Independent modulation of enterocyte migration and proliferation by growth factors, matrix proteins, and pharmacologic agents in an in vitro model of mucosal healing

Surgery. 1992 Aug;112(2):299-307; discussion 307-8.


Background: Gastrointestinal mucosa heals by restitution and proliferation. These are difficult to distinguish in vivo.

Methods: Human Caco-2 enterocytes were cultured on matrix proteins (collagen I, laminin, fibronectin) with growth factors (epidermal growth factor [EGF] and transforming growth factor-beta 1 [TGF-beta 1]) and the tyrosine kinase and prostaglandin inhibitors genistein and indomethacin. Healing was modeled by means of monolayer expansion, proliferation by means of 3H-thymidine uptake, and restitution by means of mitomycin-blocked migration.

Results: Changing matrix composition failed to alter proliferation, but collagen I stimulated migration more than laminin or fibronectin (laminin/collagen, 68% +/- 2%; p less than 0.05). EGF (30 ng/ml) increased proliferation on both collagen (225% +/- 11% of basal) and laminin (206% +/- 26%) but increased migration only over laminin (210% +/- 17%) (all, p less than 0.05). TGF-beta 1 (200 pg/ml) stimulated migration over laminin (187% +/- 18%, p less than 0.005) but inhibited migration over collagen (89% +/- 3%, p less than 0.01) and did not affect 3H-thymidine uptake. When cultured on laminin, EGF but not TGF-beta 1 altered organization of the alpha 2 integrin subunit. Genistein (100 mumol/L) inhibited basal and EGF-stimulated 3H-thymidine uptake. In addition, it prevented EGF stimulation of replication-blocked migration (81% +/- 10% vs 190% +/- 20% of basal, p less than 0.0001) without altering basal replication-blocked migration. Indomethacin (10(-5) mol/L) did not alter migration but inhibited basal and EGF-stimulated proliferation by 7% +/- 1% (each, p less than 0.005).

Conclusions: Restitution and proliferation appear independently regulated by matrix and growth factors. It may be possible to individually target specific phases of mucosal healing by means of pharmacologic agents.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / drug effects
  • Cell Line
  • Cell Movement / drug effects
  • Epidermal Growth Factor / pharmacology
  • Extracellular Matrix Proteins / pharmacology*
  • Genistein
  • Growth Substances / pharmacology*
  • Humans
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / physiopathology*
  • Isoflavones / pharmacology
  • Lasers
  • Mitomycin / pharmacology
  • Transforming Growth Factor beta / pharmacology
  • Tyrosine 3-Monooxygenase / antagonists & inhibitors
  • Wound Healing*


  • Extracellular Matrix Proteins
  • Growth Substances
  • Isoflavones
  • Transforming Growth Factor beta
  • Mitomycin
  • Epidermal Growth Factor
  • Genistein
  • Tyrosine 3-Monooxygenase