Progenitors of interstitial cells of cajal in the postnatal murine stomach.
OBJECTIVE
Maintaining the integrity of networks of interstitial cells of Cajal (ICC) is essential to preserve orderly contractile activity and neuroregulation in the gastrointestinal tract and to restore these functions after tissue damage or surgeries. Maintenance of ICC requires insulin-dependent or insulin-like growth factor I (IGF-I)-dependent production of membrane-bound stem cell factor (SCF) and may involve regeneration from local progenitors. Our goal was to identify ICC precursors in postnatal murine gastric muscles.


METHODS
We used flow cytometry and immunohistochemistry to examine freshly dissected and cultured muscles for cells expressing CD34, an adhesion molecule expressed by stromal tumors; CD44, which occurs on mesenchymal stem cells; and receptors for SCF (Kit), insulin (Insr), and IGF-I (Igf1r). Slow waves were studied by intracellular recording.


RESULTS
In gastric muscles, we identified rare, Kit(low)CD44(+)CD34(+)Insr(+)Igf1r(+) cells resembling common embryonic precursors of ICC and smooth muscle. These putative progenitors were absent from organotypic cultures lacking mature ICC (Kit(+)CD44(+)CD34(-)Insr(-)Igf1r(-)) due to prolonged insulin/IGF-I deprivation but were rescued by IGF-I that also prevented ICC loss. Soluble SCF failed to prevent the loss of mature ICC but dramatically expanded the putative progenitors, which supported robust slow wave activity despite retaining an immature, Kit(+)CD44(+)CD34(+)Insr(+)Igf1r(+) phenotype. Differentiation of these cells into mature, network-forming ICC required IGF-I. Conversely, restoration of ICC networks by IGF-I after prolonged insulin and IGF-I deprivation required the survival of the presumed progenitors.


CONCLUSIONS
Kit(low)CD44(+)CD34(+)Insr(+)Igf1r(+) cells may be local progenitors for gastric ICC and stromal tumors. Loss of these cells may contribute to gastrointestinal dysmotilities.
Lorincz
Andrea
A
Department of Physiology and Cell Biology, University of Nevada, Reno, USA.
Redelman
Doug
D
Horváth
Viktor J
VJ
Bardsley
Michael R
MR
Chen
Hui
H
Ordög
Tamás
T
D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000096:biosynthesis*; D002478:Cells, Cultured; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013270:Stomach / Q000166:cytology* / Q000276:immunology
D018952:Antigens, CD34; D018960:Hyaluronan Receptors; D007334:Insulin-Like Growth Factor I; D019009:Proto-Oncogene Proteins c-kit; D011972:Receptor, Insulin