Reprint of "The developing oligodendrocyte: key cellular target in brain injury in the premature infant"
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Derivation of Glial Restricted Precursors from E13 mice
Published on: June 20, 2012
Joseph J Volpe1, Hannah C Kinney, Frances E Jensen
1Department of Neurology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. joseph.volpe@childrens.harvard.edu
Insights
Premature infant brain injury targets developing oligodendrocytes. Research reveals maturation-dependent vulnerabilities and potential therapies, with clinical trials upcoming.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- Premature infant brain injury is a significant cause of neurodevelopmental disability.
- Cerebral white matter injury, targeting developing oligodendrocytes, is a major concern.
- Premature infants are susceptible to hypoxia-ischemia and systemic infection/inflammation.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying oligodendrocyte vulnerability in premature infants.
- To understand how maturation-dependent factors influence oligodendrocyte injury.
- To identify potential therapeutic interventions for preventing brain injury in premature neonates.
Main Methods:
- Analysis of human brain tissue and experimental models of preterm brain injury.
- Investigation of oligodendroglial lineage development and maturation.
- Examination of cellular and molecular pathways involved in injury, including microglial activation, excitotoxicity, and free radical damage.
Main Results:
- Premyelinated oligodendrocytes (pre-OLs) exhibit unique maturation-dependent vulnerabilities.
- Hypoxia-ischemia and infection/inflammation trigger injury through downstream mechanisms like microglial activation, excitotoxicity, and free radical attack.
- A confluence of maturation-dependent factors renders pre-OLs susceptible to these injury pathways.
Conclusions:
- Understanding the cellular and molecular basis of pre-OL vulnerability is crucial for developing targeted therapies.
- Experimental models show promising protective effects of identified interventions.
- Clinical trials are anticipated to evaluate the efficacy of these interventions in premature infants.
Abstract:
Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon.
