Platelet-derived growth factor receptor α (PDGFRα)-expressing "fibroblast-like cells" in diabetic and idiopathic gastroparesis of humans.

Coordinated gastrointestinal (GI) motor activity requires a complex interplay of various cell types including inhibitory and excitatory nerves, glia, smooth muscle cells (SMC), immune cells and interstitial cells of Cajal (ICC).1 ICC generate slow waves, set the smooth muscle membrane potential gradient, and are mechanotransducers.2 ICC express Kit receptor tyrosine kinase.3 Another type III receptor tyrosine kinase expressed in the GI tract is platelet-derived growth factor receptor (PDGFR). This receptor has two subtypes (α and β) and four known ligands (A, B, C, and D as well as AB).4 Both receptor subtypes are expressed in mesenchymal cells which are common precursors of ICC and longitudinal SMC.5 PDGFRα is expressed in subepithelial myofibroblasts and PDGFRβ in vascular pericytes in the mature GI tract.4 PDGF signaling plays critical roles in mammalian organogenesis4, 6 and murine GI villous morphogenesis.7 Selective inhibition of PDGFR has been shown to suppress longitudinal SMC differentiation.5 Interstitial cells with fibroblast like ultrastructure have been described as “fibroblast-like cells (FLC)”. Their initial description conflicted on their contacts with SMC and nerve varicosities8, 9. Subsequently, Horiguchi et al. described gap junctions between FLC and SMC in Kit mutant W/Wv mice.10 At the same time, using sialylated glycoprotein CD34 immunoreactivity (ir), FLC were localized to be adjacent to but distinct from ICC in human small intestine.11 CD34-ir and Kit-ir cells were exclusive, but their processes closely intermingled.12 Later, SK3 (small conductance calcium-activated potassium channels type 3)-ir was described to closely overlap with CD34-ir in human GI musculature and these SK3-ir CD34-ir cells remained preserved in human diseases where ICC were lacking.13 SK channels are involved in control of neuronal excitability14, 15 and have potential functional significance in GI musculature,16-18 although conditional genomic deletion of SK3 did not result in overt phenotypic changes in mice.19 Recently, Iino et al. described PDGFRα-ir in FLC in murine GI tract which overlapped strongly with SK3-ir.20 Consistent with prior literature, these FLC were distinct but closely associated with ICC, enteric nerve fibers and myenteric ganglia, and these cells persisted in ICC deficient Wv/Wv mutant mice.20, 21 Recent work has suggested a potential role of PDGFRα- and SK3-ir FLC in inhibitory neurotransmission in mice.22, 23 We have recently shown that together with other cellular abnormalities, all patients studied with diabetic (DG) and idiopathic gastroparesis (IG) have ICC abnormalities24 with half of these patients showing significant decrease in ICC numbers.25 The distribution of the PDGFRα-ir FLC in human GI tract in health or disease is unknown. Nor is it known if there is co-localization of PDGFRα staining and SK3 staining cells in humans as seen in animal models. Furthermore, it is unknown if gastroparesis patients with and without preserved ICC numbers have a drop-out in the number of PDGFRα-ir FLC. The aims of this study were therefore to describe the distribution and morphology of the FLC in human gastric muscle (circular and longitudinal) and myenteric plexus region using antibodies against PDGFRα and SK3 and to determine if FLC are altered in number or distribution in DG and IG.