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Neural stem cell therapy of foetal onset hydrocephalus using the HTx rat as experimental model

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Abstract

Foetal onset hydrocephalus is a disease starting early in embryonic life; in many cases it results from a cell junction pathology of neural stem (NSC) and neural progenitor (NPC) cells forming the ventricular zone (VZ) and sub-ventricular zone (SVZ) of the developing brain. This pathology results in disassembling of VZ and loss of NSC/NPC, a phenomenon known as VZ disruption. At the cerebral aqueduct, VZ disruption triggers hydrocephalus while in the telencephalon, it results in abnormal neurogenesis. This may explain why derivative surgery does not cure hydrocephalus. NSC grafting appears as a therapeutic opportunity. The present investigation was designed to find out whether this is a likely possibility. HTx rats develop hereditary hydrocephalus; 30–40% of newborns are hydrocephalic (hyHTx) while their littermates are not (nHTx). NSC/NPC from the VZ/SVZ of nHTx rats were cultured into neurospheres that were then grafted into a lateral ventricle of 1-, 2- or 7-day-old hyHTx. Once in the cerebrospinal fluid, neurospheres disassembled and the freed NSC homed at the areas of VZ disruption. A population of homed cells generated new multiciliated ependyma at the sites where the ependyma was missing due to the inherited pathology. Another population of NSC homed at the disrupted VZ differentiated into βIII-tubulin+ spherical cells likely corresponding to neuroblasts that progressed into the parenchyma. The final fate of these cells could not be established due to the protocol used to label the grafted cells. The functional outcomes of NSC grafting in hydrocephalus remain open. The present study establishes an experimental paradigm of NSC/NPC therapy of foetal onset hydrocephalus, at the etiologic level that needs to be further explored with more analytical methodologies.

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Abbreviations

AJ :

adherent junctions

BrdU :

bromodeoxyuridine

CE :

ciliated ependyma

CSF :

cerebrospinal fluid

df :

disruption front/disruption focus

DIV :

days in vitro

E:

ependyma

GFAP :

glial fibrillary acidic protein

GJ :

gap junctions

hyHTx :

hydrocephalic Texas rat

LV :

lateral ventricle

NB :

neuroblasts

NE :

neurospheres

NPC :

neural progenitor cells

NSC :

neural stem cells

nHTx :

non-hydrocephalic Texas rat

PH :

periventricular heterotopia

PN :

postnatal

se :

septum

st :

striatum

SVZ :

sub-ventricular zone

VZ :

ventricular zone

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Acknowledgements

The authors wish to acknowledge the valuable technical support of Mr. Genaro Alvial and the Confocal and Electron Microscopy Core Facilities of Universidad Austral de Chile.

Funding

This study is supported by Fondecyt 1111018 to EMR; Hydrocephalus Association Established Investigator Award No. 51002705 to PM, EMR, CEJ and Doctoral Conicyt Fellowship (Chile) to RH.

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  1. Roberto Henzi

    Present address: Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de los Andes, Santiago, Chile

Authors and Affiliations

  1. Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile

    Roberto Henzi, Karin Vío, Clara Jara, Esteban M. Rodríguez & Montserrat Guerra

  2. Department of Neurosurgery, Alpert Medical School at Brown University, Providence, RI, USA

    Conrad E. Johanson

  3. Department of Neurosurgery Division of Pediatric Neurosurgery, Washington University and the Saint Louis Children’s Hospital, St. Louis, MO, USA

    James P. McAllister

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All procedures performed in studies involving animals were in accordance with the ethical standards of the National Research Council of Chile (Conicyt). The ethics committee of Universidad Austral de Chile approved the experimental protocol. This article does not contain any studies with human participants performed by any of the authors.

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Dedicated to Prof. Michael Pollay for his enthusiastic support to carry out the present research.

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Henzi, R., Vío, K., Jara, C. et al. Neural stem cell therapy of foetal onset hydrocephalus using the HTx rat as experimental model. Cell Tissue Res 381, 141–161 (2020). https://doi.org/10.1007/s00441-020-03182-0

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