Sex Differences in Poststroke Inflammation: a Focus on Microglia Across the Lifespan.

Stroke is one of the leading causes of death worldwide and currently only few therapeutic options are available. Stroke is a sexually dimorphic disease contributing to the difficulty in finding efficient treatments. Poststroke neuroinflammation is geared largely by brain microglia and infiltrating peripheral immune cells and largely contributes to sex differences in the outcome of stroke. Microglia, since very early in the development, are sexually divergent, imprinting specific sex-related features. The diversity in terms of microglial density, morphology, and transcriptomic and proteomic profiles between sexes remains in the adulthood and is likely to contribute to the observed sex-differences on the postischemic inflammation. The impact of sexual hormones is fundamental: changes in terms of risk and severity have been observed for females before and after menopause underlining the importance of altered circulating sexual hormones. Moreover, aging is a driving force for changes that interact with sex, shifting the inflammatory response in a sex-dependent manner. This review summarizes the present literature on sex differences in stroke-induced inflammatory responses, with the focus on different microglial responses along lifespan.

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays.

Human pluripotent stem cell (hPSC)-derived neuron cultures have emerged as models of electrical activity in the human brain. Microelectrode arrays (MEAs) measure changes in the extracellular electric potential of cell cultures or tissues and enable the recording of neuronal network activity. MEAs have been applied to both human subjects and hPSC-derived brain models. Here, we review the literature on the functional characterization of hPSC-derived two- and three-dimensional brain models with MEAs and examine their network function in physiological and pathological contexts. We also summarize MEA results from the human brain and compare them to the literature on MEA recordings of hPSC-derived brain models. MEA recordings have shown network activity in two-dimensional hPSC-derived brain models that is comparable to the human brain and revealed pathology-associated changes in disease models. Three-dimensional hPSC-derived models such as brain organoids possess a more relevant microenvironment, tissue architecture and potential for modeling the network activity with more complexity than two-dimensional models. hPSC-derived brain models recapitulate many aspects of network function in the human brain and provide valid disease models, but certain advancements in differentiation methods, bioengineering and available MEA technology are needed for these approaches to reach their full potential.

Glia-Derived Extracellular Vesicles: Role in Central Nervous System Communication in Health and Disease.

Glial cells are crucial for the maintenance of correct neuronal functionality in a physiological state and intervene to restore the equilibrium when environmental or pathological conditions challenge central nervous system homeostasis. The communication between glial cells and neurons is essential and extracellular vesicles (EVs) take part in this function by transporting a plethora of molecules with the capacity to influence the function of the recipient cells. EVs, including exosomes and microvesicles, are a heterogeneous group of biogenetically distinct double membrane-enclosed vesicles. Once released from the cell, these two types of vesicles are difficult to discern, thus we will call them with the general term of EVs. This review is focused on the EVs secreted by astrocytes, oligodendrocytes and microglia, aiming to shed light on their influence on neurons and on the overall homeostasis of the central nervous system functions. We collect evidence on neuroprotective and homeostatic effects of glial EVs, including neuronal plasticity. On the other hand, current knowledge of the detrimental effects of the EVs in pathological conditions is addressed. Finally, we propose directions for future studies and we evaluate the potential of EVs as a therapeutic treatment for neurological disorders.