Dataset Information

Development of a 3D in vitro model of Dupuytren’s disease as a platform for drug screening

ABSTRACT: Background: Dupuytren’s disease (DD) is a common fibrotic disorder of the hand, characterized by progressive thickening and contracture of the palmar and digital fascia. Surgical excision remains the primary treatment; however, there are currently no therapies to prevent disease progression or recurrence. This study aims to develop a 3D in vitro model to test novel antifibrotic therapies. The model is based on decellularized pathological DD tissue seeded with patient-derived fibroblasts, capturing the role of both cellular and extracellular matrix components in disease progression. Methods: Fibrotic DD tissues were obtained from surgical excisions, sectioned, and decellularized. In parallel, primary fibroblasts were isolated from patient samples. The decellularized extracellular matrices (dECMs) were characterized with respect to biochemical composition, collagen structure, and mechanical properties. Fibroblasts were seeded onto the dECMs and cultured stepwise to initially promote proliferation, followed by differentiation into myofibroblasts. Secretomes of cells cultivated on the established 3D model were compared to those from conventional 2D cultivations. To evaluate the model´s relevance and effectiveness we tested the antifibrotic drug minoxidil. Results: The dECMs retained the pathological architecture and mechanical properties of native DD tissue, although individual ECM components were reduced after decellularization. Fibroblasts successfully adhered, proliferated, and repopulated the scaffold. The relevance of the 3D model was demonstrated by the presence of myofibroblasts with disease–relevant secretome. The responsiveness to the drug minoxidil was significantly more complex in the 3D model than in conventional 2D cultures. Conclusion: We demonstrated that dECM seeded with DD fibroblasts represents a relevant 3D in vitro model of Dupuytren’s disease. The model enables antifibrotic drug screening, as demonstrated by the testing of minoxidil. Our model provides a reproducible platform also suitable for the investigation of cells and ECM contributions to palmar fascial fibrosis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Adam Eckhardt

LAB HEAD: Adam Eckhardt

PROVIDER: PXD072354 | Pride | 2026-04-06

REPOSITORIES: Pride

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			Action	DRS
	ExplanationatorynotesKnitlovaCAMB-D-25-00260.xlsx	Xlsx
	PLK300_OE480_250425_FGU22_EA04_0-2uL_DIA-FAIMS_90M_60G.raw	Raw
	PLK300_OE480_250425_FGU22_EA05_0-2uL_DIA-FAIMS_90M_60G.raw	Raw
	PLK300_OE480_250425_FGU22_EA06_0-2uL_DIA-FAIMS_90M_60G.raw	Raw
	PLK300_OE480_250425_FGU22_EA11_0-2uL_DIA-FAIMS_90M_60G.raw	Raw

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Publications

Development of a 3D In Vitro Model of Dupuytren's Disease as a Platform for Drug Screening.

Knitlova Jarmila J Eckhardt Adam A Hadraba Daniel D Vondrasek David D Stachon Roman R Filova Elena E Jencova Vera V Havlickova Kristyna K Kobets Tatyana T Ostadal Martin M Bacakova Lucie L

Cellular and molecular bioengineering 20260119 1

<h4>Background</h4>Dupuytren's disease (DD) is a common fibrotic disorder of the hand, characterized by progressive thickening and contracture of the palmar and digital fascia. Surgical excision remains the primary treatment; however, there are currently no therapies to prevent disease progression or recurrence. This study aims to develop a 3D in vitro model to test novel antifibrotic therapies. The model is based on decellularized pathological DD tissue seeded with patient-derived fibroblasts, ...[more]

PMID: 41907097

Similar Datasets

Project description:Dupuytren's disease (DD) is a classic example of pathological fibrosis which results in a debilitating disorder affecting a large sector of the human population. It is characterized by excessive local proliferation of fibroblasts and over-production of collagen and other components of the extracellular matrix (ECM) in the palmar fascia. The fibrosis progressively results in contracture of elements between the palmar fascia and skin causing flexion deformity or clawing of the fingers and a severe reduction in hand function. While much is known about the pathogenesis and surgical treatment of DD, little is known about the factors that cause its onset and progression, despite many years of research. Gene expression patterns in DD patients now offers the potential to identify genes that direct the pathogenesis of DD. In this study, we used primary cultures of fibroblasts derived from excisional biopsies of fibrotic tissue from DD patients to compare the gene expression profiles on a genome-wide basis with normal control fibroblasts. Our investigations have identified genes that may be involved with DD pathogenesis including some which are directly relevant to fibrosis. In particular, these include significantly reduced expression levels of three matrix metallopeptidases (MMP1, MMP3, MMP16), follistatin, and STAT1, and significantly increased expression levels of fibroblast growth factors (FGF9, FGF11), a number of collagen genes and other ECM genes in DD patient samples. Many of these gene products are known to be involved in fibrosis, tumour formation and in the normal processes of tissue remodelling. In addition, alternative splicing was identified in some DD-associated genes. These highly sensitive genomic investigations provide new insight into the molecular mechanisms that may underpin the development and progression of DD. Four exon arrays of DD primary fibroblasts derived from fibrotic tissue were compared to fibroblasts derived from skin punch biopsies from individuals who did not show DD symptoms.

Project description:Background: Fibrosis is a pathological scarring process characterized by persistent myofibroblasts activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC, and, as a consequence, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming. Methods: We tested the antifibrotic effects of resting and interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in three in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation and ECM degradation. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting- or primed-MSC-CM and proteomic characterization of resting- and primed-MSC-CM. Results: We report that MSC-CM treatment prevented TGF-β induced fibroblast activation and reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were higher when primed rather than resting MSC-CM was used. Priming increased the ability of MSC-CM to remodel the extracellular matrix reducing its content of collagen I and fibronectin. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. DKK1 inhibition reduced the anti-fibrotic effects of MSC-CM. Thus, cytokine priming increases antifibrotic factors in the MSC-CM which in turn amplify the anti-fibrotic effects of MSC-CM. Conclusions: In a pro-fibrotic in vitro environment MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and inflammatory signals, as well as by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution