Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium.
Milk fat globule-EGF factor 8 (MFG-E8)/lactadherin participates in several cell surface-mediated regulatory events. Although its mRNA is present in the gut, the physiological roles of MFG-E8 in the intestinal mucosa have not been explored. Here we show that MFG-E8 was expressed in intestinal lamina propria macrophages from mice. Using a wound-healing assay, MFG-E8 was shown to promote the migration of intestinal epithelial cells through a PKCepsilon-dependent mechanism. MFG-E8 bound to phosphatidylserine and triggered reorientation of the actin cytoskeleton in intestinal epithelial cells at the wound edge. Depleting MFG-E8 in mice by administration of anti-MFG-E8 antibody or targeted deletion of the MFG-E8 gene resulted in a slowing of enterocyte migration along the crypt-villus axis and focal mucosal injury. Moreover, in septic mice, intestinal MFG-E8 expression was downregulated, which correlated with intestinal injury, interrupted enterocyte migration, and impaired restitution. Treatment with recombinant MFG-E8 restored enterocyte migration, whereas deletion of MFG-E8 impeded mucosal healing in mice with sepsis. These results suggest that a decrease in intestinal MFG-E8 impairs intestinal mucosal repair in sepsis. Together, our data indicate that MFG-E8 plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing and suggest that recombinant MFG-E8 may be beneficial for the treatment of bowel injuries.
Bu
Heng-Fu
HF
Molecular and Cellular Pathobiology Program and Center for Digestive Disease and Immunobiology, Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60614, USA.
Zuo
Xiu-Li
XL
Wang
Xiao
X
Ensslin
Michael A
MA
Koti
Vjola
V
Hsueh
Wei
W
Raymond
Adam S
AS
Shur
Barry D
BD
Tan
Xiao-Di
XD
D000199:Actins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000954:Antigens, Surface / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
D000199:Actins; D000906:Antibodies; D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D010718:Phosphatidylserines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051744:Protein Kinase C-epsilon