Altered bone morphogenetic protein signalling in the Helicobacter pylori-infected stomach.
Morphogens regulate epithelial cell fate decisions in the adult gastrointestinal tract. The authors hypothesized that influx of inflammatory cells into the lamina propria may disturb the normal expression gradients of morphogens (morphogenetic landscape) in gastrointestinal epithelia. Changes in the activity of the bone morphogenetic protein (BMP) pathway in normal and Helicobacter pylori-infected gastric mucosa were therefore examined. It is shown that BMP receptors, the activated (phosphorylated) form of the intracellular BMP signal transduction protein SMAD1, and BMP target ID2 all localize to gastric epithelial cells that are at the end of the axis of epithelial renewal in normal mucosa. Colonization of human gastric mucosa with H. pylori was associated with an increase in BMP2 expression due to influx of inflammatory cells that produce BMP2. Furthermore, whereas no BMP4 was detected in the normal antrum, focal infiltrates of BMP4-expressing cells were found in the H. pylori-infected stomach. This influx of BMP-expressing cells was associated with an increase in epithelial BMP signalling. Interestingly, a shift in activity of the BMP pathway was observed towards the precursor cell compartment (isthmus) of the gastric units. Thus, H. pylori infection results in an influx of inflammatory cells that disturb the normal activity gradient of a morphogenetic pathway with an established role in epithelial cell fate regulation. The data suggest that morphological changes in epithelial histology may result from alterations in the morphogenetic landscape secondary to changes in the cellular composition of the lamina propria.
Bleuming
S A
SA
Department of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands, and Department of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland.
Kodach
L L
LL
Garcia Leon
M J
MJ
Richel
D J
DJ
Peppelenbosch
M P
MP
Reitsma
P H
PH
Hardwick
J C
JC
van den Brink
G R
GR
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000032:analysis; D019485:Bone Morphogenetic Proteins / Q000032:analysis / Q000378:metabolism*; D002452:Cell Count; D004847:Epithelial Cells / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism; D013272:Stomach Diseases / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000032:analysis
C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; C498211:BMPR1A protein, human; C498214:BMPR1B protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I