Pericytes in Health and Disease
Pericytes are the perivascular or mural cells of micro vessels. They are of mesenchymal origin and capable of differentiating into a number of different cell lineages. They are intimately associated with endothelial cells and communicate with them via direct physical contact or through paracrine signaling pathways. These interactions are important for blood vessel maturation, remodelling, and maintenance. Pericytes are versatile and their varying morphological characteristics and distribution make them difficult to study. The lack of universal pericytes markers is a major problem. A number of different functions have been attributed to pericytes, and in some organs they have more specific roles. The role of pericytes in tumor vessels is debated, but pericytes may contribute to stability, and might protect the vessels from antiangiogenic therapy. Understanding the process of angiogenesis in angiogenesis dependent diseases role of pericytes may be of therapeutic benefit.This article gives an overview of pericytes their role in health and disease particularly in relation to oral cavity.
Key words: Disease; Endothelial Cell; Functions; Markers; Origin; Pericytes; Structure.
Pericytes also known as mural cells or perivascular cells are contractile cells located on the abluminal side of the endothelium in micro vessels. They communicate with endothelial cells via direct physical contact or through paracrine signaling pathways. These interactions are important for blood vessel maturation, remodelling, and maintenance.1 Pericytes are also known as Rouget cells after their discoverer, Charles Rouget, but the more suitable term pericyte (peri; around, cyte; cell) was coined by Zimmerman in the early 1920s, as the cells were found to wrap themselves around and along the vessel.They share many characteristics with smooth muscle cells that surround larger blood vessels as well as fibroblasts and myofibroblasts.2
Pericytes are of mesenchymal origin and have been shown to have mesenchymal stem cell properties capable of differentiating into other types of mesenchymal cells, including fibroblasts, osteoblasts, chondrocytes, and adipocytes.3,4 Thus this article covers the areas of origin, structure, pericyte’s interaction with endothelial cell, markers, functions; and role of pericytes in health and disease. It provides the current state of knowledge and thoughts for future investigations in these areas.
Morphological characteristics vary from one tissue to another, within the same tissue, or even within the same capillary bed. Pericytes normally possess a cell body with a prominent nucleus and a small content of cytoplasm with several long processes embracing the abluminal endothelial wall (Figure 1). The cells are embedded within the basement membrane which surrounds capillary tubes, and in vitro studies have shown that pericytes and endothelial cells contribute to the formation of this basement membrane. Pericytes are intimately associated with the endothelial surface and their cytoplasmic protrusions contact endothelial cells along the length of the vessel.2 Pericyte density also varies between different areas of the body, and morphology differs depending on species, tissue, and type of vessel and stage of vessel.
Pericytes – Endothelial cell interactions
Blood vessels constitute the elaborate transport system by adequate supply of oxygen and nutrients, and removal of waste material from our body. Blood vessels are composed of two or three different cell types, depending on the type of vessel and its size. All vessels have an inner lining of endothelial cells surrounded by perivascular mural cells (pericytes and vascular smooth muscle cells, vSMC). The smallest-diameter vessels, i.e. arterioles, venules, and capillaries, are associated with solitary pericytes, while multiple concentric layers of vSMC surround larger vessels. The largest arteries have a third outer layer of adventitial fibroblasts.5
Figure 1: Pericytes are in close association with the abluminal side of micro vessel endothelial cells. Protruding cytoplasmic processes wrap themselves around the vessel wall. (Courtesy: Nisancioglu MH, et al., 20105)
The cell-cell contacts between pericytes and endothelial cells are crucial for the regulation of vascular formation, stabilization, remodelling, and function and differ depending on the activation state of the blood vessel.6 There are several different types of cell surface contacts between pericytes and endothelial cells.7 In peg and socket contacts cytoplasmic processes from either cell type insert into invaginations of the other cell. In adherens junctions pericytes and endothelial cells connect their cytoskeleton through cytoplasmic membranes with catenins and cadherins. In gap junction adjacent cell membranes fuse or are separated by a 2-3 nm space.8 (Figure 2) Interactions between endothelial cells and mural cells (pericytes and vascular smooth muscle cells) in the blood vessel wall have recently come into focus as central processes in the regulation of vascular formation, stabilization, remodeling, and function. Failure or abnormal interactions between the two cell types, results in cardiovascular defects, tumor angiogenesis, diabetic microangiopathy, ectopic tissue calcification, and stroke.6
Pericytes in Health
