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Updating Old Ideas and Recent Advances Regarding the Interstitial Cells of Cajal

Updating Old Ideas and Recent Advances Regarding the Interstitial Cells of Cajal

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Review
Updating old ideas and recent advances regarding theInterstitial Cells of Cajal
P. Garcia-Lopez
1
, V. Garcia-Marin
⁎ 
,1
, R. Martínez-Murillo, M. Freire
Cajal Institute, CSIC, Avda Doctor Arce 37, 28002
Madrid, Spain
A R T I C L E I N F O A B S T R A C T
 Article history:
Accepted 1 June 2009Since their discovery by Cajal in 1889, the Interstitial Cells of Cajal (ICC) have generatedmuch controversy in the scientific community. Indeed, the nervous, muscle or fibroblasticnature of the ICC has remained under debate for more than a century, as has their possiblephysiological function. Cajal and his colleagues considered them to be neurons, whilecontemporary histologists like Kölliker and Dogiel categorized these cells as fibroblasts.More recently, the role of ICC in the origin of slow-wave peristaltism has been elucidated,and several studies have shown that they participate in neurotransmission (
intercalationtheory
). The fact that ICC assemble in the circular muscular layer and that they originatefrom cells which emerge from the ventral neural tube (VENT cells), a source of neurons, gliaand ICC precursors other than the neural crest, suggests a neural origin for this particular subset of ICC. The discovery that ICC express the Kit protein, a type III tyrosine kinasereceptor encoded by the proto-oncogene
c-kit
, has helped better understand their physiological role and implication in pathological conditions. Gleevec, a novel moleculedesigned to inhibit the mutant activated version of c-Kit receptors, is the drug of choice totreat the so-called gastrointestinal stromal tumours (GIST), the most common non-epithelial neoplasm of the gastrointestinal tract. Here we review Cajal's originalcontributions with the aid of unique images taken from Cajal's histological slides(preserved at the Cajal Museum, Cajal Institute, CSIC). In addition, we present a historicalreview of the concepts associated with this particular cell type, emphasizing current datathat has advanced our understanding of the role these intriguing cells fulfil.© 2009 Elsevier B.V. All rights reserved.
Keywords:
CajalInterstitial Cells of Cajal
Contents
1. Introduction: the controversial origin of ICC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. Location and morphology of ICC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.1. Intravillous and periglandular plexi. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Auerbach plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.3. Deep muscular plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.4. Intramuscular plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.5. Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
B R A I N R E S E A R C H R E V I E W S X X ( 2 0 0 9 ) X X X
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Corresponding author.
Fax: +34 91 585 47 54.E-mail address:vgmarin@cajal.csic.es(V. Garcia-Marin).
1
Both authors contributed equally to this article.
BRESR-100704; No. of pages: 16; 4C:
0165-0173/$
see front matter © 2009 Elsevier B.V. All rights reserved.doi:10.1016/j.brainresrev.2009.06.001
available at www.sciencedirect.comwww.elsevier.com/locate/brainresrev
ARTICLE IN PRESS
Please cite this article as: Garcia-Lopez, P., et al., Updating old ideas and recent advances regarding the Interstitial Cells of Cajal, Brain Res. Rev. (2009), doi:10.1016/j.brainresrev.2009.06.001
 
