Retrieval of germinal zone neural stem cells from the cerebrospinal fluid of premature infants with intraventricular hemorrhage

Abstract

Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolated from the hemorrhagic cerebrospinal fluid obtained during therapeutic neuroendoscopic lavage in preterm infants with severe intraventricular hemorrhage. Our analyses demonstrate that these neural stem cells, although similar to human fetal cell lines, display distinctive hallmarks related to their regional and developmental origin in the germinal zone of the ventral forebrain, the ganglionic eminences that give rise to interneurons and oligodendrocytes. These cells can be expanded, cryopreserved, and differentiated in vitro and in vivo in the brain of nude mice and show no sign of tumoral transformation 6 months after transplantation. This novel class of neural stem cells poses no ethical concerns, as the fluid is usually discarded, and could be useful for the development of an autologous therapy for preterm infants, aiming to restore late neurogliogenesis and attenuate neurocognitive deficits. Furthermore, these cells represent a valuable tool for the study of the final stages of human brain development and germinal zone biology.

Human Neural Stem Cells for Cell-Based Medicinal Products

“…So far, most clinical trials have used fetal NSC (fNSC), but NSC from other sources such as pluripotent stem cells (PSC) are increasingly reaching the clinical stage. Furthermore, newer sources for primary NSC, such as the cerebrospinal fluid (CSF) of spina bifida or from premature infants with intracerebroventricular hemorrhage (ICVH) have been reported [ 4 , 5 , 6 , 7 ] and may become available in the near future ( Figure 1 ).…”

“…We and others have recently reported that primary NSC can be isolated from the CSF, collected for diagnostic or therapeutic purposes, of infants diagnosed with severe intracerebroventricular hemorrhage (IVH) or neural tube defects (NTD) [ 4 , 5 , 6 , 7 , 51 ].…”

“…Ventricular neuroendoscopy is performed in these patients as a therapeutic approach to reduce the intracranial pressure and the associated deleterious effects of the high intracranial pressure and of the blood degradation products. We have recently demonstrated that NSC can be easily retrieved from the collected CSF and the cells can be effectively expanded and banked and are not tumorigenic [ 4 ]. As these CSF samples are usually discarded, the isolation of CSF-derived NSC does not raise special ethical concerns.…”

Advances and Perspectives in Dental Pulp Stem Cell Based Neuroregeneration Therapies

“…The scarce numbers of adult NSCs or their aberrant alterations in neurodegenerative diseases suppose the lack of a reliable endogenous mechanism to replenish neurons in the event of their loss. Not in vain, stem cells offer the potential to reduce deleterious signaling and improve traumatic lesions [ 28 , 29 ], and also to slowdown the progression of devastating neurodegenerative diseases such as Huntington’s (HD) [ 30 , 31 ], Parkinson’s (PD) [ 32 , 33 ] or Alzheimer’s disease (AD) [ 34 , 35 , 36 ]. The idea of using stem cells to treat neurodegenerative diseases was proposed very long ago, obtaining valuable and abundant data using fetal human tissue [ 31 , 37 , 38 ] or induced pluripotent stem cells (IPSCs) [ 39 , 40 ].…”

“…However, these methods raise both safety and ethical concerns that are still under intense debate [ 41 , 42 , 43 , 44 , 45 , 46 ]. The main practical problems are the security, the very low yields of extraction, and the troublesome conditions of intervention on premature infants to harvest human NSCs [ 34 ]. Stem cells from the spinal cord of 8-week fetuses have been tested in clinical trials for chronic spinal cord injury [ 47 , 48 ].…”