Hypoxia Alters Cell Cycle Regulatory Protein Expression and Induces Premature Maturation of Oligodendrocyte Precursor Cells

Periventricular white matter injury (PWMI) is a common form of brain injury sustained by preterm infants. A major factor that predisposes to PWMI is hypoxia. Because oligodendrocytes (OLs) are responsible for myelination of axons, abnormal OL development or function may affect brain myelination. At present our understanding of the influences of hypoxia on OL development is limited. To examine isolated effects of hypoxia on OLs, we examined the influences of hypoxia on OL development in vitro.Cultures of oligodendrocyte precursor cells (OPCs) were prepared from mixed glial cultures and were 99% pure. OPCs were maintained at 21% O(2) or hypoxia (1% or 4% O(2)) for up to 7 days. We observed that 1% O(2) lead to an increase in the proportion of myelin basic protein (MBP)-positive OLs after 1 week in culture, and a decrease in the proportion of platelet-derived growth factor receptor alpha (PDGFRalpha)-positive cells suggesting premature OL maturation. Increased expression of the cell cycle regulatory proteins p27(Kip1) and phospho-cdc2, which play a role in OL differentiation, was seen as well.These results show that hypoxia interferes with the normal process of OL differentiation by inducing premature OPC maturation

Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

Oligodendrocytes derive from progenitors (OPCs) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis but was characterized by a profound defect of differentiation associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPCs is not sufficient to induce a lineage switch but acts as an important determinant of the coordination between RNA splicing and protein synthesis necessary for myelin formation.This work was supported by NIH-NINDS grants R37NS042925 and NS-R0152738 (P.C.) and F31NS077504 (J.L.H.), the UK Multiple Sclerosis Society (R.J.M.F.), and NIH-NIMH grant R01MH090948 (J.Z.)

A systematic review of multidomain and lifestyle interventions to support the intrinsic capacity of the older population

Introduction: The focus on intrinsic capacity (IC) could help clinicians to design interventions to improve the health of the older population. This review aims to map the current state of the art in the field of multi-domain interventions based on the IC framework, to allow health professionals in identifying personalized clinical interventions, oriented to empower the older people with a holistic and positive approach. Methods: A systematic review of the literature was conducted in July 2021 analyzing manuscripts and articles of the last 10.5 years from PubMed, Scopus, Embase, Google Scholar and Elsevier databases. A total of 12 papers were included. Results: The majority of successful interventions are based on a goal setting approach where the older people are involved in the definition of the strategy to follow to remain active and independent. None of the study have used the IC as a framework to design a clinical intervention. Conclusion: To the best of our knowledge, no other reviews are reported in the literature regarding the IC. Our study offers several research directions, which may take the existing debates to the next level