CD34+ stromal cells/telocytes (CD34+SCs/TCs) are an important interstitial, perivascular, peri/endoneurial and periadnexal cellular component in the dermis and hypodermis (subcutaneous adipose tissue) of the skin. Most CD34+ stromal cells are known to correspond to telocytes, a new cellular type identified by electron microscopy 
. Ultrastructurally, these cells show a small somatic body and two to five long cytoplasmic processes (telopodes) and are located in the stroma of multiple anatomical sites. Although telocytes show a characteristic ultrastructure, they present immunophenotypic heterogeneity, depending on anatomical location 
. In addition to CD34 positivity TCs are also described as CD34/PDGFRα double positive 
. Expression of vimentin, CD117, CD29, VEGF, and estrogen and progesterone receptors has also been observed in some locations 
. The immunophenotype profile of telocytes (CD34+/PDGFRα+/vimentin+/CD31-) differentiates them from fibroblasts (CD34-/PDGFRα+/vimentin+/CD31-) and endothelial cells (CD34+/PDGFRα-/vimentin+/CD31+) 
. In general, a specific immunomarker for TCs is still an issue of study. Several roles have been hypothesized for CD34+SCs/TCs, including intercellular communication, control and organization of the extracellular matrix, structural support, endocytosis, creation of tissular microenvironments, guidance to migration, contribution of scaffolds, immunomodulation, neurotransmission, control and regulation of other cell types, stem cell modulation and participation in regeneration, repair and tumor stroma formation 
. In addition, several tumors can have their origin in CD34+SCs/TCs 
. In the skin, the suggested roles of CD34+SCs/TCs include mechanical support, regeneration (tandem between TCs and stem cells), communication (intercellular contacts and extracellular vesicles) and endocytosis, immune regulation, modulation of fibroblasts, mast cells and macrophages, reduction of inflammatory response, participation in metabolism, homeostasis, (neo) angiogenesis and in the interaction between collagen and elastic fibers 
Our objective is to review the characteristics and morphologic behaviour of CD34+SCs/TCs in normal and pathological skin (Table 1
), contributing our own observations. Because CD34+SCs/TCs are interstitial cells, they can be part of, related to or influenced by pathologic processes of the various anatomical components present in the skin. These anatomical components of the skin comprise the epidermis, the melanocytic system, the dermal connective tissue and individual cells (macrophages, mast cells and dermal Langerhans cells), the microvasculature, preterminal cutaneous nerves, sensory nerve endings and Merkel cells, eccrine and apocrine sweat glands, hair follicles, sebaceous glands, adipose tissue and the nail. To obtain a broad view of CD34+SCs/TCs in skin pathology, we will explore the most important histological patterns in dermatopathology 
, by providing examples. In previous works, we studied these cells in the peripheral nervous system 
and in adipose tissue 
, both in normal and pathologic conditions. Therefore, CD34+SCs/TCs will only be briefly considered in these skin components.
Table 1. Contributions about CD34+SCs/TCs in the skin.
|In Normal Conditions
||In Pathological Conditions
|Identification, distribution, morphology, ultrastructure
|and immune markers 
|Isolation, in vitro studies, cytokine profile 
||Wound Healing 
|Hypothesized roles 
||Basal and squamous cell carcinoma 
2. CD34+SCs/TCs in the Normal Skin
Several authors have studied the behavior of telocytes in the normal skin, establishing their characteristics and distribution 
. We will briefly consider these aspects of CD34+SCs/TCs in the skin, especially their dermal location and arrangement in the interstitium and around blood and lymphatic vessels, nerves and cutaneous annexes (hair follicles, and sweat and sebaceous glands).
CD34+SCs/TCs are more numerous in the reticular and deep dermis than in the superficial dermal layer (Figure 1A). These CD34+ cells show similar morphologic characteristics to CD34+SCs/TCs in other tissues and organs, with a small somatic region and bipolar or multipolar, long, thin processes (telopodes) (Figure 1B–E). In the interstitium, CD34+SCs/TCs are arranged among collagen bundles and elastic fibers.
