| 1. |
- Nazmi, Arshed, et al.
(författare)
-
Lymphocytes Contribute to the Pathophysiology of Neonatal Brain Injury
- 2018
-
Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury.Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell-deficient neonatal mice (Rag1-/- mice) using a mouse model of HI-induced preterm brain injury. Flow cytometry was performed to determine the presence of different types of immune cells in mouse brains following HI. In addition, immunostaining for CD3 T cells and CD20 B cells was performed on postmortem preterm human infant brains with PVL.Mature lymphocyte-deficient Rag1- / - mice showed protection from white matter loss compared to wild type mice as indicated by myelin basic protein immunostaining of mouse brains. CD3+ T cells and CD20+ B cells were observed in the postmortem preterm infant brains with PVL. Flow cytometry analysis of mouse brains after HI-induced injury showed increased frequency of CD3+ T, αβT and B cells at 7days after HI in the ipsilateral (injured) hemisphere compared to the contralateral (control, uninjured) hemisphere.Lymphocytes were found in the injured brain after injury in both mice and humans, and lack of mature lymphocytes protected neonatal mice from HI-induced brain white matter injury. This finding provides insight into the pathology of perinatal brain injury and suggests new avenues for the development of therapeutic strategies.
|
|
| 2. |
- Nilsson, Gisela M A, 1973, et al.
(författare)
-
Two different isoforms of osteopontin modulate myelination and axonal integrity
- 2023
-
Ingår i: Faseb Bioadvances. - 2573-9832. ; 5:8, s. 336-353
-
Tidskriftsartikel (refereegranskat)abstract
- Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform-specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN-KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs-iOPN-KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN-KO mice compared to control mice. Accordingly, adult OPN-KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin-related proteins. In contrast, neonatal oligodendrocytes from OLs-iOPN-KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs-iOPN-KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform-specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
|
|
| 3. |
- Song, Juan, et al.
(författare)
-
Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats
- 2022
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 42:9, s. 1632-1649
-
Tidskriftsartikel (refereegranskat)abstract
- Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.
|
|
| 4. |
- Zelco, Aura
(författare)
-
Characterization of immune cell profiles in meninges and brain parenchyma following injury in the developing mouse brain
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preterm newborns are particularly susceptible to complications such as hypoxia-ischemia (HI), which can result in brain injury and subsequent cognitive and/or motor function disabilities, including cerebral palsy. Immune cells have been shown to be involved in the development of perinatal brain damage, commonly with detrimental effects. There is recent evidence that the membranes around the brain parenchyma, the meninges, might also have important roles in the immune response after injury in the adult brain, for example, by being a site of peripheral immune cell infiltration into the brain parenchyma. However, the role of the meninges in preterm brain injury is not known. Thus, the aim of this doctoral thesis was to identify the roles of immune cells in the meninges and brain parenchyma after preterm brain injury using a mouse model of HI-induced preterm brain injury. In Paper I we found that T and B cells accumulate in post-mortem brains and meninges in preterm infants with brain injury. Similarly, in mouse experiments we found that T and B cells respond to the HI injury and infiltrate into the parenchyma. Additionally, genetic deletion of T and B cells resulted in reduced white matter tissue loss 7 days after HI. Paper II shows that innate lymphoid cells subtype 2 (ILC2s) also accumulate in the meninges 7 days after HI, but ILC2-impaired mice show no differences in inflammatory response, tissue loss, or glial immunoreactivity compared to wild type mice after HI, demonstrating a non-essential role for this immune cell subtype after preterm brain injury. Using single cell RNA sequencing, Paper III presents the cellular composition and the unique transcriptional identities of meningeal immune cells in neonatal mice such as border-associated macrophages, monocytes, and microglia. We also identify the possible involvement of neutrophils in the injury process 6 hours after HI. To conclude, the findings of this thesis reveal the participation of immune cells in the brain parenchyma and in the meninges to the development of HI injury. We provide insights into the unique single cell profile in the meninges in the immature mouse brain and thus contribute to the understanding of immune cell involvement in the injury process and the inflammatory reactions after preterm brain injury.
|
|
| 5. |
- Zelco, Aura, et al.
(författare)
-
Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain.
- 2021
-
Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 35:15-16, s. 1190-1207
-
Tidskriftsartikel (refereegranskat)abstract
- The meninges are important for brain development and pathology. Using single-cell RNA sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared with their adult counterparts. We also identified novel meningeal microglia-like cell populations that may participate in white matter development. Early after the hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell resolution view of the importance of meningeal leukocytes at the early stage of development in health and disease.
|
|
| 6. |
- Zelco, Aura, et al.
(författare)
-
Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury.
- 2020
-
Ingår i: Frontiers in cellular neuroscience. - : Frontiers Media SA. - 1662-5102. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental deficits. Therefore, we hypothesized that ILCs, and especially ILC2s, play a role in preterm brain injury.C57Bl/6J mice at postnatal day 6 were subjected to hypoxia-ischemia (HI) insult induced by left carotid artery ligation and subsequent exposure to 10% oxygen in nitrogen. The presence of ILCs and ILC2s in the brain was examined at different time points after HI. The contribution of ILC2s to HI-induced preterm brain damage was explored using a conditionally targeted ILC2-deficient mouse strain (Rorα fl/fl IL7r Cre ), and gray and white-matter injury were evaluated at 7 days post-HI. The inflammatory response in the injured brain was assessed using immunoassays and immunochemistry staining.Significant increases in ILCs and ILC2s were observed at 24 h, 3 days, and 7 days post-HI in the injured brain hemisphere compared with the uninjured hemisphere in wild-type mice. ILC2s in the brain were predominantly located in the meninges of the injured ipsilateral hemispheres after HI but not in the brain parenchyma. Overall, we did not observe changes in cytokine/chemokine levels in the brains of Rorα fl/fl IL7r Cre mice compared with wild type animals apart from IL-13. Gray and white-matter tissue loss in the brain was not affected after HI in Rorα fl/fl IL7r Cre mice. Correspondingly, we did not find any differences in reactive microglia and astrocyte numbers in the brain in Rorα fl/fl IL7r Cre mice compared with wild-type mice following HI insult.After HI, ILCs and ILC2s accumulate in the injured brain hemisphere. However, ILC2s do not contribute to the development of brain damage in this mouse model of preterm brain injury.
|
|
