Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation and Inhibit the Development of Hydrocephalus After Experimentally Induced Perinatal Intraventricular Hemorrhage

Abstract

Intraventricular hemorrhage (IVH) is a severe complication of preterm birth associated with cerebral palsy, intellectual disability, and commonly, accumulation of cerebrospinal fluid (CSF). Histologically, IVH leads to subependymal gliosis, fibrosis, and disruption of the ependymal wall. Importantly, expression of aquaporin channels 1 and 4 (AQP1 and AQP4) regulating respectively, secretion and absorption of cerebrospinal fluids is altered with IVH and are associated with development of post hemorrhagic hydrocephalus. Human cord blood derived unrestricted somatic stem cells (USSCs), which we previously demonstrated to reduce the magnitude of hydrocephalus, as having anti-inflammatory, and beneficial behavioral effects, were injected into the cerebral ventricles of rabbit pups 18 h after glycerol-induced IVH. USSC treated IVH pups showed a reduction in ventricular size when compared to control pups at 7 and 14 days (both, P < 0.05). Histologically, USSC treatment reduced cellular infiltration and ependymal wall disruption. In the region of the choroid plexus, immuno-reactivity for AQP1 and ependymal wall AQP4 expression were suppressed after IVH but were restored following USSC administration. Effects were confirmed by analysis of mRNA from dissected choroid plexus and ependymal tissue. Transforming growth factor beta (TGF-β) isoforms, connective tissue growth factor (CTGF) and matrix metalloprotease-9 (MMP-9) mRNA, as well as protein levels, were significantly increased following IVH and restored towards normal with USSC treatment (P < 0.05). The anti-inflammatory cytokine Interleukin-10 (IL-10) mRNA was reduced in IVH, but significantly recovered after USSC injection (P < 0.05). In conclusion, USSCs exerted anti-inflammatory effects by suppressing both TGF-β specific isoforms, CTGF and MMP-9, recovered IL-10, restored aquaporins expression towards baseline, and reduced hydrocephalus. These results support the possibility of the use of USSCs to reduce IVH consequences in prematurity.

Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A

“…Twenty six studies assessed astrogliosis using the marker of GFAP, and 9 studies were excluded from the meta-analysis due to lack of available data or the brain structure assessed unable to be classified as either grey or white matter. [46, 50, 57, 64, 65, 69, 72, 73, 75]. Of the remaining 17 studies, a total of 20 study entries assessing grey matter and 20 study entries assessing white matter were included in the meta-analysis.…”

Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model

“…Hydrocephalus induced by IVH is associated with unfavorable long-term outcomes [ 35 , 36 ]. The possible mechanisms of hydrocephalus may be attributed to unbalanced CSF-generating and CSF-clearing, in which choroid plexus makes a critical impact [ 37 , 38 , 39 , 40 ].The choroid plexus, which is composed of choroid plexus epithelial cells and fenestrated vascular endothelial cells, constructs the BBB and regulates the movement of water and solutes [ 12 , 41 ]. Controlling paracellular and transcellular channels, junction protein can affect the permeability of ChP [ 42 ].…”

Analysis of Spontaneous and Induced Osteogenic Differentiation in 3D-micromasses of Human Multipotent Stem Cells

“…ethical restrictions, USSCs represent a safer source of stem cell acquisition, coming from umbilical cord blood (14). The development of three-dimensional growth and migration of osteogenic cells often requires artificial scaffolds; however, these can cause immunoreactions and their degradation products have unpredictable effects on adjacent cells (15).…”