Figure 1. CD34+SCs/TCs in normal skin. (A–E) CD34 immunochemistry. Hematoxylin counterstain. (F,G) Double immunochemistry for CD34 (brown) and αSMA (red). (H) Ultrathin section. Uranyl acetate and lead citrate, Inserts of (D,E,H): Immunofluorescence labelling for CD34 (green). Insert of (G) Double immunofluorescence labelling for CD34 (green) and αSMA (red). DAPI counterstain. A: Panoramic view, in which a greater number of CD34+SCs/TCs is observed in the reticular dermis. (B–E) Morphologic characteristics of dermal CD34+SCs/TCs. Note a small somatic region from which long, thin bipolar or multipolar processes (telopodes) emerge. (F,G) Presence of CD34+SCs/TCs (brown) around vessels. The vascular mural cells are stained red. In (F), CD34+SCs/TCs are observed surrounding a nerve (arrow). (H) Ultrastructural image of a telocyte (arrow) around a vessel. Inserts show similar images in immunofluorescence to the corresponding Figure in immunochemistry. Vessel lumen:lu. Bar: (A) 150 µm, (B–E,G) 25 µm, (F) 80 µm, (H) 3 µm.
The distribution of CD34+SCs/TCs around blood and lymphatic vessels in the skin varies depending on the size, location and type of vessel. All skin vessels, except those in the papillary dermis, are surrounded by CD34+SCs/TCs, which are an important component in the adventitia of the larger vessels and form a delimiting layer in most of the smaller ones (Figure 1
F,G). If we consider this delimiting layer of the smallest vessels as a very thin adventitia, we can posit that CD34+SFs/TCs extend continuously through most of the skin blood vessels and constitute an important component of their adventitia. As in other locations, these CD34+SCs/TCs show long, thin processes (Figure 1
F,G), with ultrastructural characteristics of telopodes (Figure 1
H). Regarding vessel location in the skin 
, we will consider the CD34+SCs/TCs in vessel loops in the papillary dermis, the two horizontal vascular plexuses, including the upper, located 1–1.5 mm below the skin surface, and that situated at the dermal subcutaneous interface, as well as the vessels that connect both plexuses. The papillary vessel loops, formed by ascending precapillary arterioles–capillaries and descending capillary–postcapillary venules that originate and terminate, respectively, in the upper horizontal plexus show endothelial and mural cells (vascular smooth muscle cells and pericytes), but are devoid of CD34+SCs/TCs (Figure 2
A,B). This important finding also occurs in the mucosa layer of some organs (e.g., intestine and gallbladder) 
and can explain the behavior of some pathological processes (see below). Except in the papillary dermis, CD34+SCs/TCs are found around vessels and in the interstitial tissue in the dermis, including the upper horizontal plexus (Figure 2
C) and the dermal subcutaneous junction plexus. The arteries in the dermal subcutaneous junction plexus show several layers of CD34+SCs/TCs (Figure 2
D). The veins in this plexus, equipped with two cusped valves (Figure 2
E) that prevent the retrograde flow of blood 
, also present CD34+SCs/TCs, though fewer than in the arteries (Figure 2
E). In addition, CD34+SCs/TCs are observed surrounding small groups of smooth muscle cells in the pre-collector and collector lymphatic vessels in the dermal subcutaneous junction (Figure 2
Figure 2. CD34+SCs/TCs in normal skin. Double immunochemistry for CD34 (brown) and αSMA (red). (A,B) Absence of interstitial and perivascular CD34+SCs/TCs in the papillary dermis. Note a vessel in (A), in which the perivascular CD34+SCs/TCs are absent as the vessel enters the papillary dermis (arrow). (C) Vessels in the upper horizontal plexus and numerous CD34+SCs/TCs in perivascular and interstitial location. (D,E) The wall of an artery (D) and veins (E) in the plexus located in the dermal subcutaneous junction. Several layers of CD34+SCs/TCs are observed in the arterial adventitia (D, arrowhead) and in smaller numbers around veins (E, arrowhead). Note the presence of cusped valves in the latter (arrows). (F,G) CD34+SCs/TCs (brown) surrounding groups of smooth muscle cells (red) in pre-collector lymphatic vessels, in which the endothelial cells do not express CD34. H: CD34+SCs/TCs around fascicles of arrector pili muscle. Vein (E) and lymphatic (F,G) lumen: lu. Bar: (A,C,F,G,H) 45 µm, (B) 55 µm, (D,E) 80 µm.
