Disruption of gastrointestinal PDGFRα ⁺ cells leads to loss of postjunctional inhibitory motor responses

Fibroblast-like cells (FLCs) exist in the smooth muscle layers of visceral organs, yet in many instances their functional role(s) have not been identified. FLCs express platelet-derived growth factor receptor (PDGFR) α and are a novel class of excitable cells recently described in visceral organs. Crenolanib is a benzamidine quinolone derivative originally developed as an inhibitor of PDGFR to treat certain solid tumors with PDGFRα overexpression mutations. In the present study, we used crenolanib to disrupt PDGFRα expression and signaling in the gastrointestinal (GI) tracts of <i>BALB/c</i> mice. Intraperitoneal injections of crenolanib (100 µg/g body wt) or DMSO control vehicle were given to littermates from postpartum P1 through P15. Crenolanib-injected mice were smaller in size and weight. The gastrointestinal tracts were also shorter and appeared partially distended. qPCR revealed downregulation of key gene transcripts involved in PDGFRα cell signaling including <i>Pdgfra</i>, <i>Kcnn3</i>, and <i>P2ry1</i>. Confocal immunofluorescence demonstrated significant decreases in PDGFRα and SK3 protein expression. c-Kit expression was slightly inhibited, but gastric, intestinal, and colonic pacemaker activity was not affected by crenolanib. Purinergic inhibitory postjunctional motor responses were greatly attenuated in the GI tracts of crenolanib-treated animals compared with vehicle-treated controls in response to electric field-evoked nerve stimulation. These data provide evidence for a functional role of PDGFRα⁺ cells in inhibitory neuroeffector motor responses throughout the gastrointestinal tract.<b>NEW & NOTEWORTHY</b> The physiological roles of newly described PDGFRα⁺ interstitial cells in neurotransmission within the gastrointestinal (GI) tract have predominantly come from studies on isolated cells. Here we used an inhibitor of PDGFRα, crenolanib, to examine the effects of PDGFRα⁺ cells in enteric inhibitory neurotransmission. Crenolanib caused loss of PDGFRα⁺ cells and neurally evoked fast inhibitory junction potentials associated with purine neurotransmission, providing evidence for the function of PDGFRα⁺ cells within intact tissues of the GI tract.