choi SJ, Chang YS.

Abstract

OBJECTIVE:

We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSC) 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.

METHODS:

Severe IVH was induced by injecting 100 uL of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human umbilical cord blood (UCB)-derived MSCs (1×10⁵ cells in 10ul 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.

RESULTS:

Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, decreased impaired behavioral tests, increased TUNEL-positive cells, increased astrogliosis, reduced corpus callosum thickness, reduced myelin basic protein expression, and increased the inflammatory cytokines interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α at P6 but not at P11 after induction of severe IVH.

CONCLUSIONS:

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.