CD34+SCs/TCs are also concentrated around skin annexes, including the arrector pili muscle (hair erector muscles) (Figure 2H). CD34+SCs/TCs are prominent around the excretory, ductal and secretory portions of the sweat glands, originating intertwined networks (Figure 3A,B). In hair follicles, CD34+SCs/TCs extend from the infundibulum to the deep segments, forming a varying number of parallel layers (Figure 3C,D). Sebaceous glands are also surrounded by typical CD34+SCs/TCs, with long, thin processes (Figure 3E).
Figure 3. CD34+SCs/TCs around sweat glands, hair follicles and sebaceous glands. (A,B,E) Double immunochemistry for CD34 (brown) and αSMA (red). Hematoxylin counterstain. (C,F) Immunochemistry for CD34. Hematoxylin counterstain. (D) Ultrathin section. Uranyl acetate and lead citrate. (A,B) CD34+SCs/TCs (brown) are observed around the sweat glands at different magnifications. Myoepithelial cells are stained red. (C) Several layers of CD34+SCs (brown) around a hair follicle. (D) Ultrastructural image of telopodes of two telocytes (arrows) surrounding a hair follicle. (E) CD34+SCs/TCs (brown) around a sebaceous gland. (F) A cluster of very small, densely grouped CD34+ stromal cells with multiple intricate processes between the bulge region of a hair follicle and a sebaceous gland. Note CD34+SCs/TCs (arrows) interposed between the cluster of small CD34+ stromal cells and the hair epithelium. Bar; (A–C,F) 25 µm, (D) 3 µm, (E) 80 µm.
We observed isolated clusters of very small, closely grouped CD34+ stromal cells with multiple intricate processes in the stroma around the hair follicle between the opening of the sebaceous gland and the end of the erector muscle attachment (bulge region) (Figure 3
F). Clusters were separated from hair and the sebaceous gland epithelium by rows of CD34+SCs/TCs (Figure 3
F). The very small CD34+ stromal cells (minute/dwarf CD34+SCs/TCs?) may correspond to the mesenchymal stromal/stem cells isolated from the hair follicle dermal sheath 
, an issue that requires further studies.
5. General Considerations and Required Future Studies about CD34+SCs/TCs in Normal and Pathological Skin
In our review of the characteristics, distribution and behavior of CD34+SCs/TCs in normal and pathological skin, to which we have added our own observations, the following facts are remarkable. In normal skin, we confirm previous studies by other authors on the characteristics and distribution of CD34+SCs in skin appendages and other dermal components 
. In addition, we have specified and/or contributed the following: (a) the relationship of CD34+SCs/TCs with blood and lymphatic vessels in the two horizontal vascular plexuses and connecting vessels in the dermis, (b) the absence of CD34+SCs/TCs around vessels and in the interstitium of the papillary dermis, which may contribute to preventing excessive repair phenomena in simple erosions of the skin, as occurs in superficial areas of the mucosa of the intestine and gallbladder, and affect the formation of tumor stroma 
and the behavior of melanomas, depending on the level of invasion (e.g., whether or not the papillary dermis is exceeded) and c) the presence around the bulge region of the hair follicle of isolated groups of very small CD34+ stromal cells, which may correspond to the mesenchymal stromal/stem cells isolated from the hair follicle dermal sheath 
. Future studies are required in the last two sections.
We have reviewed the behavior of CD34+SCs/TCs in one or several diseases in each of the principal non-tumoral and tumoral histopathological patterns of the skin. The purpose was to obtain a comprehensive outline, without making the work overly long. Although there are important studies on the behavior of CD34+SCs/TCs in non-tumoral pathological processes of the skin, such as systemic fibrosis 
and psoriasis 
, this is not the case for most non-tumoral pathological processes.
The participation of CD34+SCs/TCs in the organization of the extracellular matrix explains the important role of these cells in fibrosing/sclerosing diseases—as the Italian school has demonstrated in systemic sclerosis (scleroderma) 
—as well as in the basophilic degeneration of collagen and mucinosis. In scleroderma, we show the coexpression of CD34 and αSMA in some stromal cells, which suggests the participation of CD34+SCs/TCs as a source of myofibroblasts in this lesion. Likewise, we highlight the association of CD34+SCs/TCs with degenerative fibers in the basophilic degeneration of collagen, and the presence of spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells in cutaneous myxoid cysts, as an example of local mucinosis.
