Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.

The SH-SY5Y cell line is a simple and inexpensive in vitro experimental model for studying Parkinson disease (PD). This experimental model is a useful tool for elucidating pathophysiological mechanisms of PD and in the development of new pharmacological therapies. In this review, we aim to summarize current protocols for SH-SY5Y cell culturing and differentiation and PD experimental designs derived from the SH-SY5Y cell line. The most efficient protocol for differentiation of the SH-SY5Y cell line into dopaminergic neurons seems to be the addition of retinoic acid to the growth medium, followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) addition in a low concentration of fetal bovine serum. PD pathological changes, such as neuronal apoptosis and the intraneuronal alpha-synuclein aggregation, can be reproduced in the SH-SY5Y cell line either by the use of neurotoxic agents [such as rotenone, 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine] or by genetic modification (transfection of the alpha-synuclein wild-type or mutant gene, genetic manipulation of other genes involved in PD). In addition, compounds with a potential neuroprotective role may be tested on neurotoxicity-induced SH-SY5Y models. The cell line can also be used for testing PD pathophysiological mechanisms such as the prion-like neuronal transmission of alpha-synuclein or the microbiota influence in PD. In conclusion, the use of the SH-SY5Y cell line represents a basic but consistent first step in experiments related to PD, but which must be followed by the confirmation of the results through more complex in vitro and in vivo experimental models.

CD36 is an integral membrane protein primarily known for its function as a fatty acid transporter, yet also playing other biological roles from lipid metabolism to inflammation modulation. These pleiotropic effects are explained by the existence of multiple different ligands and the extensive distribution in numerous cell types. Moreover, the receptor is related to various pathologies and it may prove to be a good target for prospective therapeutic strategies. In the neurovascular unit (NVU), CD36 is expressed in cells like microglia, microvascular endothelial cells, astrocytes and neurons. In the normal brain, CD36 was proven to be involved in phagocytosis of apoptotic cells, oro‐sensory detection of dietary lipids, and fatty acid transport across the blood brain barrier (BBB). CD36 was also acknowledged as a potentially important player in central nervous system (CNS) disorders, such as Alzheimer Disease‐associated vascular dysfunction and oxidative stress and the neuroinflammatory response in stroke. Despite continuous efforts, the therapeutic arsenal for such diseases is still scarce and there is an increasing interest in discovering new molecular targets for more specific therapeutic approaches. In this review, we summarize the role of CD36 in the normal function of the NVU and in several CNS disorders, focusing on the dysregulation of the NVU and the potential therapeutic modulation.

Extracellular vesicles (EVs) are particles released in the extracellular space from all cell types in physiological and pathological conditions and emerge as a new way of cell-cell communication by transferring their biological contents into target cells. The levels and composition of circulating EVs differ from a normal condition to a pathological one, making them real circulating biomarkers. EVs have a very complex contribution in both health and disease, most likely in relationship between diabetes and cardiovascular disease. The involvement of EVs to the development of cardiovascular complications in diabetes remains an open discussion for therapists. Circulating EVs may offer a continuous access path to circulating information on the disease state and a new perspective in finding a correct diagnosis, in estimating a prognosis and also in applying an effective therapy. Besides their role as biomarkers and targets for therapy, EVs can be exploited as biological tools in influencing the different processes affected in diabetic cardiovascular diseases. This chapter will summarize the current knowledge about EVs as biological vectors modulating diabetic cardiovascular diseases, including atherosclerosis, coronary artery disease, and peripheral arterial disease. Finally, we will point out EVs' considerable value as clinical biomarkers, therapeutic targets, and potential biomedical tools for the discovery of effective therapy in diabetic cardiovascular diseases.

Non-myelinating Schwann cells (NMSCs) are one of the two major phenotypes of Schwann cells. NMSCs are of different types and have various locations. In the peripheral nervous system, NMSC, named Remak Schwann cells (RSC), accommodate multiple small-caliber axons, forming Remak bundles. NMSC, named perisynaptic/terminal Schwann cells, are found at the distal end of motor nerve terminals at the neuromuscular junction (NMJ). Thus, NMSCs proved to serve different functions according to their distribution such as maintenance of the axon and NMJ, peripheral nerve regeneration, or remodeling of the NMJ. Schwann cells (SCs) retain their proliferation capacity in the case of nerve injury or demyelination and provide support for the neuronal cells through paracrine signaling. Here we present an overview of their phenotypes and tissue distribution focusing on their emerging involvement in various peripheral nerve diseases.

Extracellular vesicles (EVs) involved in the intercellular communication hold cell-specific cargos that contain proteins, various species of RNA and lipids. EVs are emerging as powerful tools for diagnosis and therapy in most diseases but little is known about their role in central nervous system (CNS) physiology or disease. Considering the extraordinary intricated cytoarchitecture of the brain, the implication of EVs in its pathophysiology is difficult to establish. Blood circulating EVs derived from local or distant vascular cells or EVs released from brain into the cerebrospinal fluid (CSF) may influence the brain activity. EVs released in the blood stream from various tissues may influence the brain by passing through the blood-brain barrier (BBB) or through choroid plexus. Since the choroid plexus has also a clearance role, it might be possible that EVs carrying brain abnormal proteins to pass into the blood can be detected. Thus, considering that EVs are specialized cargos bearing combined signals between cells, they might be an interesting therapy target in the future for both regulating neurogenesis and abnormal protein clearance. We present here data gathered about EVs that may influence the CNS functionality and be involved in most common neurodegenerative diseases.

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