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Glial-restricted progenitor cells: a cure for diseased brain?

ABSTRACT: The central nervous system (CNS) is home to neuronal and glial cells. Traditionally, glia was disregarded as just the structural support across the brain and spinal cord, in striking contrast to neurons, always considered critical players in CNS functioning. In modern times this outdated dogma is continuously repelled by new evidence unravelling the importance of glia in neuronal maintenance and function. Therefore, glia replacement has been considered a potentially powerful therapeutic strategy. Glial progenitors are at the center of this hope, as they are the source of new glial cells. Indeed, sophisticated experimental therapies and exciting clinical trials shed light on the utility of exogenous glia in disease treatment. Therefore, this review article will elaborate on glial-restricted progenitor cells (GRPs), their origin and characteristics, available sources, and adaptation to current therapeutic approaches aimed at various CNS diseases, with particular attention paid to myelin-related disorders with a focus on recent progress and emerging concepts. The landscape of GRP clinical applications is also comprehensively presented, and future perspectives on promising, GRP-based therapeutic strategies for brain and spinal cord diseases are described in detail.

SUBMITTER: Rogujski P

PROVIDER: S-EPMC10935984 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Glial-restricted progenitor cells: a cure for diseased brain?

Rogujski Piotr P Lukomska Barbara B Janowski Miroslaw M Stanaszek Luiza L

Biological research 20240312 1

The central nervous system (CNS) is home to neuronal and glial cells. Traditionally, glia was disregarded as just the structural support across the brain and spinal cord, in striking contrast to neurons, always considered critical players in CNS functioning. In modern times this outdated dogma is continuously repelled by new evidence unravelling the importance of glia in neuronal maintenance and function. Therefore, glia replacement has been considered a potentially powerful therapeutic strategy ...[more]

PMID: 38475854

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Project description:BackgroundCell transplantation-based treatments for neurological disease are promising, yet graft rejection remains a major barrier to successful regenerative therapies. Our group and others have shown that long-lasting tolerance of transplanted stem cells can be achieved in the brain with systemic application of monoclonal antibodies blocking co-stimulation signaling. However, it is unknown if subsequent injury and the blood-brain barrier breach could expose the transplanted cells to systemic immune system spurring fulminant rejection and fatal encephalitis. Therefore, we investigated whether delayed traumatic brain injury (TBI) could trigger graft rejection.MethodsGlial-restricted precursor cells (GRPs) were intracerebroventricularly transplanted in immunocompetent neonatal mice and co-stimulation blockade (CoB) was applied 0, 2, 4, and 6 days post-grafting. Bioluminescence imaging (BLI) was performed to monitor the grafted cell survival. Mice were subjected to TBI 12 weeks post-transplantation. MRI and open-field test were performed to assess the brain damage and behavioral change, respectively. The animals were decapitated at week 16 post-transplantation, and the brains were harvested. The survival and distribution of grafted cells were verified from brain sections. Hematoxylin and eosin staining (HE) was performed to observe TBI-induced brain legion, and neuroinflammation was evaluated immunohistochemically.ResultsBLI showed that grafted GRPs were rejected within 4 weeks after transplantation without CoB, while CoB administration resulted in long-term survival of allografts. BLI signal had a steep rise following TBI and subsequently declined but remained higher than the preinjury level. Open-field test showed TBI-induced anxiety for all animals but neither CoB nor GRP transplantation intensified the symptom. HE and MRI demonstrated a reduction in TBI-induced lesion volume in GRP-transplanted mice compared with non-transplanted mice. Brain sections further validated the survival of grafted GRPs and showed more GRPs surrounding the injured tissue. Furthermore, the brains of post-TBI shiverer mice had increased activation of microglia and astrocytes compared to post-TBI wildtype mice, but infiltration of CD45+ leukocytes remained low.ConclusionsCoB induces sustained immunological tolerance towards allografted cerebral GRPs which is not disrupted following TBI, and unexpectedly TBI may enhance GRPs engraftment and contribute to post-injury brain tissue repair.

Project description:Neuroinflammatory and neurodegenerative diseases are influenced by the complex interplay of different cell types within the brain, and understanding the proportions and dynamics of neuronal, glial, and endothelial cells is crucial for deciphering the mechanisms of these diseases. Certain risk factors, such as age and sex differences, are thought to play a significant role in the susceptibility, progression, and response to neurological disease. Therefore, investigation of age- and sex-related differences in cell type proportions is needed to elucidate the biological basis of these diseases. Advances in sequencing technology have enabled large-scale transcriptomic studies, such as the Genotype-Tissue Expression (GTEx) project, providing valuable resources for investigating the cellular landscape of the human brain. In this analysis, we used brain sample data from the GTEx project, comprising 1646 samples with an age range of 20-70 years. The relative abundance of excitatory and inhibitory neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells was estimated from the RNA sequencing data using a deconvolution-based analysis. Spearman correlation analysis between the individuals' calendar ages and cell type proportions revealed a statistically significant decrease in the proportion of neurons with increasing age. In contrast, the proportions of astrocytes and endothelial cells showed a significant increase. Furthermore, endothelial cells exhibited the strongest correlation coefficient, positively associating with age. In addition, the findings indicate sex-based differences in age-related changes to cell type proportions. An age-associated decrease in neuronal proportions was only observed in male donors, while no significant change was found in females. Additionally, an age-associated increase in astrocyte proportions was exclusively seen in males, whereas only females exhibited a significant increase in microglia proportions. Furthermore, we identified sex-based differences in baseline cell type proportions. Male originating samples exhibited higher proportions of excitatory neurons, while female samples showed higher proportions of microglia and endothelial cells. Our results show that both age and sex affect the proportions of cell types in non-diseased brain tissue samples. These findings contribute to our understanding of the effects of age and sex differences on the cellular composition of the brain and shed light on the potential roles of age and sex in neurological diseases.

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Glial-restricted progenitor cells: a cure for diseased brain?

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Glial-restricted progenitor cells: a cure for diseased brain?

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