Telocytes in their context with other intercellular communication agents.

The past decade has borne witness to an explosion in our understanding of the fundamental complexities of intercellular communication. Previously, the field was solely defined by the simple exchange of endocrine, autocrine and epicrine agents. Then it was discovered that cells possess an elaborate system of extracellular vesicles, including exosomes, which carry a vast array of small and large molecules (including many epigenetic agents such as a variety RNAs and DNA), as well as large organelles that modulate almost every aspect of cellular function. In addition, it was thought that electrical communication between cells was limited mainly to neurotransmitters and neuromodulators in the nervous system. Also within the past decade, it was found that - in addition to neurons - most cells (both mammalian and non-mammalian) communicate via elaborate bioelectric systems which modulate many fundamental cellular processes including growth, differentiation, morphogenesis and repair. In the nervous system, volume transmission via the extracellular matrix has been added to the list. Lastly, it was discovered that what had previously been regarded as simple connective cells in most tissues proved to be miniature communication devices now known as telocytes. These unusually long, tenuous and sinuous cells utilize elaborate electrical, chemical and epigenetic mechanisms, including the exchange of exosomes, to integrate many activities within and between nearly all types of cells in tissues and organs. Their interrelationship with neural stem cells and neurogenesis in the context of neurodegenerative disease is just beginning to be explored. This review presents an account of precisely how each of these varied mechanisms are relevant and critical to the understanding of what telocytes are and how they function.

On the possible role of protein vibrations in information processing in the brain: three Russian dolls.

Until recently it was held that the neurocomputations conducted by the brain involved only whole neurons as the operating units. This may however represent only a part of the mechanism. This theoretical and academic position article reviews the considerable evidence that allosteric interactions between proteins (as extensively described by Fuxe et al., 2014), and in particular protein vibrations in neurons, form small scale codes that are involved as parts of the complex information processing systems of the brain. The argument is then developed to suggest that the protein allosteric and vibration codes (that operate at the molecular level) are nested within a medium scale coding system whose computational units are organelles (such as microtubules). This medium scale code is nested in turn inside a large scale coding system, whose computational units are individual neurons. The hypothesis suggests that these three levels interact vertically in both directions thus materially increasing the computational capacity of the brain. The whole hierarchy is thus similar to three nested Russian dolls. This theoretical development may be of use in the design of experiments to test it.

Intercellular Signaling in Cancer-the SMT and TOFT Hypotheses, Exosomes, Telocytes and Metastases: Is the Messenger in the Message?

This review examines the current two leading hypotheses relating to cancer neogenesis-the somatic mutation theory (SMT) and the tissue organization field theory (TOFT)-and focuses on four specific issues. What are the details of the process that changes the epigenetic cargo of the exosomes a cell produces when it becomes malignant? Can exosomes produced by a malignant cell induce on their own a metastatic cancer in the target tissue? What is the functional significance of the fact that exosomes from cancer cells carry in their loads segments of genomic DNA bearing cancer-related mutations across the entire spectrum? What is the evolutionary advantage for the organism of the production by its cancer cells of exosomes that carry epigenetic instructions for the building of elaborate molecular mechanisms that promote the growth of metastatic cancers? These issues are examined with a view of determining the support they give to one or other of the two hypotheses. The conclusion is that they support a specific form of TOFT in which exosomes play a key role.

The role of epigenetic-related codes in neurocomputation: dynamic hardware in the brain.

This paper presents a review of recent work on the role that two epigenetic-related systems may play in information processing mechanisms in the brain. The first consists of exosomes that transport epigenetic-related molecules between neurons. The second consists of homeoproteins like Otx2 that carry information from sense organs to primary sensory cortex. There is developing evidence that presynaptic neurons may be able to modulate the fine microanatomical structure in the postsynaptic neuron. This may be conducted by three mechanisms, of which the first is well established and the latter two are novel. (i) By the well-established activation of receptors that trigger a chain of signalling molecules (second messengers) that result in the upregulation and/or activation of a transcription factor. The two novel systems are the exosome system and homeoproteins. (ii) Exosomes are small vesicles that are released upon activation of the axon terminal, traverse the synaptic cleft, probably via astrocytes and are taken up by the postsynaptic neuron. They carry a load of signalling proteins and a variety of forms of RNA. These loads may then be transported widely throughout the postsynaptic neuron and engineer modulations in the fine structure of computational machinery by epigenetic-related processes. (iii) Otx2 is a transcription factor that, inter alia, controls the development and survival of PV+ GABAergic interneurons (PV cells) in the primary visual cortex. It is synthesized in the retina and is transported to the cortex by a presently unknown mechanism that probably includes direct cell-to-cell transfer, and may, or may not, include transfer by the dynein and exosome systems in addition. These three mechanisms explain a quantity of data from the field of de- and reafferentation plasticity. These data show that the modality of the presynaptic neuron controls to a large extent the modality of the postsynaptic neuron. However, the mechanism that effects this is currently unknown. The exosome and the homeoprotein hypotheses provide novel explanations to add to the well-established earlier mechanism described above.