Abstract
BackgroundDupuytren’s disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The disease is characterized by the formation of collagen rich- cords which gradually shorten by the action of myofibroblasts resulting in finger contractures. It is a disease that is confined to humans, and a major limiting factor in investigating this disorder has been the lack of a faithful animal model that can recapitulate its distinct biology. The aim of this study was to develop such a model by determining if Dupuytren’s disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures.Methods1x107 fluorescently labeled DD- and CT-derived fibroblasts were transplanted into the left and right forepaws of nude rats respectively. Cells were tracked at regular intervals for a period of two months by quantifying emitted fluorescent signal using an IVIS imaging system. After a period of 62 days rat forepaw connective tissues were harvested for histology and total RNA was isolated. Human-specific probes were used to perform real time RT-PCR assays to examine the expression patterns of gene products associated with fibrosis in DD. Rat forepaw skin was also harvested to serve as an internal control.ResultsBoth CT- and DD-derived fibroblasts survived for a period of 62 days, but DD-derived cells showed a significantly greater level of persistent fluorescent signal at the end of this time than did CT-derived cells. mRNA expression levels of α-smooth muscle actin (α-SMA), type I- and type III- collagens were all significantly elevated in the forepaw receiving DD cord-derived fibroblasts in comparison to CT-derived fibroblasts. Masson’s trichrome stain confirmed increased collagen deposition in the forepaw that was injected with DD cord-derived fibroblasts.ConclusionsFor the first time we describe an animal model for Dupuytren’s disease at the orthotopic anatomical location. We further show that gene expression differences between control (CT) and diseased (DD) derived fibroblasts persist when these cells are transplanted to the forepaw of the nude rat. These preliminary findings indicate that, with further refinements, this animal model holds promise as a baseline for investigating novel therapeutic regimens to determine an effective strategy in treating DD.
Highlights
Dupuytren’s disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands
Labelling of DD and carpal tunnel (CT) cells with DiR dye had no effect on cell viability or proliferation In order to track our populations of cells over time in situ in the forepaw, we first labelled them with VybrantTM DiR, a lipophilic dye that is only weakly fluorescent in aqueous solution but is strongly fluorescent and photostable when present in cell membranes
We further confirmed that DiR did not have any significant effect on the proliferative capacity of either DD or CT cells, nor did it elicit any cytotoxic effect when compared to unlabeled cell populations (Fig. 1)
Summary
Dupuytren’s disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The aim of this study was to develop such a model by determining if Dupuytren’s disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures. Dupuytren’s disease (DD) is a complex, progressive, fibroproliferative disorder which commonly affects populations of northern European descent and has a prevalence of >7 % in the United States [1]. Dupuytren’s disease generally begins as a hard nodule on the palm and slowly progresses into a fibrous cord that pulls the affected digit into a flexed contracted position [4, 5]. Recent studies show that cells derived from primary nodule and cord have similar gene expression profiles [9], indicating that both nodule- and cord-derived fibroblasts are appropriate subjects of study in examining the progression of DD
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