Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

Abstract

I ntraventricular hemorrhage (IVH) is a serious complication of preterm birth, and the number of infants at high risk for developing IVH is increasing as a result of the rise in the absolute number and improved survival of very premature infants with recent advances in neonatal intensive care medicine. 1,2 Over half of infants with severe IVH (grade ≥3) die or develop posthemorrhagic hydrocephalus (PHH), which requires shunt surgery in up to 70% of cases.3 IVH is associated with brain damage, especially to the periventricular white matter, which is exacerbated by PHH, and finally results in increased mortality and long-term neurological morbidity, such as seizure, cerebral palsy, and developmental retardation in survivors. [4][5][6] Until now, however, there has not been any effective treatment to prevent PHH or ameliorate brain damage after severe IVH in preterm infants, so it remains a major problem of neonatal intensive care.Although the precise mechanism has not been completely delineated, the pathogenesis of communicating progressive posthemorrhagic ventricular dilatation has been explained by inflammation within subarachnoid spaces attributable to blood contact and deposition of blood products. 7,8 This obliterative arachnoiditis leads to dysfunction of arachnoid granulations, which reduces cerebrospinal fluid (CSF) resorption and increases intracranial pressure, resulting in venous infarction with decreased cerebral perfusion. 8 Moreover, inflammatory cytokines originating from blood products in the cerebral ventricles may injure the periventricular white matter. 9,10 Therefore, new therapeutic modalities with anti-inflammatory capabilities to treat PHH and brain damage after severe IVH would be of great value.Recent preclinical research reported that an anti-inflammatory agent, a cycloxygenase-2 inhibitor, noticeably reduced reactive gliosis and improved neurological impairment after IVH in a newborn rabbit model. This finding indicates that modulating inflammation could be a key factor in IVH therapy for preterm Background and Purpose-Severe intraventricular hemorrhage (IVH) in premature infants and the ensuing posthemorrhagic hydrocephalus cause significant mortality and neurological disabilities, and there are currently no effective therapies. This study determined whether intraventricular transplantation of human umbilical cord blood-derived mesenchymal stem cells prevents posthemorrhagic hydrocephalus development and attenuates brain damage after severe IVH in newborn rats. Methods-To induce severe IVH, 100 μL of blood was injected into each lateral ventricle of postnatal day 4 (P4) SpragueDawley rats. Human umbilical cord blood-derived mesenchymal stem cells or fibroblasts (1×10 5 ) were transplanted intraventricularly under stereotaxic guidance at P6. Serial brain MRI and behavioral function tests, such as the negative geotaxis test and rotarod test, were performed. At P32, brain tissue and cerebrospinal fluid were obtained for histological and biochemical analyses. Results-Intraventricular tran...

Mesenchymal Stem Cells for Severe Intraventricular Hemorrhage in Preterm Infants: Phase I Dose-Escalation Clinical Trial

“…We previously demonstrated that local intraventricular transplantation of 1 × 10 5 MSCs significantly attenuated brain injury and the progress of PHH after severe IVH in newborn rats 21. With systemic intravenous administration, doses fivefold higher were required for equivalent therapeutic efficacy 15.…”

“…In comparison to adult tissue‐derived MSCs, its advantages include easier extraction, lower immunogenicity 16, higher in vitro proliferation capacity 17, 18, and better in vivo therapeutic efficacy 19. Recently, we have shown that xenotransplantation of human UCB‐derived MSCs significantly attenuates brain injury and the progress of PHH after severe IVH in immunocompetent newborn rats 15, 20, 21. Furthermore, we have observed that treatment of BPD in premature infants with intratracheal transplantation of allogeneic human UCB‐derived MSCs is safe, feasible, and not associated with adverse respiratory, growth, or neurodevelopmental effects 22.…”

Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

“…Because of their multilineage differentiation potential, the protective effects of MSC transplantation were initially ascribed to the engraftment of these cells in injured tissues and their subsequent transdifferentiation to repair and replace damaged cells (37,38). However, the very low rate of in vivo engraftment and differentiation of transplanted MSCs (8,15,39) suggests that long-term survival of MSCs might not be essential for their beneficial effects (28,40). Therefore, the therapeutic effects of MSC transplantation might not be associated with their differentiation and direct replenishment of damaged tissue parenchymal cells.…”

“…Recently, several preclinical studies have demonstrated the promise of stem cell therapies in attenuating tissue injuries in newborn animal models of BPD (5-10), HIE (11), and IVH (12)(13)(14)(15). Furthermore, phase I clinical studies in newborn infants with BPD (16), HIE (17), or severe IVH have shown that stem cell treatments for newborn infants might be safe, feasible, and potentially efficacious.…”

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

“…The rotarod test was conducted to evaluate the motor function of rats as described by Ahn et al 14 All the animals were trained for the test 1 day before surgery. Only rats with a latency of >60 s before falling off were used for analysis.…”