Updating old ideas and recent advances regarding the Interstitial Cells of Cajal

Since their discovery by Cajal in 1889, the Interstitial Cells of Cajal (ICC) have generated much controversy in the scientific community. Indeed, the nervous, muscle or fibroblastic nature of the ICC has remained under debate for more than a century, as has their possible physiological function. Cajal and his colleagues considered them to be neurons, while contemporary histologists like Kölliker and Dogiel categorized these cells as fibroblasts. More recently, the role of ICC in the origin of slow-wave peristaltism has been elucidated, and several studies have shown that they participate in neurotransmission (intercalation theory). The fact that ICC assemble in the circular muscular layer and that they originate from cells which emerge from the ventral neural tube (VENT cells), a source of neurons, glia and ICC precursors other than the neural crest, suggests a neural origin for this particular subset of ICC. The discovery that ICC express the Kit protein, a type III tyrosine kinase receptor encoded by the proto-oncogene c-kit, has helped better understand their physiological role and implication in pathological conditions. Gleevec, a novel molecule designed to inhibit the mutant activated version of c-Kit receptors, is the drug of choice to treat the so-called gastrointestinal stromal tumours (GIST), the most common non-epithelial neoplasm of the gastrointestinal tract. Here we review Cajal's original contributions with the aid of unique images taken from Cajal's histological slides (preserved at the Cajal Museum, Cajal Institute, CSIC). In addition, we present a historical review of the concepts associated with this particular cell type, emphasizing current data that has advanced our understanding of the role these intriguing cells fulfil.