Current address: Department of Surgical Research, Enders 1074, The Childrens Hospital, Harvard Medical School, Boston, MA 02115, U.S.A.
MOTOGENIC AND BIOSYNTHETIC RESPONSE OF ADULT SKIN FIBROBLASTS TO TGF-β ISOFORMS (−1, −2 AND −3) DETERMINED BY ‘TISSUE RESPONSE UNIT’: ROLE OF CELL DENSITY AND SUBSTRATUM
Version of Record online: 2 JAN 2013
© The Author(s) Journal compilation © 1999 International Federation for Cell Biology
Cell Biology International
Volume 23, Issue 9, pages 593–602, September 1999
How to Cite
Ellis, I.R., Banyard, J. and Schor, S.L. (1999), MOTOGENIC AND BIOSYNTHETIC RESPONSE OF ADULT SKIN FIBROBLASTS TO TGF-β ISOFORMS (−1, −2 AND −3) DETERMINED BY ‘TISSUE RESPONSE UNIT’: ROLE OF CELL DENSITY AND SUBSTRATUM. Cell Biology International, 23: 593–602. doi: 10.1006/cbir.1999.0423
- Issue online: 2 JAN 2013
- Version of Record online: 2 JAN 2013
- Received 17 February 1999; accepted 14 April 1999
- Cited By
- TGF-β isoforms;
- cell migration;
- wound healing
We have recently demonstrated that the three principal mammalian isoforms of transforming growth factor β (TGF-β) exert distinct effects upon: (1) the migration of confluent adult fibroblasts into 3D gels of native type I collagen fibres (i.e. TGF-β−1 and −2 had no apparent motogenic activity, whilst TGF-β−3 induced a dose-dependent stimulation of cell migration); and (2) the synthesis of hyaluronan (HA) by these cells is also affected by the TGF-β isoforms in a manner which parallels their effect on cell migration. The objective of the present study is to elucidate the manner in which this differential activity of the TGF-β−1, −2 and −3 may be modulated by experimental parameters. Data presented in this communication indicate that cytokine bioactivity is determined by a combination of cell density and the nature of the macromolecular substratum. Thus, we now report that all three TGF-β isoforms inhibit the migration of subconfluent cells in the collagen gel assay. Our data confirm that the migration of confluent cells is stimulated by TGF-β−3 and further indicate that this motogenic activity is completely abrogated by either TGF-β−1 or −2 when these are co-incubated with TGF-β−3. In contrast to these results obtained using a native type I collagen substratum, all three isoforms stimulated adult fibroblast migration in the transmembrane assay (in which cells are adherent to a 2-D porous polycarbonate substratum). The precise effect of TGF-β isoforms on HA synthesis was also affected by cell density and the nature of the substratum in a manner which paralleled their diverse effects on cell migration (i.e. stimulation, inhibition or no effect). Streptomyces hyaluronidase completely neutralized the TGF-β−3-induced stimulation of confluent fibroblast migration, thus suggesting a mechanistic link between the cytokine-induced cell migration and HA synthesis under these conditions. Taken together, these data indicate that: (1) the bioactivity of TGF-β−1, −2 and −3 are determined by cell density, the macromolecular substratum and the presence of other cytokines; and (2) it is therefore necessary to define cytokine bioactivity within the context of a larger ‘tissue response unit’ which more fully defines the activity state of the target cell and its microenvironment.