In Dental pulp: Pericytes are capillary associated fibroblasts. They are present partially encircling the capillaries. They have contractile properties and capable of reducing the size of the capillary lumen. Their nuclei can be distinguished as round or oval bodies closely associated with the outer surface of the terminal arterioles or pre-capillaries (Figure 3) Pre-capillaries exhibit a complete or incomplete single layer of muscle cells surrounding the endothelial lining.9
Figure 2: Pericytes surrounding endothelial cells share the basement membrane with endothelial cells. A direct pericyte– endothelial contact is established via junctional complexes located to peg– socket contacts at sites were the basement membrane is absent. (Courtesy: Nisancioglu MH, et al., 20105)
Figure 3: Peripheral pulp and small arteriole or pre-capillaries exhibiting two thin layers of smooth muscle cells surrounding the endothelial cell lining of vessel, Nucleus of pericytes. (Courtesy: Kumar GS, 20119)
In Periodontal ligament (PDL): Periodontal ligament maintains homeostasis in periodontal tissues by supplying stem cells located around blood vessels. Periodontal ligament stem cells possess pericytes-like characteristics and may localize as pericytes in the PDL. This is useful in stem cell biology in periodontal research and stem cell-based periodontal therapy.10 The relative frequency of pericytes to endothelial cells varies also in different tissues.11 The pericytes coverage of the endothelium is partial and can range from 10-50% with the highest found in the central nervous system (CNS).12 In the brain, pericytes contribute to the blood-brain barrier (BBB) and maintain the integrity of structural vessels.13 Pericytes have special functions in many organs and have therefore been given additional names in these organs i.e. Itoh cells or Hepatic stellate cells (HSC) in the liver and mesangial cells in the kidney.14
Regulation of blood flow: Vascular smooth muscle cells of larger vessels regulate blood flow via contraction and relaxation. It has long been postulated that pericytes in a similar fashion are contractile cells that contribute to the regulation of blood flow via communication with endothelial cells.1
Inflammation: The complex process of inflammation involves a response from both the local tissue and the vasculature. The vascular component is characterized by increased vessel permeability to fluid, macromolecules, and immune cells. Pericytes contribute to the inflammatory response in these events, mainly through fine-tuning of the vasculature.3
Immune function: Several studies show that brain pericytes might serve as macrophages. Pericytes were also reported to express numerous marker components of macrophages. Some argue that the reported observations might relate to perivascular macrophages instead of pericytes.15
Wound healing: Mesenchymal cells present in early wounds were divided into two groups: primitive mesenchymal cells and macrophages. Primitive mesenchymal cells incorporated in the thick basement membrane of recently formed capillaries, and differentiate into fibroblasts. After becoming encased in vascular basement membrane these cells, pericytes featured areas of cytoplasmic contact with underlying endothelium. It is proposed that the pericyte-endothelial “contacts” act as a regulatory mechanism for capillary proliferation during wound healing.16
Vascular development / Angiogenesis: Pericytes play an important role in the formation of blood vessels. The formation of stable and mature blood vessels is achieved via the production of extra cellular matrix (ECM) and recruitment of pericytes and vascular smooth muscle cells (VSMC).17The role of pericytes in tumours is unclear. Potentially, pericytes may stabilise blood vessels, inhibit endothelial proliferation, maintain capillary diameter, regulate blood flow, and provide endothelial survival signals via heterotypic contacts and soluble factors. There is a mutual interplay between endothelial cells and pericytes in the direction of the angiogenic process, assigning to the pericytes a putative morphogenetic role.18
Pericytes acquire specialized characteristics in different organs, depending on the functions of each organ. Both pericyte density and vessel coverage, for example, vary among tissues. In certain organs, such as the kidney, liver, and brain, pericytes appear to have more specialized roles. Role of pericytes may be of therapeutic benefit in understanding the process of angiogenesis in a number of angiogenesis dependent diseases such as cancer, atherosclerosis, scars, keloids, psoriasis, ulcers, wound healing, arthritis, diabetes and retinopathy.5
Markers for Pericytes
Pericytes are largely defined based on morphology and location, but they are also commonly identified using molecular markers. Initial methods to identify better markers for pericytes had limited success which relied on immuno-histochemistry for a combination of cytoskeletal proteins thought to be uniquely expressed by pericytes. Pericytes were found to stain for both muscle and non-muscle isoactin.15 None of the markers routinely used in the identification of pericytes, is completely specific for pericytes and neither are they expressed by pericytes in all tissues and organs.6 Thus, the lack of a single marker for pericytes can give rise to misinterpretation of results and defining the true role of pericytes becomes difficult. Recently, regulator of G protein signalling 5 was discovered to be a novel Pericyte gene. (Table 1)