In addition to psoriasis, in which CD34+Sc/TCs have been studied by other authors 
, we have contributed the behavior of reactive CD34+SCs/TCs in examples of several histopathological patterns of non-tumoral processes of the skin. The examples include erythema multiforme, pemphigus, Hailey–Hailey disease, lichen planus, bullous pemphigoid, granuloma annulare, leukocytoclastic and lymphocytic vasculitis, folliculitis/perifolliculitis, rosacea and verruca vulgaris. In general, CD34+SCs/TCs surround perivascular inflammatory infiltrates in the reticular dermis but are absent when these infiltrates are located in the papillary dermis—a reflection of the distribution of these cells in normal conditions. Perivascular and interstitial CD34+SCs/TCs are usually absent in large inflammatory infiltrates and in granulomas but present around them. Several factors are known to be involved in immune cell control in the interstitial migration of CD4+ T lymphocytes in the inflamed dermis 
and CD34+SCs/TCs in the reduction of the inflammatory response in skin wound healing models 
. Future studies are required to typify inflammatory cells arranged around vessels and surrounded by perivascular CD34+SCs/TCs in the reticular dermis affected by pathological processes, and to evaluate the possible role of CD34+SCs/TCs in retaining and modulating inflammatory cells in the perivascular spaces.
The expression of CD34 has been explored more in stromal cells of tumors and tumor-like conditions than in the entities outlined above, primarily for diagnostic purposes (47–62). In the examples with neoplastic CD34+ stromal cells, we paid particular attention to the characteristics of their nuclei in dermatofibrosarcoma—barely considered in the literature—and the CD34 arrangement around vessels in sclerosing fibroma (perivascular CD34+ stromal cell collagenoma). In examples of cases in which stromal cells are the neoplastic component whose CD34 expression varies, further studies are required for the loss of CD34 expression, degenerative phenomena or both possibilities in the stromal cells of myxofibrosarcoma.
In examples of reactive CD34+SCs/TCs in skin tumors and tumor-like conditions formed by cell lines other than CD34+ stromal cells, we highlight (a) findings supporting the hypothesis that in tumors formed by αSMA+ cells (e.g., pericytic/myopericytic tumors and leiomyomas) or by CD34+ cells (e.g., solitary fibrous tumor), reactive stromal cells in the borders express the other marker, (b) the epithelial tumors can present CD34+ or αSMA+ stromal cells, or even both types of cells, depending on the tumoral region examined, (c) specific distribution of CD34+SCs/TCs in some lesions, as occurs in nevus sebaceous of Jadassohn and seborrheic keratosis, (d) CD34+SC/TC changes in size and morphology in certain tumors, such as trichoepithelioma and Merkel cell tumor, and (e) an important increase in CD34+SC/TC numbers in some cases of melanocytic nevi, neurofibromas and granular cell tumors.
A remarkable finding from our observations on CD34+SCs/TCs in the skin is the partial or total absence of CD34+ stromal cells in some pathological processes, which may be due to (a) the existence of regions without CD34+SCs/TCs in normal conditions, as occurs in the papillary dermis, (b) loss of CD34 expression in CD34+SCs/TCs and gain of other markers, including αSMA expression, which is the case of some stromal cells in systemic sclerosis and in the stroma of some tumors, and (c) degenerative phenomena, which occurs in some stromal cells in systemic sclerosis and in neoplastic cells in myxofibrosarcoma. Further studies are required in these issues, mainly in the gain of other markers by CD34+SCs/TCs during the development of pathological processes of the skin. Future studies should also consider the practical applicability of the findings described for CD34+SCs/TCs in the normal and pathologic skin, including their possible therapeutic implications.
In conclusion, we have reviewed the current state of knowledge about CD34+SCs/TCs in stromal and pathological skin, including our own observations. While CD34+SCs/TCs have been widely explored in normal conditions, they have only been studied in a few pathological processes of the skin. We have contributed examples of entities included in the principal non-tumoral and tumoral histopathological patterns of the skin to obtain a broad overview of the behavior of CD34+SCs/TCs in these conditions and to lay the groundwork for future studies, including the practical applicability.