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Updated: Nov 8, 2025
Modeling Neonatal Intraventricular Hemorrhage Through Intraventricular Injection of Hemoglobin
Published on: August 25, 2022
Human Cord Blood Derived Unrestricted Somatic Stem Cells Restore Aquaporin Channel Expression, Reduce Inflammation
Deepti Purohit1, Dina A Finkel1, Ana Malfa1
1The Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, NY, United States.
Insights
Unrestricted somatic stem cells (USSCs) reduced hydrocephalus in preterm rabbit pups with intraventricular hemorrhage (IVH). USSC treatment restored aquaporin expression and exerted anti-inflammatory effects, supporting their potential use in treating IVH complications.
Area of Science:
- Neonatal Neurology
- Stem Cell Therapy
- Cerebrospinal Fluid Dynamics
Background:
- Intraventricular hemorrhage (IVH) is a severe complication of preterm birth, leading to hydrocephalus and neurological deficits.
- IVH disrupts cerebrospinal fluid (CSF) regulation by altering aquaporin (AQP) expression and causing ependymal wall damage.
- Previous studies indicated unrestricted somatic stem cells (USSCs) can mitigate hydrocephalus and possess anti-inflammatory properties.
Purpose of the Study:
- To investigate the therapeutic potential of human cord blood-derived USSCs in a rabbit model of IVH-induced hydrocephalus.
- To evaluate the effects of USSC treatment on ventricular size, histological damage, and molecular markers associated with IVH.
Main Methods:
- Glycerol-induced IVH was performed in rabbit pups, followed by intraventricular injection of USSCs or vehicle control.
- Ventricular size was measured at 7 and 14 days post-IVH.
- Histological analysis assessed cellular infiltration and ependymal integrity.
- Immunohistochemistry and mRNA analysis quantified the expression of aquaporins (AQP1, AQP4), inflammatory markers (TGF-β, CTGF, MMP-9), and anti-inflammatory cytokines (IL-10).
Main Results:
- USSC treatment significantly reduced ventricular size in IVH pups compared to controls.
- Histological examination revealed reduced cellular infiltration and preserved ependymal wall integrity in USSC-treated pups.
- USSC administration restored AQP1 and AQP4 expression, suppressed TGF-β, CTGF, and MMP-9, and recovered IL-10 levels.
Conclusions:
- USSCs demonstrate significant therapeutic effects in reducing hydrocephalus following IVH in a preclinical model.
- USSC treatment modulates key molecular pathways, including restoring aquaporin expression and exerting potent anti-inflammatory actions.
- These findings support the potential clinical application of USSCs for managing the complications of intraventricular hemorrhage in preterm infants.
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.
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