Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride

Abstract

Objective. To develop a murine model for use in examining the role of microchimeric cells and certain chemical exposures in the pathogenesis of systemic sclerosis (SSc). Methods. Female BALB/cJ retired breeder mice were bled before and after vinyl chloride injection. The DNA from their white blood cells was obtained, and the number of microchimeric cell equivalents was determined by quantitative polymerase chain reaction using DNA primers specific for the H-2K b gene, a sequence not found in BALB/cJ mice. Skin was obtained at autopsy, embedded in paraffin, sectioned, and stained with Masson's trichrome. Hydroxyproline analyses were performed on 4-mm skin biopsy samples. Results. Microchimeric cells were identified and quantitated before and after 20 daily intraperitoneal injections of vinyl chloride. The number of microchi-meric cells in the peripheral blood increased an average of 48-fold after treatment with vinyl chloride. Histologic examination of the skin of these same mice (which had an increased number of microchimeric cells) showed inflammation, with abundant fibroblasts and a heavy mononuclear infiltration in the dermis. The collagen fibers appeared densely packed and disorganized. His-tologic examination of the skin of untreated retired breeder mice and treated virgin mice appeared normal. Quantitative assays to determine the collagen content of skin biopsy samples obtained from treated microchi-meric mice compared with nontreated microchimeric or with treated nonmicrochimeric mice showed a 2-3-fold increase in collagen content in the treated microchi-meric mice. Extraordinary splenomegaly was present in the vinyl chloride-treated microchimeric mice, accompanied by cellular infiltration and fibrosis. Conclusion. The results suggest that vinyl chloride injections into BALB/cJ retired breeder mice lead to activation of microchimeric cells, which causes the cells to divide and multiply. The correlation between the 48-fold increase in microchimeric cells and the appearance of dermal inflammation and fibrosis similar to that of graft-versus-host disease suggests that activated mi-crochimeric cells may be a necessary factor in the pathogenesis of autoimmune diseases such as SSc.

Cells from a vanished twin as a source of microchimerism 40 years later in a male with a scleroderma-like condition.

“…Besides genetic factors, chimerism in this case may be dependent on other factors such as inflammation, environmental exposure (e.g., hydrocarbons), timing or the method used to obtain and isolate PBMC. A decade ago, in a mouse model Christner et al 15 showed marked proliferation of pre-existing microchimeric cells of fetal origin following intraperitoneal injections of vinyl chloride, associated with the development of fibrosis and a heavy mononuclear infiltration in the dermis. We suggest that a similar expansion and recruitment of microchimeric cells may have occurred in this scleroderma-like patient after hydrocarbon exposure, in contrast to his mother, who had no such exposure.…”

Fetal microchimerism and maternal health during and after pregnancy

“…3,26 It is also possible that chronic tissue injury might actually promote the establishment of microchimerism. Christner et al 28 used murine models of skin fibrosis to show that fetal cells were recruited to sites of injury and other rodent work also implicates fetal microchimerism in tissue repair rather than disease pathogenesis. 29,30 In women, male cells were found in a high proportion of those with hepatitis C, thyroid adenomas and polymorphic eruption of pregnancy (PEP).…”

Multi-lineage potential of fetal cells in maternal tissue: a legacy in reverse

“…Jimenez and Tarantal used rhesus monkeys (Macaca mulatta) to study feto-maternal trafficking (Jimenez and Tarantal, 2003) and demonstrated long-term persistence of male CD34 + cells in one or more maternal tissues (Jimenez et al, 2005). Fetal cell microchimerism has also been examined in mice (Liégeois et al, 1981;Bonney and Matzinger, 1997;Christner et al, 2000) and, more recently, in rats (Wang et al, 2004).…”