Identification of Mesenchymal Stem Cells in Perinodular Fat and Skin in Dupuytren's Disease: A Potential Source of Myofibroblasts with Implications for Pathogenesis and Therapy

Abstract

Dupuytren's disease (DD) is a fibroproliferative disorder characterized by aberrant proliferation of myofibroblasts, the source of which remains unknown. Recent studies indicate that circulating and tissue-resident mesenchymal stem cells (MSCs) can differentiate into myofibroblasts. Therefore, the aim of this study was to profile MSCs from phenotypically distinct DD sites including cord, nodule, skin overlying nodule (SON), and perinodular fat (PNF) compared with unaffected internal controls, that is, distant palmar fat (DPF) and transverse palmar fascia (Skoog's fibers) as well as external control carpal tunnel (CT) tissue including skin, fat, and fascia. Freshly isolated primary fibroblasts as well as cells grown up to passage 5 (P5) from DD (n=27) and CT (n=14) samples were analyzed for the presence of established MSC markers CD73, CD90, and CD105 and absence of hematopoietic marker CD34 using fluorescence-activated cell sorting, in-cell quantitative western blotting, immunohistochemistry, and immunocytochemistry. Freshly isolated cells from SON, PNF, and cord biopsies had a higher number of CD34(-)73(+)90(+)105(+) cells compared with Skoog's fibers and CT controls. P3 cells obtained from all DD biopsies compared with CT samples differentiated into osteocytes, adipocytes, and chondrocytes. P3 cord and nodule cells expressed intense α-smooth muscle actin staining compared with skin and fat cells. Stem cell markers including stem cell factor, MSC-homing marker CXCR4, and Wnt/β-catenin downregulator Dkk-1 were all upregulated in SON and PNF compared with CT skin and CT fat, respectively, as shown by real-time quantitative polymerase chain reaction. However, osteogenic marker OSF-1 had a significantly higher expression in the PNF (P=0.002) and cord (P=0.01) compared with the nodule. In conclusion, we have shown the presence of MSCs in specific DD tissue phenotypes compared with internal and external control tissue. These findings provide preliminary support for a potential alternative source of disease myofibroblasts originating from sites such as SON and PNF as opposed to palmar fascia alone.

Microarray Analysis of Dupuytren’s Disease Cells: The Profibrogenic Role of the TGF-� Inducible p38 MAPK Pathway

“…Its lower expression in D cells additionally supports the evidence of accentuated myo�ibroblast phenotype of D cells. Bayat and co-workers [70,71] report similar results. They also detected CD34 and CD90 positive cell populations in cells isolated from the cord and nodule of DD patients.…”

Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target

“…However, we and others have shown that at passage 5 the phenotypes of myofibroblasts and normal human dermal fibroblasts tend to merge (30,31). In addition, whereas the cell of origin for Dupuytren's myofibroblasts remains controversial, there is accumulating evidence that the adjacent tissues, including the overlying dermis, make a significant contribution and that these cells are more akin to Dupuytren's myofibroblasts than fibroblasts from carpal tunnel fascia (20). Moreover, Dupuytren's disease is restricted to the palm of the hands in patients with a genetic predisposition.…”

“…Recent data suggest that the tissues overlying the Dupuytren's nodules, including the dermis, are likely to constitute a source for myofibroblast precursors during disease progression (20). Therefore, we studied the effect of TGF-β1 on dermal fibroblasts from palmar and nonpalmar skin from patients with Dupuytren's disease, as well as palmar dermal fibroblasts from normal individuals unaffected by Dupuytren's disease.…”

Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders

“…Many studies were conducted in older populations with at least one analysis group >50 years of age (33)(34)(35)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). The range of symptom duration varied substantially within and across studies.…”

“…We apply it here to refer to the potentially heterogeneous biomarker associations in populations according to symptom severity or duration, age, gender, and the like. Many of the sufficient-quality studies in this review have been conducted among older patients at the time of surgery (44,45,47,48,50,54,58). Comparatively fewer authors have researched MSD biomarkers in younger subjects with incipient disorders (40,41).…”