Blockade of kit signaling induces transdifferentiation of interstitial cells of Cajal to a smooth muscle phenotype

Background & Aims: Interstitial cells of Cajal (ICC) serve as pacemaker cel ls and mediators of neurotransmission from the enteric nervous system to ga strointestinal muscles. ICC develop from mesenchymal cells that express c-K it, and signaling via Kit receptors is necessary for normal development of ICC. We studied the fate of functionally developed ICC after blockade of Hi t receptors to determine whether ICC undergo cell death or whether the phen otype of the cells is modified. The fate of undeveloped ICC was also invest igated. Methods: Neutralizing, anti-Kit monoclonal antibody (ACK2) was admi nistered to mice for 8 days after birth. ICC in the small intestine were ex amined by immunohistochemistry and electron microscopy. Occurrence of apopt osis was also assayed. Results: When Kit receptors were blocked, ICC nearly disappeared from the small intestine. Apoptosis was not detected in region s where ICC are normally distributed. Remaining Kit-immunopositive cells in the pacemaker region of the small intestine developed ultrastructural feat ures similar to smooth muscle cells, including prominent filament bundles a nd expression of the muscle-specific intermediate filament protein, desmin, and smooth muscle myosin. ICC of the deep muscular plexus normally develop after birth in the mouse. Precursors of these cells remained in an undiffe rentiated state when Kit was blocked. Conclusions: These data, along with p revious studies showing that ICC in the pacemaker region of the small intes tine and longitudinal muscle cells develop from the same Kit-immunopositive precursor cells, suggest inherent plasticity between the ICC and smooth mu scle cells that is regulated by Kit-dependent cell signaling.