Novel delivery system for inducing quiescence in intestinal stem cells in rats by transforming growth factor beta 1.
OBJECTIVE
Intestinal mucosa, a tissue in a dynamic state of rapid cellular proliferation, is often adversely affected by cytotoxic drugs. The purpose of this study was to develop an oral delivery system targeting transforming growth factor (TGF) beta 1 locally and analyze its effects on the epithelial stem cells of gastrointestinal mucosa.


METHODS
Rats were treated with recombinant TGF-beta 1 in alginate beads perorally or with recombinant TGF-beta 1 in phosphate-buffered saline perorally or intraperitoneally. Control animals received phosphate-buffered saline only. The size of the villi was measured. Proliferating and mitotic indices were determined by quantifying immunohistochemical staining for proliferating cell nuclear antigen.


RESULTS
Alginate beads released no TGF-beta 1 in acid. However, in pH 7.4, TGF-beta 1 was released in an active form. Histomorphometrical analysis showed a marked reduction in villus height (50%-70%) in the intestinal mucosa of animals treated perorally with recombinant TGF-beta 1 in alginate beads. Also, the proliferating and mitotic indices were significantly reduced (P < 0.01) in these animals as compared with controls and other routes of administration.


CONCLUSIONS
This study shows that recombinant TGF-beta 1 administered using a novel oral delivery system induces stem cell quiescence in the intestinal mucosa of the rat.
Puolakkainen
P A
PA
Department of Medicine, University of Washington, Seattle.
Ranchalis
J E
JE
Gombotz
W R
WR
Hoffman
A S
AS
Mumper
R J
RJ
Twardzik
D R
DR
D000284:Administration, Oral; D000464:Alginates; D000818:Animals; D002455:Cell Division; D016503:Drug Delivery Systems; D004847:Epithelial Cells; D004848:Epithelium / Q000276:immunology; D020723:Glucuronic Acid; D006603:Hexuronic Acids; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology* / Q000276:immunology; D008297:Male; D008940:Mitotic Index; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000494:pharmacology
D000464:Alginates; D006603:Hexuronic Acids; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D020723:Glucuronic Acid