Apoptotic cell death of human interstitial cells of Cajal

Abstract

Interstitial cells of Cajal (ICC) are specialized mesenchyme-derived cells that regulate contractility and excitability of many smooth muscles with loss of ICC seen in a variety of gut motility disorders. Maintenance of ICC numbers is tightly regulated, with several factors known to regulate proliferation. In contrast, the fate of ICC is not established. The aim of this study was to investigate whether apoptosis plays a role in the regulation of ICC numbers in the normal colon. ICC were identified by immunolabeling for the c-Kit receptor tyrosine kinase and by electron microscopy. Apoptosis was detected in colon tissue by immunolabeling for activated caspase-3, terminal dUTP nucleotide end labeling, and ultrastructural changes in the cells. Apoptotic ICC were identified and counted in double labeled tissue sections. Apoptotic ICC were identified in all layers of the colonic muscle. In the muscularis propria 1.5 ± 0.2% of ICC were positive for activated caspase-3 and in the circular muscle layer 2.1 ± 0.9% of ICC were positive for TUNEL. Apoptotic ICC were identified by electron microscopy. Apoptotic cell death is ongoing in ICC. The level of apoptosis in ICC in healthy colon indicates that these cells must be continually regenerated to maintain intact networks.

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

“…These spatial interactions suggested two possible roles of the TC: the TC may favor the spreading of neurotransmission signals directed to ICC (3); the TC could, on demand, differentiate in ICC. This last hypothesis was based on the following data: (i) the ICC number did not change significantly with age while these cells underwent apoptosis (3,39,41); (ii) no mitotic ICC were ever described (3); (iii) mitotic cells resembling the so-called FLC have been observed in areas were ICC, previously destroyed, re-appeared (41); (iv) it is commonly accepted that the TC might be adult mesenchymal stromal cells located in the connective tissue able to differentiate in different cell types of common embryonic origin (47,65).…”

“…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. ICC loss might be due to apoptosis (39) and trans/ de-differentiation (40,41) whereas ICC replacement includes cell repair, proliferation from adult ICC and ICC stem cell precursors proliferation (42).…”

“…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. ICC loss might be due to apoptosis (39) and trans/ de-differentiation (40,41) whereas ICC replacement includes cell repair, proliferation from adult ICC and ICC stem cell precursors proliferation (42). As reported above, the c-Kit signaling pathway is responsible for ICC development and maintenance of the phenotype.…”

Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal

“…12 It has also been shown that ICC undergo apoptosis in healthy colon as a natural process to regulate numbers that must continually regenerate to maintain functional networks. 48 Recently a population of presumed ICC progenitor/stem cells has been identified in murine gastric muscles. …”

Interstitial cells of Cajal — systematic review

“…The direct mechanism of regression of Cajal cells is apoptosis [14], trans/de-differentiation [12,61], while regeneration of ICC is associated with: proliferation of mature ICC [10], renovation of damaged cells and restoration from stem cells [36]. The newest reports say that mature ICC can still proliferate [10,36,39].…”