Blood–brain barrier and foetal-onset hydrocephalus, with a view on potential novel treatments beyond managing CSF flow

Abstract

Despite decades of research, no compelling non-surgical therapies have been developed for foetal hydrocephalus. So far, most efforts have pointed to repairing disturbances in the cerebrospinal fluid (CSF) flow and to avoid further brain damage. There are no reports trying to prevent or diminish abnormalities in brain development which are inseparably associated with hydrocephalus. A key problem in the treatment of hydrocephalus is the blood–brain barrier that restricts the access to the brain for therapeutic compounds or systemically grafted cells. Recent investigations have started to open an avenue for the development of a cell therapy for foetal-onset hydrocephalus. Potential cells to be used for brain grafting include: (1) pluripotential neural stem cells; (2) mesenchymal stem cells; (3) genetically-engineered stem cells; (4) choroid plexus cells and (5) subcommissural organ cells. Expected outcomes are a proper microenvironment for the embryonic neurogenic niche and, consequent normal brain development.

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

“…As discussed above, the protection would exclude cell replacement. Therefore, the effect could be through the production of growth factors or cytokines, vascular effects, reduction of oxidative stress, and modulation of the inflammatory response, as it has been described in other experimental treatments [11,15,50]. Because a heterogeneous population has been transplanted to hydrocephalic hyh mice, more than one effect is expected.…”

“…Implantation of a ventricular shunt is the most common treatment but presents frequent complications such as obstruction, infection, fracture, migration, overdrainage, or underdrainage [9,10]. For this reason, alternative strategies, such as stem cell therapies, have been proposed hopeful in the treatment of hydrocephalus [11].…”

VEGF Signaling in Neurological Disorders

“…Hydrocephalus can occur regardless of the age and non-surgical treatments other than shunt surgery are rare and have been primarily reported in the postnatal and adult populations [ 38 , 39 ]. However, those in prenatal conditions or foetal-onset hydrocephalus have shown a limited surgical treatment managing flow of cerebrospinal fluid and that potential novel treatments have been limited until recently [ 38 , 40 ]. The timing of VEGF inhibition in early stage of ischemic or hemorrhagic stroke and that of pro-VEGF therapy in the stroke recovery phase following acute ischemia after SAH echoes the significance of VEGF signaling at a different pathogenic stage, age and concentration in hydrocephalus [ 12 , 16 , 41 , 42 ].…”

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

“…1 Interestingly, recent studies suggest that the dysfunction of cellular constituents of the bloodbrain barrier, including pericytes, may contribute in hydrocephalus. 47 Our discovery of an association between CITED2 and TPBG in human pericytes calls for new investigation on TPBG playing a pathogenic role in the above cardiovascular and brain defects.…”