Cd34+ Stromal Cells/Telocytes in Normal and Pathological Skin

Abstract

We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis—e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey–Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)—vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).

Scleroderma-like Impairment in the Network of Telocytes/CD34+ Stromal Cells in the Experimental Mouse Model of Bleomycin-Induced Dermal Fibrosis

“…In keeping with previous studies on human skin [23,31], the distribution of TCs/CD34 + stromal cells in skin sections from mice treated with subcutaneous injections of bleomycin or saline (control) for 4 weeks was firstly investigated by CD34 immunostaining (Figure 2A-F). In control mouse skin, CD34 + stromal cells displaying a spindle-shaped morphology with long cytoplasmic extensions and, therefore, identifiable as TCs (i.e., TCs/CD34 + stromal cells), were arranged in a widespread network extending in the entire dermis, except for dermal white adipose tissue, and surrounding cutaneous adnexa (Figure 2A-C).…”

“…Although currently anomalies in TCs/CD34 + stromal cells have been detected in a number of human pathological tissues, much work has yet to be done to clarify their functional implications [14,23,[25][26][27][28][29][30][31][44][45][46][47][48][49][50][51][52][53][54][55]. For instance, preclinical animal models reproducing tissue alterations of TCs/CD34 + stromal cells, much like those found in human diseases, may clearly represent an invaluable tool for elucidating the effective contribution of these cells to disease pathogenesis and/or pathophysiology, which could often only be supposed [25].…”

“…To investigate whether TCs/CD34 + stromal cells could transdifferentiate into myofibroblasts by losing the CD34 marker and acquiring the expression of α-smooth muscle actin (α-SMA) as proposed in several pathologies including tissue fibrosis [16,23,41], skin sections from control and bleomycin-treated mice were subjected to CD34/α-SMA double immunostaining (Figure 3A-C). In addition to skin specimens from mice treated with bleomycin for 4 weeks that displayed sclerotic changes, we considered it was important to include in this analysis also skin specimens from mice injected with bleomycin for only 2 weeks as an early disease stage group.…”

“…In the skin in physiological conditions, TCs/CD34 + stromal cells form an extensive scaffold-like cellular network which compartmentalizes the dermis, where telopodes intimately surround microvessels, nerve endings, and skin adnexa, and establish intercellular contacts with a variety of cell types, such as fibroblasts, macrophages, mast cells, and tissueresident stem cells [9,[19][20][21][22][23]. Owing to their peculiar spatial distribution and multitude of cell-to-cell communications together with an extraordinary ability to release different kinds of extracellular vesicles, TCs are regarded as important players in the intercellular signaling mechanisms underlying local tissue homeostasis, whose disruption may result into different disorders [4,6,7,14,[24][25][26][27][28].…”

“…Owing to their peculiar spatial distribution and multitude of cell-to-cell communications together with an extraordinary ability to release different kinds of extracellular vesicles, TCs are regarded as important players in the intercellular signaling mechanisms underlying local tissue homeostasis, whose disruption may result into different disorders [4,6,7,14,[24][25][26][27][28]. Thus far, abnormalities in TCs/CD34 + stromal cells have been reported in a variety of skin pathologies, ranging from tumor and tumor-like conditions to inflammatory and fibrosing/sclerosing diseases such as systemic sclerosis (SSc, scleroderma), a complex connective tissue disease in which immune system disturbances and microvascular injury evolve into progressive generalized fibrosis of the skin and internal organs [23,[28][29][30][31][32][33][34][35][36]. In this regard, by means of TEM and CD34 immunostaining, fibrotic skin lesions from patients with SSc were found to be characterized by a severe impairment in the dermal network of TCs/CD34 + stromal cells, but it remains to be clarified in which extent this may be ascribed to either cellular degeneration and loss or possible transformation into disease-triggering profibrotic myofibroblasts [23,31,32].…”