Heterogeneous synthetic phenotype of cloned scleroderma fibroblasts may be due to aberrant regulation in the synthesis of connective tissues

Abstract

Clones of dermal fibroblasts from the skin of 4 normal subjects and 5 patients with progressive systemic sclerosis (PSS; scleroderma) were established, and their synthetic and proliferative characteristics were compared. A limiting‐dilution assay was used to determine frequencies of cloning in the microcultures of dermal fibroblasts plated. The clones derived from single cells were expanded in vitro and examined (in passages C–H) for growth and synthesis of glycosaminoglycan (GAG) and collagenase‐sensitive protein (CSP). The clonogenicity of PSS fibroblasts was not significantly different from that of normal fibroblasts. Normal fibroblast clones were characterized by low levels of GAG and CSP synthesis, and there was a correlation between the GAG and CSP phenotypes. In contrast, clones of PSS fibroblasts were often, but not always, high producers of GAG and CSP, but there was no correlation between the levels of GAG and CSP synthesis. It appears that scleroderma skin is composed of fibroblast clones that are unable to regulate the synthesis of connective tissue components and often synthesize large amounts of connective tissue macromolecules.

Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia

“…From lung tissue, for example, fibroblasts have been shown to be heterogeneous with regard to morphology (15,34), proliferative capacity (6,20,24,34,48), surface marker (Thy-1, MHC class II, CD4) expression (11,34), type and amount of collagen production (11,16), intracellular metabolic pathways (15), and cytokine production (15). In addition, fibroblasts from nonpulmonary tissues have been shown to be heterogeneous with regard to proliferation (2,22), size and shape (18,19), presence of lipid droplets (29), collagen synthesis (13,16,21,36,40,49,51), expression of growth factors (16), response to and synthesis of PGE 2 , and expression of C1q surface receptors, among others. One wonders about heterogeneity in some of the other key functions of fibroblasts, such as capacity for transition to other cell types (i.e., myofibroblast and/or SM cell), migration, protease expression, and propensity to apoptosis.…”

Low oxygen stimulates proliferation of fibroblasts seeded as single cells

“…The ease with which fibroblasts proliferate from either tissue explants or established cultures stands in sharp contrast with the difficulty encountered when growing them from single cells. A number of investigators have shown that single dermal fibroblasts, as obtained through dilutional techniques, fail to proliferate in spite of optimal culture conditions (Korn et al, 1984;Whiteside et al, 1988). In this report, we tested the hypothesis that low oxygen tension, which has been shown to stimulate the proliferation and lifespan of fibroblasts (Taylor et al, 1974;Packer and Fuehr, 1977;Balin et al, 19841, would initiate and maintain their proliferation starting from single cells.…”

Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A

“…Although the pathogenesis of SSc is still unknown, it is obvious that skin fibrosis results from excessive accumulation of extracellular matrix (2) and that skin fibroblasts from patients with SSc express more collagen mRNA and protein than do normal skin fibroblasts in vivo and in vitro (3)(4)(5). A number of researchers have examined the mechanisms of the abnormal functions of SSc fibroblasts (6)(7)(8)(9)(10), but many facets of the pathogenesis of SSc remain to be elucidated.…”