Abstract
Considerable evidence accumulated over the past decade supports that telocytes (TCs)/CD34+ stromal cells represent an exclusive type of interstitial cells identifiable by transmission electron microscopy (TEM) or immunohistochemistry in various organs of the human body, including the skin. By means of their characteristic cellular extensions (telopodes), dermal TCs are arranged in networks intermingled with a multitude of neighboring cells and, hence, they are thought to contribute to skin homeostasis through both intercellular contacts and releasing extracellular vesicles. In this context, fibrotic skin lesions from patients with systemic sclerosis (SSc, scleroderma) appear to be characterized by a disruption of the dermal network of TCs, which has been ascribed to either cell degenerative processes or possible transformation into profibrotic myofibroblasts. In the present study, we utilized the well-established mouse model of bleomycin-induced scleroderma to gain further insights into the TC alterations found in cutaneous fibrosis. CD34 immunofluorescence revealed a severe impairment in the dermal network of TCs/CD34+ stromal cells in bleomycin-treated mice. CD31/CD34 double immunofluorescence confirmed that CD31−/CD34+ TC counts were greatly reduced in the skin of bleomycin-treated mice compared with control mice. Ultrastructural signs of TC injury were detected in the skin of bleomycin-treated mice by TEM. The analyses of skin samples from mice treated with bleomycin for different times by either TEM or double immunostaining and immunoblotting for the CD34/α-SMA antigens collectively suggested that, although a few TCs may transition to α-SMA+ myofibroblasts in the early disease stage, most of these cells rather undergo degeneration, and then are lost. Taken together, our data demonstrate that TC changes in the skin of bleomycin-treated mice mimic very closely those observed in human SSc skin, which makes this experimental model a suitable tool to (i) unravel the pathological mechanisms underlying TC damage and (ii) clarify the possible contribution of the TC loss to the development/progression of dermal fibrosis. In perspective, these findings may have important implications in the field of skin regenerative medicine.
Highlights
Growing evidence indicates that dermal tissue structuring and remodeling during skin development and repair depends on the existence of different fibroblast populations [1,2]
The likelihood that TCs may behave as a kind of guide for stem cells or function themselves as progenitors capable of differentiating into other cell types has raised a lot of expectations about their possible use in the field of regenerative medicine [6,16,17,18]
Histological examination of hematoxylinand eosin-stained tissue sections demonstrated the presence of skin sclerotic changes with a considerable increase in dermal thickness of bleomycin-treated mice as compared with age- and sex-matched control mice (Figure 1A,B)
Summary
Growing evidence indicates that dermal tissue structuring and remodeling during skin development and repair depends on the existence of different fibroblast populations [1,2]. It has been shown that embryonic skin fibroblasts originate from two distinct lineages, one forming the upper dermis including the hair growth-regulating dermal papilla and the arrector pili muscle, while the other giving rise to the reticular fibroblasts that synthesize the bulk of the fibrillar extracellular matrix of the lower dermis, and to the adipocytes and the stromal fraction that constitute the dermal white adipose tissue [1,2] In such a scenario, the relatively recent discovery of telocytes (TCs) as a distinctive cell type populating the stromal compartment of the skin and other organs added further complexity to fibroblast heterogeneity [3,4,5,6,7,8]. Concerning the origin of TCs/CD34+ stromal cells, they may derive in the embryo from mesenchymal stem cells (mesodermal origin) or from the neural crest, depending on location, while in postnatal life their source remains mostly unclear [8]
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