Morphological evidence for telocytes as stromal cells supporting satellite cell activation in eccentric contraction-induced skeletal muscle injury

Abstract

Although telocytes (TCs) have been proposed to play a “nursing” role in resident satellite cell (SC)-mediated skeletal muscle regeneration, currently there is no evidence of TC-SC morpho-functional interaction following tissue injury. Hence, we explored the presence of TCs and their relationship with SCs in an ex vivo model of eccentric contraction (EC)-induced muscle damage. EC-injured muscles showed structural/ultrastructural alterations and changes in electrophysiological sarcolemnic properties. TCs were identified in control and EC-injured muscles by either confocal immunofluorescence (i.e. CD34+CD31− TCs) or transmission electron microscopy (TEM). In EC-injured muscles, an extended interstitial network of CD34+ TCs/telopodes was detected around activated SCs displaying Pax7+ and MyoD+ nuclei. TEM revealed that TCs invaded the SC niche passing with their telopodes through a fragmented basal lamina and contacting the underlying activated SCs. TC-SC interaction after injury was confirmed in vitro by culturing single endomysial sheath-covered myofibers and sprouting TCs and SCs. EC-damaged muscle-derived TCs showed increased expression of the recognized pro-myogenic vascular endothelial growth factor-A, and SCs from the same samples exhibited increased MyoD expression and greater tendency to fuse into myotubes. Here, we provide the essential groundwork for further investigation of TC-SC interactions in the setting of skeletal muscle injury and regenerative medicine.

Telocytes in the Normal and Pathological Peripheral Nervous System

“…However, among other procedures, ultrastructural studies have clearly demonstrated that TCs are different from fibroblasts [ 1 , 2 , 3 ]. Likewise, it is widely accepted that cells ultrastructurally identifiable as TCs largely correspond to the CD34+ stromal cells (TCs/CD34+SCs) observed in light microscopy [ 43 ].…”

Presence/Absence and Specific Location of Resident CD34+ Stromal Cells/Telocytes Condition Stromal Cell Development in Repair and Tumors

“…A new cellular type named telocyte was identified by electron microscopy and described in 2010 (Popescu and Faussone-Pellegrini, 2010; Faussone Pellegrini and Popescu, 2011;Popescu, 2011). This cell type largely corresponds to the CD34+ stromal cells observed in light microscopy (Rusu et al, 2016;Manetti et al, 2019). Several roles have been hypothesized for CD34+ stromal cells/telocytes (CD34+SCs/TCs) in (a) the maintenance and modulation of tissue homeostasis, including organization and control of the extracellular matrix, structural support, creation of microenvironments, integration of tissue components, control and regulation of other cells, and immunomodulation (Faussone Pellegrini and Popescu, 2011;Popescu, 2011;Popescu and Nicolescu, 2013;Díaz-Flores et al, 2014, 2016aCretoiu et al, 2016Cretoiu et al, , 2020 regeneration and repair (Faussone Pellegrini and Popescu, 2011;Popescu, 2011;Popescu et al, 2011;Ceafalan et al, 2012;Bani and Nistri, 2014;Díaz-Flores et al, 2015a,b, 2016b.…”

“…Several roles have been hypothesized for CD34+ stromal cells/telocytes (CD34+SCs/TCs) in (a) the maintenance and modulation of tissue homeostasis, including organization and control of the extracellular matrix, structural support, creation of microenvironments, integration of tissue components, control and regulation of other cells, and immunomodulation ( Faussone Pellegrini and Popescu, 2011 ; Popescu, 2011 ; Popescu and Nicolescu, 2013 ; Díaz-Flores et al, 2014 , 2016a ; Cretoiu et al, 2016 , 2020 ; Vannucchi et al, 2016 ) regeneration and repair ( Faussone Pellegrini and Popescu, 2011 ; Popescu, 2011 ; Popescu et al, 2011 ; Ceafalan et al, 2012 ; Bani and Nistri, 2014 ; Díaz-Flores et al, 2015a,b , 2016b ; Vannucchi et al, 2016 ). In regeneration, CD34+SCs/TCs act on neighboring parenchymal stem cells, regulating their proliferation and maturation ( Faussone-Pellegrini and Bani, 2010 ; Popescu, 2011 ; Ceafalan et al, 2012 ; Gherghiceanu and Popescu, 2012 ; Rusu et al, 2016 ; Vannucchi and Faussone-Pellegrini, 2016 ; Cretoiu et al, 2017 ; Manetti et al, 2019 ). In repair through granulation tissue, CD34+SCs/TCs play an important role as precursor cells.…”

A Two-Step Immunomagnetic Microbead-Based Method for the Isolation of Human Primary Skin Telocytes/CD34+ Stromal Cells

“…In this regard, the ability of TCs to form complex interstitial networks and communicate with neighboring cells by establishing multiple intercellular contacts or releasing extracellular vesicles containing bioactive molecules, together with the evidence that such TC networks are severely impaired in a variety of pathologies, led to proposing that these cells may exert a wide spectrum of functions important for the maintenance of tissue homeostasis [ 2 , 4 , 5 , 10 , 28 , 29 , 57 , 58 ]. For instance, owing to their strategic position in relation to tissue-resident stem cell niches in various organs and satellite cells in the skeletal muscle, it has been postulated that TCs may play a pivotal role in stem cell survival, proliferation, differentiation, maturation, and guidance, eventually stimulating tissue regenerative processes [ 5 , 19 , 52 , 59 , 60 , 61 , 62 ]. Furthermore, TCs are usually found to intimately surround microvessels with their telopodes and may express proangiogenic growth factors, such as vascular endothelial growth factor, and several microRNAs with angiogenic functions, suggesting that they may influence EC functions contributing to vascular homeostasis and neovascularization processes [ 41 , 63 , 64 ].…”