Mesenchymal stem cells transplantation for neuroprotection in preterm infants with severe intraventricular hemorrhage

Abstract

Severe intraventricular hemorrhaging (IVH) in premature infants and subsequent posthemorrhagic hydrocephalus (PHH) causes significant mortality and life-long neurological complications, including seizures, cerebral palsy, and developmental retardation. However, there are currently no effective therapies for neonatal IVH. The pathogenesis of PHH has been mainly explained by inflammation within the subarachnoid spaces due to the hemolysis of extravasated blood after IVH. Obliterative arachnoiditis, induced by inflammatory responses, impairs cerebrospinal fluid (CSF) resorption and subsequently leads to the development of PHH with ensuing brain damage. Increasing evidence has demonstrated potent immunomodulating abilities of mesenchymal stem cells (MSCs) in various brain injury models. Recent reports of MSC transplantation in an IVH model of newborn rats demonstrated that intraventricular transplantation of MSCs downregulated the inflammatory cytokines in CSF and attenuated progressive PHH. In addition, MSC transplantation mitigated the brain damages that ensue after IVH and PHH, including reactive gliosis, cell death, delayed myelination, and impaired behavioral functions. These findings suggest that MSCs are promising therapeutic agents for neuroprotection in preterm infants with severe IVH.

Keywords: Cell transplantation; Hydrocephalus; Intracranial hemorrhage; Mesenchymal stromal cells; Premature infant.

Fig. 1

Animal modeling of intraventricular hemorrhaging (IVH) in preterm infants using rat pups at postnatal day 4. The brain magnetic resonance imaging (MRI) after 2 days of direct injection of 200 µL dam's blood showed significant enlargement of the ventricles filled with the injected blood. About 4 weeks after IVH modeling, the brain MRI showed severe hydrocephalus.

Fig. 2

Concentration of inflammatory cytokines (interleukin [IL] 1α, IL-β, IL-6, and tumor necrosis factor [TNF]-α) in the cerebrospinal fluid obtained at postnatal day (P) 18 (A) and P32 (B) and from brain homogenate from the periventricular area at P32 (C). Data were expressed as mean±error of the mean. IVH, intraventricular hemorrhaging; NC, normal control rats; IC, IVH control rats; IM, IVH with human umbilical cord blood-derived mesenchymal stem cell transplantation; IF, IVH with human fibroblast transplantation. ^*P<0.05 vs NC. ^†P<0.05 vs IVH-M. ^#P<0.05 vs IC. Adapted from Ahn et al. Stroke 2013;44:497-504.

Fig. 3

Stem-cell transplantation attenuates ventricular dilatation and its progression after severe IVH. (A) Representative serial brain magnetic resonance images (MRIs) of each group on days 1, 7, and 28 after the induction of IVH (postnatal day 5, 11, and 32, respectively). (B) The ratio of ventricle volume to whole-brain volume measured by MRI. Data were expressed as mean±standard error of the mean. IVH, intraventricular hemorrhaging; NC, normal control rats; IC, IVH control rats; IM, IVH with human umbilical cord blood-derived mesenchymal stem cell transplantation; IF, IVH with human fibroblast transplantation. ^*P<0.05 vs NC. ^†P<0.05 vs IVH-M. ^#P<0.05 vs IC. Adapted from Ahn et al. Stroke 2013;44:497-504.