Progenitors of Interstitial Cells of Cajal in the Postnatal Murine Stomach

Abstract

Background & Aims: 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, KitlowCD44+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: KitlowCD44+CD34+Insr+Igf1r+ cells may be local progenitors for gastric ICC and stromal tumors. Loss of these cells may contribute to gastrointestinal dysmotilities. Background & Aims: 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, KitlowCD44+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: KitlowCD44+CD34+Insr+Igf1r+ cells may be local progenitors for gastric ICC and stromal tumors. Loss of these cells may contribute to gastrointestinal dysmotilities. See editorial on page 1252. See editorial on page 1252. Interstitial cells of Cajal (ICC) play critical roles in gastrointestinal motility. Multipolar myenteric ICC (ICC-MY) in phasic muscles generate and actively propagate electrical slow waves required for orderly segmenting and peristaltic contractions.1Sanders K.M. Koh S.D. Ward S.M. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract.Annu Rev Physiol. 2006; 68: 307-343Crossref PubMed Scopus (509) Google Scholar, 2Huizinga J.D. Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal.Microsc Res Tech. 1999; 47: 239-247Crossref PubMed Scopus (87) Google Scholar Elongated intramuscular ICC (ICC-IM) mediate efferent inputs to smooth muscle cells and the pacemaker apparatus3Ward S.M. Sanders K.M. Interstitial cells of Cajal: primary targets of enteric motor innervation.Anat Rec. 2001; 262: 125-135Crossref PubMed Scopus (172) Google Scholar and relay afferent mechanical signals.4Fox E.A. Phillips R.J. Martinson F.A. et al.C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach.Anat Embryol (Berl). 2001; 204: 11-26Crossref PubMed Scopus (64) Google Scholar ICC are reduced or otherwise affected in several dysmotilities, including achalasia, diabetic and idiopathic gastroparesis, mechanical ileus, intestinal pseudo-obstructions, slow-transit constipation, inflammations, and malformations.5Vanderwinden J.M. Rumessen J.J. Interstitial cells of Cajal in human gut and gastrointestinal disease.Microsc Res Tech. 1999; 47: 344-360Crossref PubMed Scopus (181) Google Scholar, 6Streutker C.J. Huizinga J.D. Driman D.K. et al.Interstitial cells of Cajal in health and disease Part I: normal ICC structure and function with associated motility disorders.Histopathology. 2007; 50: 176-189Crossref PubMed Scopus (114) Google Scholar, 7Ördög et of networks of interstitial cells of Cajal in a murine of diabetic PubMed Scopus Google Scholar, et of interstitial cells of Cajal and of electrical in murine Physiol. 2001; PubMed Scopus (181) Google Scholar, et in interstitial cells of Cajal the are associated with loss of muscle activity in mice by PubMed Scopus Google Scholar, Sanders K.M. et electrical and interstitial cell PubMed Scopus Google Scholar ICC is to the of these and from of ICC loss ICC on stem cell factor (SCF) for and Ward S.M. Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar, Huizinga J.D. et and of the interstitial cells of Cajal in the PubMed Scopus Google Scholar, Ward S.M. Sanders K.M. Interstitial cells of Cajal generate electrical slow waves in the murine Physiol. 1999; PubMed Scopus Google Scholar, J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google Scholar, J.M. et and of cultured murine interstitial cells of Cajal in to stem cell PubMed Scopus Google Scholar, S.M. et of factor of interstitial cells of Cajal in Physiol. 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Rumessen J.J. Interstitial cells of Cajal in human gut and gastrointestinal disease.Microsc Res Tech. 1999; 47: 344-360Crossref PubMed Scopus (181) Google Scholar regeneration is from mature ICC or from local for ICC have identified in ICC from mesenchymal Ward S.M. Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar, Huizinga J.D. et and of the interstitial cells of Cajal in the PubMed Scopus Google Scholar, J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google Scholar of the may also from F.A. of cells for the enteric and interstitial cells of PubMed Scopus Google Scholar to ICC have also the postnatal of the interstitial cells of Cajal to the myenteric of intestinal muscle from to Embryol (Berl). PubMed Scopus Google Scholar, Huizinga J.D. of pacemaker activity and interstitial cells of Cajal in the PubMed Scopus Google Scholar ICC precursors may in are that gastrointestinal stromal may from ICC precursors due to of et of in human gastrointestinal stromal PubMed Scopus Google Scholar, C.J. Huizinga J.D. Driman D.K. et al.Interstitial cells of Cajal in health and disease Part ICC and gastrointestinal stromal 2007; 50: PubMed Scopus Google Scholar also et of in human gastrointestinal stromal PubMed Scopus Google Scholar, C.J. Huizinga J.D. Driman D.K. et al.Interstitial cells of Cajal in health and disease Part ICC and gastrointestinal stromal 2007; 50: PubMed Scopus Google Scholar an adhesion molecule also in et of in human gastrointestinal stromal PubMed Scopus Google Scholar that a of ICC may to et stromal may from a of interstitial cells of PubMed Scopus Google Scholar and ICC progenitors. of by ICC J.M. Rumessen J.J. et and interstitial cells of Cajal in the human and gastrointestinal PubMed Scopus Google Scholar the of of cells expressing of resembling ICC be In we to identify ICC progenitors in murine gastric muscles by flow cytometry and immunohistochemistry CD34, insulin receptors (Insr), IGF-I receptors and CD44, a mesenchymal stem cell et mesenchymal stem cells a 2006; PubMed Scopus Google Scholar We that in and of cells with KitlowCD44+CD34+Insr+Igf1r+ and resembling embryonic ICC Ward S.M. Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar, J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google Scholar be expanded with SCF and into mature, slow ICC with IGF-I. These cells may ICC progenitors. and to mice were and the in with the of for the and of were by the and the of of the in the be in the cultures of Ward S.M. Sanders K.M. 