2.6. Other locations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. The physiological function of ICC from Cajal to the present day . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.1. ICC in neurotransmission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2. ICC as pacemakers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.3. Stretch sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 04. Pathological ICC and GIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 05. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1. Introduction: the controversial origin of ICC
Between1889and1893,Cajalpublishedsomearticlesdescribing a new type of cell that he classified as a primitive neuron. Thistype of cell was located in the stroma of the villi (Figs. 1A, 2), inthe Auerbach's plexus (Figs. 1A, 3), deep muscular plexus (Figs. 1A, 4A), circular muscular layer of the intestine (Figs. 1A, 4B
D),and around the acini and blood vessels of the pancreas (Fig. 5).Following Cajal's first descriptions, these cells were identifiedusing different names, including:
células simpáticas intersticiales
(sympathetic interstitial cells, 1891);
células simpáticas
(sympa-thetic cells, 1892);
neuronas simpáticas intersticiales
(sympatheticinterstitial neurons); or 
células intersticiales
(interstitial cells,1899
1904). However, Dogiel subsequently called them
Ca- jal
'
schezellen
andmorethan100yearsaftertheirdiscoverythename of 
Interstitial Cells of Cajal
(ICC) is still used.At that time, there was considerable controversy about thenatureofthesecellsandwhilesomeresearchers,includingCajaland his colleagues (LaVilla, 1897), thought they were neurons,others, such as Kölliker and Dogiel, classified them as fibro-blasts. This debate was somewhat clouded by the ongoing discussion as to whether neurons were individual structures or if they simply formed a syncitium. According to the reticularistpoint of view, neurons were thought to form an interconnectedcontinuous network built up of either axons and dendrites(Gerlach's),orexclusivelyofaxons(Golgi's).Cajal'sfirstpaperonthe nervous system (Cajal, 1888) proposed that neurons endfreely, and that they connect with each other by contiguity andnot by continuity. This relevant observation was the firstdescription of the neuronal doctrine:
neurons are independentunits from a morphological and even physiological point of view
.However, Cajal's description of the ICC as neurons was incontradiction with his neuron doctrine as he was unable torecognizetheaxonalprocessinthesecellsthatcharacteristicallyestablishes the typical network. In this respect, he recognized:
I am neither exclusive nor dogmatic. I am proud of retaining a mental flexibility which is not afraid of correction. Neuronal discontinuity, extremely evident ininnumerable examples, could sustain some exceptions. Imyself have mentioned some of them, for example thoseprobably existing in the glands, vessels and intestines (myinterstitial neurons)
(Cajal, 1933).Duringthetwentiethcentury,therehasbeenalongstanding dogmatic division regarding the nature of these cells ( Jabonero,1960;Thuneberg,1990;forareviewseeThuneberg(1999)).When analysed by light and electron microscopy, Taxi referred thesecells as
neuronoids
in an attempt to distinguish them fromneurons, Schwann cells, smooth muscle cells, fibroblasts andmacrophages, although he recognised their tendency to co-stain with nerves (Taxi, 1952, 1965; for a review seeThuneberg, (1999)). Following these findings, ultrastructural studies on theICC suggested that they were primitive muscle cells (Imaizumiand Hama, 1969; Faussone-Pellegrini et al., 1977) or fibroblast-like cells (Richardson, 1958; Komuro, 1989).The most important advance in this area came with thediscovery that ICC express the tyrosine kinase receptor (c-Kit:Maeda et al., 1992), which permitted them to be chemicallydifferentiated from other cell types sharing similar morpholo-gical characteristics in the tunica muscularis (Thuneberg, 1982;Ward and Sanders, 2001a). The use of this specific marker allowed the mesenchyma to be identified as the source of ICC(Lecoinetal.,1996)andindeed,thedetectionofc-Kitexpressionin aneural explants confirmed that ICC are not of neural crestorigin inmammals (Youngetal.,1996).Moreover,itwasshownthat both smooth muscle cells and ICC have a commonmesodermal origin (Torihashi et al., 1997; Kluppel et al., 1998).However,itisnoteworthythatasubsetofICCmightbeofneuralorigin,sincetheICCofthecircularmuscularlayeroriginatefromcellsthatemergefromtheventralneuraltube(VENTcells:Sohalet al., 2002), a source of neurons, glia and ICC precursors thatdiffer from the neural crest cells. Hence, the neuronal origin of ICCsuggestedbyCajalcouldbeatleastpartiallytrue.VENTcellsoriginate in the ventral part of the hindbrain neural tube andthey migrate through the site of attachment of the cranialnerves to colonize the gastrointestinal tract, particularly theduodenumandstomach(Sohaletal.,1996;BockmanandSohal,1998). Significantly, not all ICC express c-Kit, such as the ICC-DMP (deep muscular plexus, seeFig. 1A) in the human smallintestine (Torihashi et al., 1999; Wang et al., 2003). Moreover,there are many different cell types besides ICC that express c-Kit, such as mast cells, melanocytes, neurons and glia (Zhang andFedoroff,1997).Thus,ultrastructuralanalysishasprovedtobe essential to finally determine whether a particular cellbelongs to the ICC family. The ultrastructural characteristics of ICChavebeenwelldefined(Faussone-PellegriniandThuneberg,1999; Rumessen and Vanderwinden, 2003; Komuro, 1999) andthey have been summarized as a
gold standard
(Huizinga et al.,1997) for ICC identification.ICCare generallycharacterized by anumber of morphological aspects including the presence of: i)numerous mitochondria and caveolae; ii) a basal lamina,although discontinuous; iii) abundant intermediate filaments;iv) moderatelydeveloped Golgi apparatus, fewribosomesand a
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Please cite this article as: Garcia-Lopez, P., et al., Updating old ideas and recent advances regarding the Interstitial Cells of Cajal, Brain Res. Rev. (2009), doi:10.1016/j.brainresrev.2009.06.001
 
