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In all cells, generation and release of specific vesicles are the initial steps of back-and-forth intercellular communication. These processes are critical in normal physiology and pathophysiology. Vesicles have particular functions appropriate to their targets. When stimulated, they are released into the extracellular space. Four cytoplasmic membrane-bound structures generate their particular vesicles. Among these structures, multivesicular bodies (MVBs) can accumulate many small vesicles in their lumen; release occurs upon MVB exocytosis. Ectosomes are larger vesicles characterized by their responses and are generated directly and released independently from specific microdomains pre-established in the thickness of the plasma membrane. Most lysosomes do not generate vesicles. However, unique components of a minor form, the endo-lysosome, constitute the third class of structures that release a few vesicles by exocytosis with molecules and structures inducing changes in the extracellular environment. The autophagosome, the fourth structure, releases several heterogeneous vesicles by exocytosis with malformed bio-molecules, assembled structures, and damaged organelles. Interestingly, the frequent interaction of autophagosomes with MVBs and their exosomes contributes to the regulation and intensity of their action. The specificity and function of released vesicles depend on their membranes’ and luminal cargoes’ composition and dynamics. An ongoing investigation of the various vesicles reveals new properties regarding their generation, release, and resulting extracellular processes. The growth of information about structures and their vesicles progressively extends the knowledge base regarding cell communication and contributes to their clinical applications. LESS      Full article

Over the years, the influence of secretory mechanisms on intercellular communication has been extensively studied. In the central nervous system (CNS), both trans-synaptic (neurotransmitter-based) and long-distance (extracellular vesicles-based) communications regulate activities and homeostasis. In less than a couple of decades, however, there has been a major paradigm shift in our understanding of intercellular communication. Increasing evidence suggests that besides secretory mechanisms (via extracellular vesicles), several cells are capable of establishing long-distance communication routes referred to as Tunneling Nanotubes (TNTs). TNTs are membranous bridges classically supported by F-Actin filaments, allowing for the exchange of different types of intracellular components between the connected cells, ranging from ions and organelles to pathogens and toxic protein aggregates. The roles of TNTs in pathological spreading of several neurodegenerative conditions such as Prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) have been well established. However, the fragile nature of these structures and lack of specific biomarkers raised some skepticism regarding their existence. In this review, we will first place TNTs within the spectrum of intercellular communication mechanisms before discussing their known and hypothesized biological relevance in vitro and in vivo in physiological and neurodegenerative contexts. Finally, we discuss the challenges and promising prospects in the field of TNT studies. LESS      Full article

Prenatal testing is important for the early detection and diagnosis of rare genetic conditions with life-changing implications for the patient and their family. Gaining access to the fetal genotype can be achieved using gold-standard invasive sampling methods, such as amniocentesis and chorionic villus sampling, but these carry a small risk of miscarriage. Non-invasive prenatal diagnosis (NIPD) for select rare monogenic conditions has been in clinical service in England since 2012 and has revolutionised the field of prenatal diagnostics by reducing the number of women undergoing invasive sampling procedures. Fetal-derived genomic material is present in a highly fragmented form amongst the maternal cell-free DNA (cfDNA) in circulation, with sequence coverage across the entire fetal genome. Cell-free fetal DNA (cffDNA) is the foundation for NIPD, and several technologies have been clinically implemented for the detection of paternally inherited and de novo pathogenic variants. Conversely, a low abundance of cffDNA within a high background of maternal cfDNA makes assigning maternally inherited variants to the fetal fraction a significantly more challenging task. Research is ongoing to expand available tests for maternal inheritance to include a broader range of monogenic conditions, as well as to uncover novel diagnostic avenues. This review covers the scope of technologies currently clinically available for NIPD of monogenic conditions and those still in the research pipeline towards implementation in the future. LESS      Full article

Extracellular vesicles (EVs) are a heterogeneous population of stable lipid membrane particles that play a critical role in the regulation of numerous physiological and pathological processes. EV cargo, which includes lipids, proteins, and RNAs including miRNAs, is affected by the metabolic status of the parental cell. Concordantly, abnormalities in the autophagic-endolysosomal pathway, as seen in lysosomal storage disorders (LSDs), can affect EV release as well as EV cargo. LSDs are a group of over 70 inheritable diseases, characterized by lysosomal dysfunction and gradual accumulation of undigested molecules. LSDs are caused by single gene mutations that lead to a deficiency of a lysosomal protein or lipid. Lysosomal dysfunction sets off a cascade of alterations in the endolysosomal pathway that can affect autophagy and alter calcium homeostasis, leading to energy imbalance, oxidative stress, and apoptosis. The pathophysiology of these diseases is very heterogenous, complex, and currently incompletely understood. LSDs lead to progressive multisystemic symptoms that often include neurological deficits. In this review, a kaleidoscopic overview will be given on the roles of EVs in LSDs, from their contribution to pathology and diagnostics to their role as drug delivery vehicles. Furthermore, EV cargo and surface engineering strategies will be discussed to show the potential of EVs in future LSD treatment, both in the context of enzyme replacement therapy, as well as future gene editing strategies like CRISPR/Cas. The use of engineered EVs as drug delivery vehicles may mask therapeutic cargo from the immune system and protect it from degradation, improving circulation time and targeted delivery. LESS      Full article