The story of the ICC is a fascinating story of ever-changing medical concepts that emerged as a result of the interplay between researchers’ limitless scientific intuition and its formal constraints through the continuous development of medical methodology but always limited ^[1]. It is this interplay that lies behind the evolution of fundamentally correct concepts many decades before the methods moved to the stage of providing sound theories if not providing the evidence itself ^[1].

Thus, the great Spanish neuroanatomist, Santiago Ramon y Cajal, conducting studies on these cells, arrived at the hypothesis (1893, 1911) that networks of interstitial cells anastomosed to each other are influenced “primarily” by components of the nervous system, while interstitial cells (seen as primitive “accessory” neurons) exert direct regulatory effects on the contraction of smooth muscle in the gastrointestinal tract ^[1].

Despite the fact that more than a century has passed since Ramon y Cajal described the staining characteristics of the “interstitial nerve cell” located between the external longitudinal muscle and the circular muscle of the intestine at the level of the Auerbach’s plexus (1893, 1911), the function and developmental origin of these cells have remained unclear ^[2]. Although Ramon y Cajal and other contemporary researchers believed that these interstitial cells of Cajal were primitive neurons, it has been suggested that these cells are specialized smooth muscle cells ^[3], while other researchers have characterized them as fibroblasts ^[4].

Independent of Cajal’s research, Sir Arthur Keith (1914, 1915), the scientist who described the sino-atrial cardiac pacemaker and was apparently unaware of Cajal’s research, considered these cells to be a real pacemaker of the intestinal muscle layers ^[5]. The methods needed to prove or disprove these theories were not developed until 7–8 decades later, subsequently proving both to be essentially correct ^[1].

Between 1925 and 1965, several controversial papers were recorded with scientists presenting different opinions regarding the origin, function and distribution of the ICC. In 1970, after the development of electron microscopy, many mysteries were elucidated. The ICC presents similar properties to smooth muscle cells but also specific characteristics to perform the function of intestinal pacemaker. In the early 1980s, these cells were again brought back to the attention of gastroenterologists by Thunenberg and Faussone-Pellegrini [4,6]^[4][6].

2. Origin of the Interstitial Cells of Cajal

The gastrointestinal system consists of cells that arise from all embryonic layers [12]^[7]. The endoderm gives rise to the epithelial cells of the intestinal lumen and the epithelial cells of the intestinal glands [13]^[8]. From the mesoderm, all muscle cells, connective tissue and lymphatic and blood structures are born [12]^[7]. Neural crest cells are derived from the ectoderm. Neural crest cells migrate in the digestive system and, after that, they give birth to all enteric neurons [12,13,14]^[7][8][9]. Despite the fact that the ICC was described more than 100 hundred years ago, their origin has long been an enigma, which is due to the fact that the ICC share structural features with neural crest-derived cells (neurons, glial cells) but also share features with mesoderm-derived cells (muscle cells, fibroblasts) [13]^[8]. Despite this debate over the years, some research conducted on chickens, quails [15]^[10] and rats [16]^[11] demonstrated that the origin of the ICC is in the mesoderm. This fact, demonstrated by the previous research teams, is reinforced by other subsequent studies on rats [2,17]^[2][12]. In the past years, Faussone-Pellegrini [3,6]^[3][6] analyzed the ultrastructural evolution of the ICC in the Auerbach’s plexus and deep muscle plexus. They identified the ICC progenitor cells in newborn rats that are closely related to the nerve fibers of the myenteric plexus, but they could not establish the embryological origin of these cells [12]^[7]. Several studies from the past suggested that the ICC is derived from the mesoderm and share the same progenitor cells with cells from the smooth muscle [2,17]^[2][12]. Furthermore, Torihashi studied the evolution of c-kit reactivity markers for smooth muscles and neural crest-derived cell markers on embryonic small intestine specimens from rats [17]^[12], thus finding the existence of c-kit+ cells in the outer layers of the intestine in day 12 embryos. However, the cells at this level were not differentiated, and they did not present structural characteristics of an adult muscle cell or the ICC [17]^[12]. At embryonic day 15, cells at the level of the circular muscle layer, which are located inside the myenteric plexus, present immunoreactivity for actin and muscle myosin; in contrast, cells that develop at the place where the future longitudinal muscle tissue will be located are c-kit+ cells, but they lack the expression for actin and smooth muscle myosin [17]^[12]. In the late stages of embryonic development, a c-kit+ cell subpopulation was found to differentiate into smooth muscle cells showing positive expression for myofilament proteins; consequently, these cells lose the ability to show c-kit+ expression [17]^[12]. It is thus assumed that the ICC and smooth muscle cells have a common origin from c-kit+ progenitor cells in the primitive intestine, and all c-kit+ cells will differentiate into the ICC [17]^[12]. Another study from the literature carried out in 1998 by Kluppel ^[2] confirmed the previous results that the ICC and smooth muscle cells have the same embryonic progenitor cell. Kluppel studied the mRNA expression of smooth muscle myosin heavy chain (SMMHC) and c-kit immunoreactivity ^[2]. He found that all intestinal muscle cells initially show c-kit+ expression and expression for SMMHC; later in the developmental stages, they lose the ability to show c-kit+ expression, while all cells that will further become the ICC will keep c-kit expression but will lose expression for SMMHC ^[2]. The main conclusion of all this data is that the ICC and smooth muscle cells present the same progenitor cell [12,18]^[7][13].

3. ICC Distribution in the Human Gastrointestinal Tract

The presence of the ICC in the human gastrointestinal tract has been demonstrated over the years from the esophagus [20]^[14] to the anal canal [21]^[15]; however, these cells present different morphological features and different tissue distribution. The ICC exhibit a specific cell position, arrangement and shape based on the localization in different anatomical locations and different layers of the gastrointestinal tract. Therefore, these cells present several cellular subpopulations [22]^[16]. In the gastric region, there are reported different subtypes of the ICC and, in the small intestine and colon, the ICC present the same pattern of the subtype of the ICC in each segment [22]^[16]. All the subtypes of the ICC have the same ultrastructural characteristics, presence of numerous mitochondria, abundant intermediate filaments and gap junctions with the same cell and smooth muscle cells [22]^[16]. The ICC include a vast array of specialized cell types within the musculature of the gastrointestinal system. A number of these cell types play a pacemaker role within the gastrointestinal musculature, while others are heavily involved in the modulation of enteric neurotransmission. The most important cell types with a role in intestinal tract motility are the ICC of the myenteric plexus (MP), ICC intramuscular (IM) and ICC of the deep muscle plexus (DMP) [23]^[17].