rough and smooth endoplasmic reticula; and v) close contactsestablished with nerve varicosities and the formation of numerousgapjunctions,bothwitheachotherandwithsmoothmuscle cells.
2. Location and morphology of ICC
CajaldescribedICCatdifferentsitesintheintestinaltube.Apartfrom the classical Meissner plexus (located in the submuscular connective tissue) and the Auerbach plexus (located betweenthelongitudinalandcircularsmoothmusclefibres),Cajalfoundthem in three more plexi: the deep muscular plexus, theperiglandular and the intravillous plexi (summarized inFig. 1A). At these sites, he found small fusiform and triangular cells with little protoplasm that had a number of varicoseanastomosed processes, often ramifying at a right angle. Thesegeneral characteristics of ICC varied at their different locations(Figs. 1B
E) and thus, it is worthwhile describing the characte-ristics of the ICC at the locations where Cajal observed them.
Fig. 1
(A) Location of the different ICC subtypes according to Cajal and to the present nomenclature based on a semi-schematicdrawingofCajalCajal,1899
1904)ofalongitudinalsectionoftheguineapigsmallintestinestainedbytheGolgimethod.Accordingto Cajal: A, longitudinal muscle fibres; B, circular muscle fibres; C, submucose connective tissue in the Meissner plexus; D,Lieberkuhn glandules; E, intestinal villi;
a
, Auerbach plexus;
g
, Auerbach ganglion;
b
, deep muscular plexus;
c
, fibres from theMeissnerplexus;
e
,periglandularplexus;
 f 
,intravillousplexus.Accordingtothepresentnomenclature:ICCofthemyentericplexus(ICC-MPorICC-MY);ICCofthecircularmuscle(ICC-CM)andICCofthelongitudinalmuscle(ICC-LM),bothreferredtocollectivelyasintramuscular ICC (ICC-IM); ICC of the deep muscular plexus (ICC-DMP); ICC of submucosa and submucosal plexus (ICC-SM andSMP). (B) Multipolar ICC-MP (asterisk) from the guinea pig small intestine evident through c-Kit immunohistochemistry. Thecytoplasmic processes undergo repeated dichotomous branching and they make many contacts with those of the neighboursHanani et al., 2005 ). (C) Multipolar ICC-DMP of the guinea pig small intestine stained by c-Kit immunohistochemistry, with their secondary and tertiary slender processes mainly parallel to the axis of the circular muscle fibres (arrows:Hanani et al., 2005 ).(D) Bipolar ICC-CM from guineapig small intestine demonstrated by c-Kit immunohistochemistry that emit only a fewprocessesHanani et al., 2005 ). (E) Human exocrine pancreas. In the insterstitium, amongst the acini (a), note some spindle-shaped or triangularcells(arrows)withverylongcytoplasmicprocesses(severaltensof 
μ
m),indicatedbydashedlines.Theacinimarkedbyasterisks appear to be surrounded by periacinar pICC processes. Methylene blue staining ( Popescu et al., 2005 ).
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ARTICLE IN PRESS
Please cite this article as: Garcia-Lopez, P., et al., Updating old ideas and recent advances regarding the Interstitial Cells of Cajal, Brain Res. Rev. (2009), doi:10.1016/j.brainresrev.2009.06.001

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