White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains

Gisela Nilsson,Xiaoyang Wang,Carina Mallard,Henrik Hagberg,Mary A Rutherford,Changlian Zhu,Regina Vontell,Ana A Baburamani

doi:10.1186/s40478-021-01267-7

Abstract

Osteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN’s role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.

Highlights

Preterm infants born before 32 weeks’ gestation or with a birth weight less than 1,500 g are frequently affected by brain injuries that are associated with long-term neurological complications such as cerebral palsy, vision loss, Injury affecting the white matter adjacent to the cerebral ventricles, referred to as periventricular white matter injury (PVWMI), is the most common form of white matter injury in preterm infants and is caused by developmental immaturity, infection, and hypoxia/Nilsson et al acta neuropathol commun (2021) 9:166 ischemia
Characteristics of white matter injury Three groups of preterm infants at postmenstrual age 22–32 weeks were included in this study, including 7 control cases, 7 WMI cases, and 7 germinal matrix hemorrhage (GMH) cases (Table 1)
We found that in regions with injured white matter there was a significant increase in the numbers of microglia expressing OPN in the WMI cases compared to the control cases (p = 0.005) (Fig. 6A–H and M), while there was no significant increase in the numbers of OPNexpressing microglia associated with WMI regions in the GMH group compared to controls

Summary

Introduction

Nilsson et al acta neuropathol commun (2021) 9:166 ischemia These insults induce cell death, excitotoxicity, free-radical accumulation, energy failure, and inflammation that lead to brain lesions with focal necrosis involving reactive astrogliosis and microglia activation as well as to a decrease in pre-myelinating oligodendrocytes [72, 74]. The white matter in premature infants is rich in oligodendrocyte progenitors and premyelinating oligodendrocytes that are vulnerable to excitotoxicity, oxidative stress, and inflammation, all of which can lead to oligodendrocyte developmental arrest and disrupted myelination and white matter injury [6, 24, 46]. GMH usually develops between the thalamus and the caudate, affecting the highly vascularized subependymal germinal matrix area, and if large it can rupture into the ventricles (IVH) [47]. GMH-IVH can further trigger microglia activation, reactive astrogliosis, and inflammatory responses [7, 32, 38] in adjacent white matter contributing to white matter injury [9, 37, 62]

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