Longitudinal cell formation in the entire human small intestine is correlated with the localization of Hath1 and Klf4.
BACKGROUND
Double balloon endoscopy (DBE) enables the observation and collection of viable specimens from the entire intestine, thereby allowing more detailed investigation of how the structure and function of the human small intestine are regulated. The present study aimed to elucidate the regulation of cell formation in the human small intestine using biopsy specimens collected from an entire individual small intestine by DBE.


METHODS
The expression and the localization of representative genes for the differentiation program were analyzed in the entire small intestine of 10 patients. The functional correlation between Hath1 and Klf4 was analyzed in an intestinal cell line by using a Tet-On system.


RESULTS
In longitudinal cell formation in the small intestine, it was shown that goblet cells, but not Paneth cells, increased toward the ileum in each individual small intestine. Immunohistochemistry showed that Hath1-expressing cells migrated from the base of the crypt to the top of the villi in the terminal ileum, while Klf4-expressing cells migrated from the top of the villus, resulting in the colocalization of Hath1 and Klf4 in the terminal ileum. Coexpression of Hath1 and Klf4 upregulated the expression of phenotypic genes for goblet cells following the downregulation of those for Paneth cells.


CONCLUSIONS
Using mapping biopsy by DBE, we have demonstrated, for the first time, the molecular basis of the villus structure in the entire human small intestine in vivo. The present study showed that longitudinal cell formation was regulated by the colocalization of Hath1 and Klf4 that converted Paneth cell differentiation into goblet cell differentiation.
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Michiko
M
Iwasaki
Kiichiro
K
Tsuchiya
Ryuichi
R
Okamoto
Xiu
X
Zheng
Yoshihito
Y
Kano
Eiko
E
Okamoto
Eriko
E
Okada
Akihiro
A
Araki
Shinji
S
Suzuki
Naoya
N
Sakamoto
Keisuke
K
Kitagaki
Takumi
T
Akashi
Yoshinobu
Y
Eishi
Tetsuya
T
Nakamura
Mamoru
M
Watanabe
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D002454:Cell Differentiation / Q000235:genetics*; D058582:Double-Balloon Enteroscopy; D015870:Gene Expression; D020397:Goblet Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D007583:Jejunum / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D043322:Lactase / Q000235:genetics / Q000378:metabolism; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D019879:Paneth Cells / Q000166:cytology* / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D000072056:Transcription Factor HES-1; D000071165:Trefoil Factor-3; D023084:alpha-Defensins / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D043322:Lactase; D055262:Mucin-2; D010455:Peptides; D000072056:Transcription Factor HES-1; D000071165:Trefoil Factor-3; D023084:alpha-Defensins; C500942:ATOH1 protein, human; C500225:DEFA5 protein, human; C000715467:KLF4 protein, human; C524625:MUC2 protein, human; C082495:TFF3 protein, human; C078493:HES1 protein, human