Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium

J Clin Invest. 2007 Dec;117(12):3673-83. doi: 10.1172/JCI31841.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Antibodies / pharmacology
  • Antigens, Surface / metabolism*
  • Antigens, Surface / pharmacology
  • Cell Movement* / drug effects
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Disease Models, Animal
  • Enterocytes / metabolism*
  • Enterocytes / pathology
  • Homeostasis / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Milk Proteins / antagonists & inhibitors
  • Milk Proteins / metabolism*
  • Milk Proteins / pharmacology
  • Phosphatidylserines / metabolism
  • Protein Kinase C-epsilon / metabolism
  • RNA, Messenger / biosynthesis
  • Rats
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Sepsis / drug therapy
  • Sepsis / metabolism*
  • Sepsis / pathology
  • Wound Healing* / drug effects


  • Actins
  • Antibodies
  • Antigens, Surface
  • Mfge8 protein, mouse
  • Milk Proteins
  • Phosphatidylserines
  • RNA, Messenger
  • Recombinant Proteins
  • Protein Kinase C-epsilon