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Rumessen J.J. et and interstitial cells of Cajal in the human and gastrointestinal PubMed Scopus Google Scholar and a of ICC expressed cells; of ICC of cells; but with of was for and of cells also expressed and We studied the of these cells by immunohistochemistry with the flow cytometry mature, ICC expressed of and was to we in of the muscle in These cells to the by flow of cells that ICC also expressed and These cells were or or and in the myenteric on the of the muscle and on the of the muscle. cells with the also expressed and which we in mature et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar These in of the and be by of of and and resembling that of embryonic ICC Ward S.M. 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Interstitial cells of Cajal generate electrical slow waves in the murine Physiol. 1999; PubMed Scopus Google Scholar, et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar In with et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar for with in a loss of and we also of survival of the presumed ICC precursors and to freshly dissected a in the was by flow cytometry as as of and In these and after were of cells and the ICC and networks in of the cultured for and lacking we networks of cells with resembling ICC in the myenteric and cells were also as a but by flow cytometry in freshly were of cells the of cells in of these and in with et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar we were to activity in cultured for in growth we slow waves in of and the muscles were the loss of ICC was by the loss of the presumed precursors and of slow and the of the smooth muscle Ward S.M. 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Interstitial cells of Cajal generate electrical slow waves in the murine Physiol. 1999; PubMed Scopus Google Scholar, et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar and that mature ICC in the that SCF and IGF-I from the presumed progenitors. is in the gastrointestinal the is of and et al.Interstitial cells of Cajal and restore normal after by intestinal and in the 2006; PubMed Scopus Google Scholar, gastric Physiol. 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Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar, J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google Scholar and Ward S.M. Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar in et J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google which have identified as the of and the smooth muscle Ward S.M. Sanders K.M. of cells and the of electrical in murine PubMed Scopus Google Scholar, Huizinga J.D. et and of the interstitial cells of Cajal in the PubMed Scopus Google Scholar cells may progenitors from normal which may be by to or J.M. Rumessen J.J. Interstitial cells of Cajal in human gut and gastrointestinal disease.Microsc Res Tech. 1999; 47: 344-360Crossref PubMed Scopus (181) Google Scholar, et of interstitial cells of Cajal and of electrical in murine Physiol. 2001; PubMed Scopus (181) Google Scholar, et in interstitial cells of Cajal the are associated with loss of muscle activity in mice by PubMed Scopus Google Scholar, Sanders K.M. et electrical and interstitial cell PubMed Scopus Google Scholar, et al.Interstitial cells of Cajal and restore normal after by intestinal and in the 2006; PubMed Scopus Google Scholar of slow activity in the was mature ICC and were by KitlowCD44+CD34+Insr+Igf1r+ that of these cells may have to electrical activity slow waves in normal that was and these be to the of the pacemaker the after the precursors into mature ICC by IGF-I. slow waves in organotypic cultures reduced Ward S.M. Sanders K.M. Interstitial cells of Cajal generate electrical slow waves in the murine Physiol. 1999; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar of the may have the and of the cells the of these that slow are required to to from by smooth muscle cells in the of K.M. Koh S.D. Ward S.M. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract.Annu Rev Physiol. 2006; 68: 307-343Crossref PubMed Scopus (509) Google Scholar, 2Huizinga J.D. Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal.Microsc Res Tech. 1999; 47: 239-247Crossref PubMed Scopus (87) Google Scholar from with of SCF the of the presumed and IGF-I into mature We used IGF-I SCF for to was to and IGF-I to normal ICC networks and electrical slow waves in organotypic et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar IGF-I the of the KitlowCD44+CD34+Insr+Igf1r+ cells into slow to ICC in postnatal expressed et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar expressed IGF-I was after a in growth factor but the loss of mature that of the of IGF-I on gastric et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar, insulin and IGF-I the of interstitial cells of Cajal in the murine PubMed Scopus Google Scholar may have of ICC precursors and the of In of the and loss of by the of these may have we that the of IGF-I and insulin on ICC were by and membrane-bound SCF by gastric smooth muscle et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar and in the we that the of IGF-I be by an of et stem cell factor and receptors but insulin-like growth receptors in human Google Scholar IGF-I may in the of ICC and which to play but roles in ICC SCF is to the KitlowCD44+CD34+Insr+Igf1r+ membrane-bound SCF is for into the roles of SCF in the of ICC from embryonic precursors also by et J.J. of the interstitial cell of Cajal: and and of PubMed Scopus Google Scholar may be by of IGF-I on the precursors of and these may be for the of ICC in mutant mice that membrane-bound SCF or have reduced activity et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar In we that of ICC networks may involve from local precursors by the the of gastrointestinal muscles in with the of KitlowCD44+CD34+Insr+Igf1r+ local progenitors. is by SCF by smooth muscle et stem cell factor smooth and loss of interstitial cells of Cajal in murine diabetic 2006; PubMed Scopus Google Scholar In of damage to the also the of the precursors and a in and the of electrical slow of these progenitors into ICC requires membrane-bound which is also by the smooth muscle in to IGF-I IGF-I and insulin may also have on ICC precursors of and ICC may and to slow waves to be the KitlowCD44+CD34+Insr+Igf1r+ cells are embryonic ICC for the slow wave with of Interstitial of Cajal: the to cells of Cajal (ICC) are the pacemaker cells of gut motor and to and for of and pacemaker of primary ICC pacemaker cells associated with and intramuscular for of the pacemaker electrical slow pacemaker cells motor activity of the the of the enteric