Recapitulation of Fibromatosis Nodule by Multipotential Stem Cells in Immunodeficient Mice

Musculoskeletal fibromatosis remains a disease of unknown etiology. Surgical excision is the standard of care, but the recurrence rate remains high. Superficial fibromatosis typically presents as subcutaneous nodules caused by rapid myofibroblast proliferation followed by slow involution to dense acellular fibrosis. In this study, we demonstrate that fibromatosis stem cells (FSCs) can be isolated from palmar nodules but not from cord or normal palm tissues. We found that FSCs express surface markers such as CD29, CD44, CD73, CD90, CD105, and CD166 but do not express CD34, CD45, or CD133. We also found that FSCs are capable of expanding up to 20 passages, that these cells include myofibroblasts, osteoblasts, adipocytes, chondrocytes, hepatocytes, and neural cells, and that these cells possess multipotentiality to develop into the three germ layer cells. When implanted beneath the dorsal skin of nude mice, FSCs recapitulated human fibromatosis nodules. Two weeks after implantation, the cells expressed immunodiagnostic markers for myofibroblasts such as α-smooth muscle actin and type III collagen. Two months after implantation, there were fewer myofibroblasts and type I collagen became evident. Treatment with the antifibrogenic compound Trichostatin A (TSA) inhibited the proliferation and differentiation of FSCs in vitro. Treatment with TSA before or after implantation blocked formation of fibromatosis nodules. These results suggest that FSCs are the cellular origin of fibromatosis and that these cells may provide a promising model for developing new therapeutic interventions

An Alternative Solution to Achieve Primary Stability in Cementless Revision Hip Arthroplasty for Femur Ectasia

Revision total hip arthroplasty is technically demanding, especially when treating a large defective femur. The aim of this study was to evaluate the clinical results of cementless total hip arthroplasty revision in patients with advanced femoral bony defects. Methods: By using the canaloplasty technique, which osteotomized the proximal femur to reduce the width of canal, 12 patients were enrolled and underwent revision operation. Patients were evaluated by radiographic examination and Harris hip score before and after the index procedures. Results: The average length of follow-up was 38.7 months. All the osteotomies united at a mean of 5.3 months. Structural allografts were used on six patients to augment the thinned cortices. A total of 11 femoral components (91%) achieved and maintained stability at the last follow-up. One patient was complicated with early stem subsidence and another with deep infection. Both patients were treated successfully without late sequelae. The mean Harris hip score improved from 37.2 to 75.0 after the operation (p < 0.05). Conclusion: The canaloplasty technique could be an alternative solution to help revision surgery in some younger patients with advanced femoral defects

N-3 polyunsaturated fatty acids block the trimethylamine-N-oxide- ACE2- TMPRSS2 cascade to inhibit the infection of human endothelial progenitor cells by SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is a novel coronavirus that infects many types of cells and causes cytokine storms, excessive inflammation, acute respiratory distress to induce failure of respiratory system and other critical organs. In this study, our results showed that trimethylamine-N-oxide (TMAO), a metabolite generated by gut microbiota, acts as a regulatory mediator to enhance the inerleukin-6 (IL-6) cytokine production and the infection of human endothelial progenitor cells (hEPCs) by SARS-CoV-2. Treatment of N-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) could effectively block the entry of SARS-CoV-2 in hEPCs. The anti-infection effects of N-3 PUFAs were associated with the inactivation of NF-κB signaling pathway, a decreased expression of the entry receptor angiotensin-converting enzyme 2 (ACE2) and downstream transmembrane serine protease 2 in hEPCs upon the stimulation of TMAO. Treatment of DHA and EPA further effectively inhibited TMAO-mediated expression of IL-6 protein, probably through an inactivation of MAPK/p38/JNK signaling cascades and a downregulation of microRNA (miR)-221 in hEPCs. In conclusion, N-3 PUFAs such as DHA and EPA could effectively act as preventive agents to block the infection of SARS-CoV-2 and IL-6 cytokine production in hEPCs upon the stimulation of TMAO

Corticosteroid inhibits differentiation of palmar fibromatosis-derived stem cells (FSCs) through downregulation of transforming growth factor-β1 (TGF-β1)

<div><p>Treatment for musculoskeletal fibromatosis remains challenging. Surgical excision for fibromatosis is the standard therapy but recurrence remains high. Corticosteroids, an anti-fibrogenic compound, have been used to treat early stage palmar fibromatosis, but the mechanism is unknown. We investigated the inhibitory mechanism effect of corticosteroids in the murine model of fibromatosis nodule as well as in cultured FSCs. Quantitative reverse transcription/polymerase chain reaction (PCR) analysis and immunofluorescence (IF) staining for markers of myofibroblasts (α-smooth muscle actin and type III collagen) were used to examine the effect of dexamethasone on myofibroblasic differentiation of FSCs both in vitro and in vivo. Transforming growth factor-β1 (TGF-β1) signaling and its downstream targets were examined using western blot analysis. TGF-β1 expression in FSCs before and after dexamethasone treatment was compared. In addition, inhibition of TGF-β1 expression was examined using RNA interference (RNAi) on FSCs, both in vitro and in vivo. Treating FSCs with dexamethasone inhibited FSCs’ myofibroblastic differentiation in vitro. Treating FSCs with dexamethasone before or after implantation further inhibited formation of fibromatosis nodules. Dexamethasone suppressed expression of TGF-β1 and pSmad2/3 by FSCs in vitro. TGF-β1 knockdown FSCs showed reducing myofibroblastic differentiation both in vitro and in vivo. Finally, addition of TGF-β1 abolished dexamethasone-mediated inhibition of myofibroblastic differentiation. Dexamethasone inhibits the myofibroblastic differentiated potential of FSCs both in vitro and in vivo through inhibition of TGF-β1 expression in FSCs. TGF-β1 plays a key role in myofibroblastic differentiation.</p></div

Macroscopic examination of the effects of hypoxia-cultured MSCs on osteoarthritis progression.

<p><b>(A)</b> Femur condyles 6 and 12 weeks post-treatment. Asterisks indicate osteophyte formation. <b>(B)</b> India ink staining for articular surface of tibial plateaus.</p

Histological grading of the effect of hypoxia-cultured MSCs.

<p>Mankin scores at different part of the joint at 6 and 12 weeks post-treatment. Data are mean ± standard deviation. *P <0.05.</p

Study design.

<p><b>Evaluation of the effect of hypoxia-cultured MSCs for treatment of osteoarthritis in rabbits.</b> The numbers in parentheses indicate number of rabbits receiving ACLT and analysis. CTR: control group; H&E: haematoxylin and eosin; S.O: safranin O; P.B: Prussian blue.</p

Identification and localization of SPIO-labeled MSCs.

<p><b>(A)</b> Endocytosis of SPIO nanoparticles by MSCs visualized by Prussian blue staining (bar = 100 μm). <b>(B-D)</b> Engraftment of injected MSCs into cartilage of the (B) femoral condyle (Magnification, ×100), (C) tibial plateau (Magnification, ×100) and (D) meniscus (Magnification, ×50) by Prussian blue and Safranin-O staining. (Lower boxes, (B, C) ×200, (D) ×100).</p

Histologic analysis.

<p><b>(A, B)</b> Femur condyles of animals at 6 and 12 weeks post-treatment were assessed by <b>(A)</b> haematoxylin and eosin and <b>(B)</b> Safranin-O staining. <b>(C)</b> Quantitative analysis of safranin-O staining. Data are mean ± standard deviation. *P <0.05.</p