Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

Abstract

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the gastrointestinal tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the gastrointestinal tract, have important functions in the control of gastrointestinal motility and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances will be the focus of this review. The physiology of ICCUnique motor patterns are intrinsic to every organ of the gastrointestinal tract, which suit their functions related to mixing, absorption and anally directed movement. ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. ICC surround the Auerbach's or myenteric plexus and are associated with nerve varicosities throughout the muscle layers, the so called intramuscular ICC (Figures 1,2). Other subpopulations of ICC are associated with non-ganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figures 1,2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity. This involves rhythmic oscillations of intracellular calcium and activation of membrane ion channels that causes depolarization. Ion channels viewed as important in the generation of pacemaker activity include non-selective cat-ion channels 1 calcium-activated chloride channels [2][3][4] Interstitial cells of Cajal are not unique to the gut; they are present in other rhythmically active structures, such as the portal vein 6 and the bladder 7 . This phenomenon, however, leads to a discussion on properties of cells that are essential to give them the identity of ICC 8 . Genetic abnormalities to the Kit receptor that lead to loss of ICC in the gut, may not equally influence ICC in other organs 9 .The rhythmic depolarization generated by pacemaker ICC propagates into the circular and longitudinal muscle layers, resulting in periods of low and high excitability of the smooth muscle cells at the pacemaker frequency. Under unstimulated conditions, i.e. much of the nocturnal period, this generally does not result in muscle contraction. However, under stimulated conditions, such as a meal, distention and/or neural excitation, ...

Interstitial cells of Cajal and telocytes in the gut: twins, related or simply neighbor cells?

“…Contemporarily, physiologists were able to attribute to them the role of pacemakers for gut peristalsis, being able to generate slow waves (13,(16)(17)(18). Indeed, a combination of morphological and functional investigations was also able to demonstrate that the ICC play a role of intermediate in neurotransmission (12,(17)(18)(19). Another function attributed to some ICC populations is that of being part of the 'stretch receptor'.…”

“…Interestingly, by using one of the c-kit mutant mouse strains, the W/W e , it was reported that the ICC-DMP, commonly considered spared by the gene mutations (24,28,35,36), lost the NK1 receptor and received a significant reduced number of SP nerve endings ( Figure 3). This result was considered responsible for an anomalous tachykinergic control of the Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 9:13 PM disorders resulted in the recovery of ICC networks suggesting the existence of ICC plasticity (18). In healthy, ICC numbers are dynamic (39) indicating that the integrity of the ICC networks has to be tightly controlled with processes that regulate both ICC loss and ICC replacement.…”

Human adult dental pulp CD117/c-kit-positive networks of stromal cells

“…The CD117(c-kit)+/CD44-phenotype of cells found in the cell rich zone is suggestive for a stemness (ICCs) which are slow wave-generating cells or mediate neurotransmission [4]. ICCs are not unique to the gut and are present in other rhythmically active structures [14]. In the myenteric plexus c-kit-positive multipolar ICCs form dense networks which envelop ganglia and nerves [4].…”

Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties

“…ICC loss and injury is now a major research focus as it is recognized as a hallmark of several GI motility disorders [10], including gastroparesis [11,12], slow transit constipation [13,14] and intestinal pseudo-obstruction [15,16]. In addition, progressive depletion of ICC is known to occur as part of normal ageing [17].…”