The rapidly growing tumours have a tendency to develop an immature vascular phenotype with continuous micro vessel growth and remodelling. These abnormalities result from defects in both compartments of tumor vasculature, endothelial cells and pericytes.19 Tumor pericytes are different from normal pericytes, just like tumor vessels differ from those of the normal vasculature.(Figure 4) The cells are often loosely attached to the endothelium and extend cytoplasmic processes deep into the tumor tissue.20 Pericyte density and vessel coverage is generally reduced in tumors, but it seems to vary and depends on tumor type.21
Specific for a pericyte surface ganglioside
RGS5 Regulator of G-protein signaling-5
Novel marker for pericytes and vascular smooth muscle cells GTPase activating protein1
Hemangiopericytoma: It is a tumor thought to be derived from pericytes. It consists of numerous vascular channels showing plump endothelial nuclei and indistinct cytoplasm. These cells at the periphery of the capillaries are malignant pericytes and they often exhibit cellular pleomorphism, nuclear hyperchromatism and increased abnormal mitotic activity, etc. The malignant pericytes are often spindle shaped and these cells are often haphazardly arranged within the tumor. The blood vessels often exhibit irregular branching and therefore produce a typical 'stag-horn' appearance. The demonstration of capillary basement membrane by silver-reticulin stain reveals that these malignant pericytes are present outside the basement membrane and these cells are sharply demarcated from endothelial cells by the 'peri-endothelial ring' of reticulin fibers.22
Hemangioma: The clinical phases of Hemangioma have physiological differences, correlated with immunophenotypic profiles by Takahashi et al. During the early proliferative phase (0-12 months) the tumors express proliferating cell nuclear antigen (pericytesna), vascular endothelial growth factor (VEGF), and type IV collagenase, the former two localized to both endothelium and pericytes, and the last to endothelium. The vascular markers CD 31, von Willebrand factor (vWF), and smooth muscle actin (pericyte marker) are present during the proliferating and involuting phases, but are lost after the lesion is fully involuted.23,24
Figure 4: Pericytes in healthy tissues are in close contact with the endothelium. In tumors, pericyte numbers are reduced, and are loosely attached to the tumor micro vessels. (Courtesy: Nisancioglu MH, et al., 20105)
The Glomus Tumour: The glomus neoplasms are benign, circumscribed found in the superficial soft tissues, are characterized by an organoid structure, and are frequently but not always painful. It has been shown by Murray and Stout' that the so-called "epithelioid" cells of the glomus tumour are pericytes, originally described by the Swiss histologist Zimmermann. Incidentally, Enterline and Roberts have described a neoplasm composed of pericytes derived from lymph vessels. Pericytes of the hemangiopericytoma are not frequently elongated and spindle shaped, somewhat resembling a leiomyoblast. While pericytes of the glomus tumour are rounded or epithelioid, this resemblance has led to a mistaken diagnosis of a vascular leiomyoma or fibro sarcoma.25
Congenital epulis: The congenital epulis (gingival granular cell tumor) is a rare lesion of unknown origin found only in newborn infants. The various proposed cells of origin are of the odontogenic epithelium, undifferentiated mesenchymal cells, pericytes, fibroblasts, smooth muscle cells, nerve related cells, and histiocytes. Cells which appeared to be in a transitional state, not yet true granular cells were found juxtaposed to the vessels in the position of pericytes. Fine-structure details of these cells were consistent with pericytes. Cells of this type found farther from the vessels appeared more like the typical granular cells. The cells were filled with structures of the autophagic type devoid of normal cell organelles. These findings support the theory that these are nonneoplastic, degenerative, or reactive lesions arising from a mesenchymal cell, possibly the pericyte.26
Pericytes are contractile cells that wrap around the endothelial cells of capillaries and venules throughout the body. Pericytes are embedded in basement membrane stabilize and monitor the maturation of endothelial cells and communicate with endothelial cells by direct physical contact and paracrine signaling. This is important for pericyte differentiation to other types of mesenchymal cells. Damage to a tissue initiates proliferation of fibroblasts, activation of fibroblasts to myofibroblasts, and the formation of new blood vessels. Endothelial cells and pericytes are interdependent, so failure of proper communication between the two cells can lead to numerous human pathologies. With time, a number of other functions have been attributed to pericytes, and it seems like we are now only starting to understand the complexity of this versatile, controversial and highly intriguing cell type.
We would like to acknowledge all the staff members of department of Oral Pathology for their support and guidance.
1.Dr.Prashant B. Munde, Postgraduate Student, 2.Dr.Shubhangi P. Khandekar, Professor, 3.Dr.Alka M. Dive, Professor and Head, 4.Dr.Neha R. Upadhyaya, Postgraduate Student, Department of Oral and Maxillofacial Pathology, Maharashtra University of Health Sciences, Nashik, VSPM's Dental College and Research Centre, Digdoh Hills, Hingna Road, Nagpur, India.
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Dr. Prashant Munde,
Department of Oral Pathology,
VSPM's Dental College and Research Centre, Digdoh hills,
Hingna Road, Nagpur, India.
Ph: +91 9552982232
Source of Support: Nil, Conflict of Interest: None Declared.