Contributor:

Sypecka, Joanna (Promotor) ; Ziemka-Nałęcz, Małgorzata (Promotor pomocniczy)

Publisher:

Instytut Medycyny Doświadczalnej i Klincznej im. M. Mossakowskiego PAN

Place of publishing:

Warszawa

Degree name:

doktor

Level of degree:

2

Degree discipline :

biologia medyczna

Degree grantor:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Abstract:

Perinatal asphyxia (otherwise known as hypoxia-ischemia, HI) is the second most common cause of neonatal death worldwide. Causes of asphyxia include premature birth and often result in disruption of normal brain development, leading to hypoxic-ischemic encephalopathy (HIE). In children with mild asphyxia further development is usually normal, but severe hypoxia contributes to the development of infantile cerebral palsy, epilepsy, and may increase the risk of developing autism spectrum disorders. Diffuse damage to white matter, that is oligodendrocytes and their myelin sheaths, are among the most frequently detected pathological changes in HIE. Myelin is an electrical insulator that conditions fast propagation of nerve impulses and forms an indispensable protective barrier for axons. In the developing brain oligodendrocytes differentiate into so-called oligodendrocyte progenitor cells (OPCs). The OPCs differentiation into mature cells is most intense in the perinatal period and is regulated by, among others, trophic factors. Disturbance of neural tissue homeostasis induced by neonatal asphyxia may therefore influence the differentiation and further functioning of oligodendrocytes. Previous studies have shown that OPCs may provide neuroprotective factors, particularly in the region of damaged neural tissue. In the present study, we hypothesized that after HI, OPCs are characterized by an impaired growth and differentiation protocol that promotes their maintenance in a progenitor state and limits maturation. In this study, the potential of OPCs to secrete a selected neurotrophic factor, IGF-1, was evaluated. In addition, the changes in IGF-1 levels in neural tissue after HI injury and the potential of this factor as a therapy for HIE were investigated. Studies were performed using three HI models: in vivo (cerebral hypoxia-ischemia in 7-day-old rats); ex vivo (organotypic cultures of hippocampal slices subjected to temporary nutrient and oxygen deprivation - OGD) and in vitro (cultures of primary rat neonatal OPCs subjected to OGD). The results obtained show that in the first days after damage, OPCs do not show reduced viability but intensively proliferate, and myelin protein expression increases simultaneously. However, analysis of myelination in adult rats (10 weeks after HI) confirmed the typical clinical pattern of neonatal hypoxia-ischemia, i.e., hypotrophy of the hippocampus, corpus callosum, and striatum, as well as areas of hypomyelination in the cortex, striatum, and CA3 region and also delamination of the myelin sheets. Analysis of IGF-1 levels in neural tissue in an in vivo model showed a significant increase in IGF-1 levels after HI on the first day after injury. Ex vivo and in vitro studies showed that OPCs can be a source of IGF-1 and that OGD decreases its secretion. Supplementation of the culture medium with IGF-1 at a concentration of 50 ng/ml induced an increase in the rate of cell proliferation, while a low concentration of 10 ng/ml IGF-1 promoted the production of cell branches, which may imply the promotion of maturation of these cells. The results of the experiments conducted in the present study showed that periodic increases in IGF-1 levels, among others, may contribute to the changes in OPCs differentiation. Despite the increase in myelin protein expression after HI, the production of functional myelin sheaths is impaired. Our study indicates that IGF-1 is one of the factors that may modulate the ability of oligodendrocytes to myelinate after asphyxia, and may be considered as a potential drug to promote white matter development.

Detailed Resource Type:

PhD Dissertations

Resource Identifier:

oai:rcin.org.pl:234927

Source:

IMDiK PAN, sygn. ZS409 ; click here to follow the link

Language:

pol

Language of abstract:

eng

Rights:

Creative Commons Attribution BY 4.0 license

Terms of use:

Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -

Digitizing institution:

Mossakowski Medical Research Institute PAS

Original in:

Library of the Mossakowski Medical Research Institute PAS

Access:

Open