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Locally applied GM-CSF induces the accumulation of alpha-smooth muscle actin containing myofibroblasts
L Rubbia-Brandt1, A P Sappino, G Gabbiani
1Department of Pathology, University of Geneva, Switzerland.
Abstract:
We have examined the histological and cytoskeletal changes in rat connective tissues induced by subcutaneous perfusion with cytokines. Granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha (IL-1-alpha), transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) produced a significant fibroblast accumulation, neovascular development and a weak to moderate leukocyte infiltration, while interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) induced intense mononucleated leukocyte infiltration. Immunofluorescence staining showed that accumulated fibroblastic cells were positive for alpha-smooth muscle (SM) actin (but negative for the desmin and muscle myosin) only in GM-CSF-treated tissues. Electron microscopic examination established that a significant proportion of fibroblastic cell in GM-CSF-, IL-1-alpha- or TGF-beta-treated animals were typical myofibroblasts. Only in GM-CSF-treated animals did microfilament bundles of myofibroblasts contain alpha-SM actin, when examined by immuno electron microscopy. Our results suggest that locally applied cytokines induce the formation of distinct granulation tissues. In particular, GM-CSF stimulates alpha-SM actin synthesis in myofibroblasts, illustrating an unexpected extra-hematopoietic in vivo effect of this factor.
Insights
Cytokines like GM-CSF induce fibroblast accumulation and myofibroblast formation in rat tissues. Granulocyte macrophage-colony stimulating factor (GM-CSF) uniquely stimulates alpha-smooth muscle actin synthesis in these cells.
Area of Science:
- Connective tissue biology
- Cytokine signaling
- Cellular differentiation
Background:
- Cytokines play crucial roles in tissue repair and inflammation.
- Understanding cytokine-induced changes in connective tissue is vital for regenerative medicine.
Purpose of the Study:
- To investigate the histological and cytoskeletal effects of various cytokines on rat connective tissues.
- To identify specific cytokine-induced cellular changes, particularly in fibroblast behavior and differentiation.
Main Methods:
- Subcutaneous perfusion of rat connective tissues with specific cytokines: GM-CSF, TNF-alpha, IL-1-alpha, TGF-beta, PDGF, IL-2, and gamma-IFN.
- Histological examination for fibroblast accumulation and neovascularization.
- Immunofluorescence staining for alpha-smooth muscle (SM) actin, desmin, and muscle myosin.
- Electron microscopy to identify myofibroblasts.
- Immuno-electron microscopy to localize alpha-SM actin within myofibroblast microfilament bundles.
Main Results:
- GM-CSF, TNF-alpha, IL-1-alpha, TGF-beta, and PDGF induced significant fibroblast accumulation and neovascularization.
- IL-2 and gamma-IFN primarily caused intense mononucleated leukocyte infiltration.
- Accumulated fibroblasts in GM-CSF, IL-1-alpha, and TGF-beta treated tissues were identified as myofibroblasts.
- Only GM-CSF treatment led to alpha-SM actin expression in myofibroblast microfilament bundles, indicating a specific effect on cytoskeletal organization.
Conclusions:
- Locally applied cytokines induce distinct granulation tissue formation.
- GM-CSF exhibits an unexpected extra-hematopoietic in vivo effect by stimulating alpha-SM actin synthesis in myofibroblasts.
- These findings highlight the specific roles of cytokines in modulating connective tissue remodeling and myofibroblast differentiation.