Telocytes, exosomes, gap junctions and the cytoskeleton: the makings of a primitive nervous system?

THE FACTS Telocytes (TCs) form a remarkable new cell species found in many types of tissue. They were discovered by Professor Laurentiu-Mircea Popescu of Roumania in 2005 (Popescu et al., 2005), and are characterized by having very small cell bodies (consisting of a nucleus and a small amount of cytoplasm) and “extremely long and thin” tubular processes called telopodes (up to 100 micrometers long, yet only 20–200 nanometers wide). Telopodes consist of long thin tubes (called podomers) interspersed with short dilations (called podoms) that have the appearance of axonal boutons en passage. Podoms contain abundant mitochondria, calveoli and endoplasmic reticulum (Cretoiu et al., 2012a, 2013). TCs form a dense convoluted network linking TCs with each other, and with many other cell types including secretory acini and exocrine epithelial ducts, nerve fibers, macrophages, and blood vessels (Nicolescu et al., 2012; Popescu et al., 2012; Bosco et al., 2013). Gherghiceanu and Popescu (2012) report that TCs make contact with virtually all types of cells in the human heart including Schwann cells, endothelial cells, pericytes, macrophages, mast cells, fibroblasts, stem cells/progenitors, and working cardiomyocytes. In the urinary system they establish numerous contacts inter alia with macrophages in the sub-capsular space of the kidney, or with smooth muscle cells, nerve endings as well as blood capillaries in the ureter and urinary bladder (Zheng et al., 2012). In the esophagus the cells that they make contact with include macrophages and lymphocytes (Chen et al., 2013). In the small intestine TCs encircle muscle bundles, nerve structures, blood vessels, fundi of gastric glands and intestinal crypts Vannucchi et al. (2013). These networks contain embedded stem cells (Luesma et al., 2013). Connections by TCs with all of the aforementioned entities are made both by electron-dense nanocontacts involving junctions, and via exosomes (Nicolescu et al., 2012; Popescu et al., 2012; Luesma et al., 2013). Exosome release occurs along the telopodes (Cretoiu et al., 2012b). In the eye this gap-junction-linked network is prominent in the uvea and sclera. Moreover, exosomes (with a diameter up to 100 nm) are delivered by TCs to a wide variety of cells including cells of the iris stroma (Luesma et al., 2013), leading these authors to suggest that TCs may be involved in integrating neural, vascular and endocrine processes. Several authors have suggested that TCs are involved in tissue protection, remodeling and regeneration (Xiao et al., 2013; Zhao et al., 2013; Zheng et al., 2013) as well as mechanical support, spatial relationships with different cell types, intercellular signaling and modulation of intestinal motility (Cretoiu et al., 2013; Milia et al., 2013). Their presence in the meninges and in the choroid plexus/subventricular zone within the proximity of neural stem cells led Popescu et al. (2012) to suggest that TCs may be involved in modulating neural stem cell fate. Ongoing investigations are revealing increasingly important roles for TCs in the stabilization of healthy tissue function, so as to minimize inflammatory tissue damage and possibly oxidative damage to particular organs (Haines et al., 2013). For example, Zhao et al. reported an inverse correlation between the magnitude of infracted zones of rat myocardium and cardiac TC density (Zhao et al., 2013). TCs, therefore, function in tandem with stem cells in anatomical locations designated “stem-cell niches” resulting in an enhancement of their engraftment capability (Polykandriotis et al., 2010). Ceafalan et al. (2012) have suggested that TCs are involved in skin homeostasis, remodeling, regeneration and repair. It is of interest to note that, on a micro scale, a TC shares some of the properties of the claustrum (a nucleus in the mammalian telencephalon), namely, keeping its fingers in many pies, therein elevating the role and prospective benefits of gap junctions and a thin topology (Smythies et al., 2012, 2014). Both structures seem to be closely involved in integrating the function of multiple other structures.