The impact of trophic and immunomodulatory factors on oligodendrocyte maturation: Potential treatments for encephalopathy of prematurity

Abstract

Encephalopathy of prematurity (EoP) is a major cause of morbidity in preterm neonates, causing neurodevelopmental adversities that can lead to lifelong impairments. Preterm birth-related insults, such as cerebral oxygen fluctuations and perinatal inflammation, are believed to negatively impact brain development, leading to a range of brain abnormalities. Diffuse white matter injury is a major hallmark of EoP and characterized by widespread hypomyelination, the result of disturbances in oligodendrocyte lineage development. At present, there are no treatment options available, despite the enormous burden of EoP on patients, their families, and society. Over the years, research in the field of neonatal brain injury and other white matter pathologies has led to the identification of several promising trophic factors and cytokines that contribute to the survival and maturation of oligodendrocytes, and/or dampening neuroinflammation. In this review, we discuss the current literature on selected factors and their therapeutic potential to combat EoP, covering a wide range of in vitro, preclinical and clinical studies. Furthermore, we offer a future perspective on the translatability of these factors into clinical practice.

Keywords: cytokines; myelination; neuroinflammation; oligodendrocyte; preterm brain; trophic factors.

FIGURE 1

The underlying pathophysiology of encephalopathy of prematurity (EoP) and proposed mechanism of therapeutic intervention. Preterm birth‐related issues such as inflammation and hypoxia/hyperoxia (yellow flash) are thought to lead to oligodendrocyte (OL) death (apoptosis) and/or a maturational arrest of the oligodendrocyte lineage, through the activation of microglia (purple cell) and astrocyte (red cell) reactivity. Microglia release reactive oxygen species (ROS) and pro‐inflammatory cytokines, which leads to the death of vulnerable oligodendrocyte precursors (OPCs). Reactive astrocytes respond to inflammation and/or oxygen fluctuations by reducing their uptake of glutamate and increasing the release of proliferative factors (red dots), that inhibit the differentiation of oligodendrocyte precursor cells (OPCs). The proposed therapeutic effect of growth factor‐ and cytokine‐based treatments is indicated in dotted lines. This review summarizes growth factors (blue dots) and cytokines (green dots) that have the potential to stimulate oligodendrocyte maturation/differentiation and increase survival of these cells directly, while simultaneously inhibiting the harmful neuroimmune response caused by microglia and astrocytes. Several routes of administration are proposed, such as intranasal through a local opening in, or through the compromised blood–brain‐barrier (BBB) in the acute phase after brain injury

FIGURE 2

Proposed model of intracellular pathways that mediate the different stages of oligodendrocyte development. Astrocytes (red cell), triggered by inflammation and/or hypoxia (yellow flash), produce factors that stimulate oligodendrocyte precursor cell (OPC) proliferation, which contributes to the maturational arrest of oligodendrocytes in preterm WMI. In contrast, several factors discussed in this review either directly or indirectly stimulate oligodendrocyte maturation/differentiation, myelination, and survival, through shared intracellular pathways. IGF‐1, insulin‐like growth factor 1; EGF, epidermal growth factor; TGF, transforming growth factor (α and β); NRGs, neuregulins; GDNF, glial cell‐line derived neurotrophic factor; NTs, neurotrophins; Gp130, glycoprotein 130; IL, interleukin (4 and 10); BMP, bone morphogenetic protein; BMPR, BMP receptor; RTK, receptor tyrosine kinase; JAK, janus kinase; STAT, signal transducer and activator of transcription proteins; JNK, c‐Jun N‐terminal kinase; PI3K, phosphoinositide 3‐kinase; PTEN, phosphatase and tensin homolog; cAMP, cyclic adenosine monophosphate; ERK, extracellular signal‐regulated kinase; mTOR, mammalian target of rapamycin; FoxO1, forkhead box protein O1; Sp1, specificity protein 1; CREB, cAMP response element‐binding protein, mTORC1, mTOR complex 1; GSK3β, glycogen synthase kinase 3 β; PPARγ, peroxisome proliferator‐activated receptor γ