Evidence for integrin receptor involvement in megakaryocyte-fibroblast interaction: a possible pathomechanism for the evolution of myelofibrosis.
Megakaryocytes are assumed to be functionally linked with the evolution of myelofibrosis, complicating chronic myeloproliferative disorders. It has already been shown that megakaryocytes will promote fibroblast growth in vitro when in spatial proximity. Here, we demonstrate that the integrin receptors alpha3beta1 and alpha5beta1 are involved in this megakaryocyte-fibroblast interaction. Upon addition of anti-alpha3 and -alpha5 antibodies to megakaryocyte-fibroblast cocultures, fibroblast growth was significantly impaired, and megakaryocyte attachment to the fibroblast feederlayer was significantly reduced. Unilateral blocking of megakaryocytes with anti-alpha3 or -alpha5 antibodies resulted in a suppression of adhesion, probably reflecting the prominent function of fibronectin receptors on the megakaryocyte surface. Moreover, the oligopeptide RGDS (Asp-Gly-Asp-Ser) caused a significant reduction of fibroblast growth as well as megakaryocyte adhesion. This feature reinforces that fibronectin receptors are involved. In addition, fibroblast proliferation was impaired by the application of fibronectin antibodies recognizing the cell-binding domain. However, no effect was observable with respect to megakaryocyte adhesion. In conclusion, our in vitro studies demonstrate the involvement of beta1-integrins, in particular the fibronectin receptor in the megakaryocyte-dependent fibroblast proliferation and therefore suggest a pivotal role of megakaryocytes in the complex pathomechanism causing myelofibrosis.
Schmitz
B
B
Institute of Pathology, University of Cologne, Germany.
Thiele
J
J
Otto
F
F
Farahmand
P
P
Henze
F
F
Frimpong
S
S
Wickenhauser
C
C
Fischer
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology*; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008533:Megakaryocytes / Q000737:chemistry / Q000166:cytology*; D008875:Middle Aged; D009500:Neutralization Tests; D009842:Oligopeptides / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000503:physiopathology*; D017474:Receptors, Laminin / Q000032:analysis / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039201:Integrin alpha3beta1; D016023:Integrins; D009842:Oligopeptides; D017474:Receptors, Laminin; C047981:arginyl-glycyl-aspartic acid