Do we need to revise the role of interstitial cells of Cajal in gastrointestinal motility?

Tamás Ördög
2008 American Journal of Physiology - Gastrointestinal and Liver Physiology  
AS ITS NAME SUGGESTS, the tunica muscularis of the gastrointestinal tract is dominated by smooth muscle cells, which perform all the mechanical work required for digestion, absorption, and waste removal. The muscle layers also contain several other cell types, which, despite representing a much smaller percentage of the total cellular content, also contribute to gastrointestinal motility by regulating smooth muscle contractions. In this group belong interstitial cells of Cajal (named after
more » ... ago Ramón y Cajal and commonly referred to as ICC), which represent ϳ5% of cells within the muscular coat. ICC are mesenchymal cells that have been described throughout the gastrointestinal tract of all vertebrates studied to date (15). They can be distinguished from other cell types on the basis of their light microscopic and ultrastructural morphology (16), gene expression pattern, and surface markers (2). Until the discovery of Kit, a type III receptor tyrosine kinase, as a light microscopic marker for ICC (10), investigators could only speculate on the function of these cells on the basis of less specific histochemical staining techniques and electron microscopy and by relying on relatively crude approaches to separate them from the rest of the tissues for physiological analyses. The identification of the interaction between Kit and stem cell factor (SCF or Kitl), its natural ligand, as the most specific target for genetic and pharmacological manipulation of ICC also paved the way for further, more mechanistic investigations. The first part of the "post-Kit era" culminated in the concept that functions previously attributed solely to smooth muscle cells and the extrinsic and intrinsic innervation of the gut may be performed, mediated, or aided by ICC (16). These include the generation and propagation of electrical slow waves underlying rhythmic contractile activity in the phasic parts of the gastrointestinal tract and mediation of communication between the smooth muscle and the autonomic (systemic and enteric) nerves. Later a role in mechanoreception was added (4), and the notion that changes in ICC populations likely play a role in the pathogenesis of various diseases also emerged (19). An exponential rise in interest and studies followed, which further enriched and refined these concepts and broadened the horizon by looking beyond the gut in search of ICC-like cells to explain functions shared by tubular, smooth muscle-lined organs. From these studies emerged a more integrative and nuanced view of the physiology and pathophysiology of gastrointestinal motility and of the role of ICC therein (5, 6, 13, 16). However, significant gaps in our knowledge remain, and it could be argued that filling those gaps and devising more rational therapeutic strategies for disorders involving ICC will require critical reevaluation of the existing data and the development and application of novel concepts and methodology to gastrointestinal motility research (13, 16) . In this issue of American Journal of Physiology Gastrointestinal and Liver Physiology, Dr. Sushil Sarna takes a critical look at the evidence supporting various roles of ICC in gastrointestinal motor functions and concludes that besides setting the membrane potential of smooth muscle cells by releasing the inhibitory gaseous neurotransmitter carbon monoxide, ICC play little, if any, physiological role (17) . This concept is based on earlier views of the control of gastrointestinal motility that only assigned major roles to the smooth muscle and the autonomic (systemic and enteric) nervous system. In this paradigm, smooth muscle cells would produce electrical slow waves, perform mechanical work, and serve as the only relevant recipient and source of information needed for enteric reflexes and motor patterns. Is such a dramatic return to an old paradigm really justified? In his review, Dr. Sarna points out data in the literature that he uses as an argument to refute the current concepts on the roles of ICC in slow-wave generation, mediation of neuromuscular neurotransmission, and mechanoreception. Reexamining concepts from a new aspect is always important for furthering scientific research, and this provocative review will certainly force many in the research community to reassess the literature. It is ultimately up to the informed reader to decide about the proper course of action in response to the issues raised. Are the new data strong enough to justify shutting down efforts in a particular direction? Is the alternative concept presented compelling enough to replace the one in question, or, rather, should we consider the highlighted inconsistencies as unsolved problems requiring that we "raise our game" and employ innovative approaches to get answers? The purpose of this editorial is to jump-start this process by examining Dr. Sarna's hypothesis and by discussing whether the right action in response to the raised issues is to abandon and ignore ICC and resuscitate old paradigms or, alternatively, to give serious consideration to the remaining inconsistencies and then attempt to resolve them by applying novel, state-of-the-art concepts and methods of the postgenomic era to gastrointestinal motility research. Which Cell has the Clock for Timing the Slow Waves? Manifestations of electrical slow waves can be simultaneously recorded from both smooth muscle cells and ICC (5, 8), but which of these two cell types times their periodicity? There is no controversy that ICC possess an electrical pacemaker mechanism that is robust and capable of producing large-amplitude oscillations even in isolation. However, according to the hypothesis advanced in Sarna's review, this clock is not the physiological source of slow waves and is
doi:10.1152/ajpgi.00530.2007 pmid:18270367 fatcat:qdvrb3ss5zeela22igrq5n26ri