FGFR2 Mutation Confers a Less Drastic Gain of Function in Mesenchymal Stem Cells Than in Fibroblasts
Erika YehRodrigo AtiqueFelipe Augusto André IshiyRoberto D. FanganielloNivaldo AlonsoHamilton MatushitaKátia M. RochaMaria Rita Passos‐Bueno
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Gain-of-function mutations in FGFR2 cause Apert syndrome (AS), a disease characterized by craniosynostosis and limb bone defects both due to abnormalities in bone differentiation and remodeling. Although the periosteum is an important cell source for bone remodeling, its role in craniosynostosis remains poorly characterized. We hypothesized that periosteal mesenchymal stem cells (MSCs) and fibroblasts from AS patients have abnormal cell phenotypes that contribute to the recurrent fusion of the coronal sutures. MSCs and fibroblasts were obtained from the periostea of 3 AS patients (S252W) and 3 control individuals (WT). We evaluated the proliferation, migration, and osteogenic differentiation of these cells. Interestingly, S252W mutation had opposite effects on different cell types: S252W MSCs proliferated less than WT MSCs, while S252W fibroblasts proliferated more than WT fibroblasts. Under restrictive media conditions, only S252W fibroblasts showed enhanced migration. The presence of S252W mutation increased in vitro and in vivo osteogenic differentiation in both studied cell types, though the difference compared to WT cells was more pronounced in S252W fibroblasts. This osteogenic differentiation was reversed through inhibition of JNK. We demonstrated that S252W fibroblasts can induce osteogenic differentiation in periosteal MSCs but not in MSCs from another tissue. MSCs and fibroblasts responded differently to the pathogenic effects of the FGFR2(S252W) mutation. We propose that cells from the periosteum have a more important role in the premature fusion of cranial sutures than previously thought and that molecules in JNK pathway are strong candidates for the treatment of AS patients.Keywords:
Gain of function
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Mesenchymal stromal cells derived from amnion (AM-MSCs) can be easily obtained in large quantity by less invasive method in comparison to bone marrow-derived MSCs (BM-MSCs). However, the biological and immunosuppressive properties of AM-MSCs are still poorly characterized. Previous studies demonstrated that BM-MSCs expressed indoleamine 2,3-dioxygenase (IDO) to suppress T-cell responses. This study was designed to address whether IDO contributes to the immunosuppressive function of AM-MSCs. MSCs isolated from amnion were cultured in complete medium similar to BM-MSCs. After culture, AM-MSCs exhibited spindle shape morphology and expressed MSC markers similar to that of BM-MSCs. In addition, AM-MSCs were able to differentiate into adipocytes and osteoblasts. Fascinatingly, AM-MSCs and BM-MSCs exhibited comparable degree of immunosuppressive effect when they were co-cultured with activated T-cells. In addition, IDO secreted by AM-MSCs was responsible for induction of immunosuppressive activities in the same manner as BM-MSCs. Taken together; the results of the present study demonstrate that while AM-MSCs and BM-MSCs show similar immunosuppressive effect, AM-MSCs may have additional advantage over the BM-MSCs in terms of availability. Therefore, AM-MSCs might be considered a potential source for therapeutic applications especially for treatment of immune related diseases.
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Objective To compare the efficacy of intracavernosal injection of autologous and allogeneic mesenchymal stem cells as potential treatment of erectile dysfunction in an experimental rat model. Methods Mesenchymal stem cells were isolated from rat paratesticular fat tissue. Bilateral cavernous nerve injury was carried out followed by immediate intracavernosal injection of either autologous or allogeneic mesenchymal stem cells or mesenchymal stem cell lysates. One month after injection, erectile function was evaluated by means of intracavernosal pressure measurement. All rats were eventually killed, and penile tissues were taken for immunhistochemical and molecular investigation. Results A total of 36 S prague– D awley rats were used. The mean maximum intracavernosal pressure in the sham‐operated, autologous and allogeneic mesenchymal stem cell injection groups were significantly better compared with the vehicle injection group (80.5 [3.56], 71.1 [2.9] and 69.2 [3.2] vs 40.33 [4.4], respectively). Mean maximum intracavernosal pressure to mean arterial pressure ratios in the autologous and allogeneic mesenchymal stem cell and mesenchymal stem cell lysate injection groups were not significantly different. Conclusions Intracavernosal injection of both autologous or allogeneic mesenchymal stem cells improve erectile functions in a rat model of cavernous nerve injury. Allogeneic mesenchymal stem cells might provide clinicians with ready to use, standardized and, in certain cases, more effective products. More studies focusing on long‐term immunological aspects of allogeneic mesenchymal stem cells are required.
Stem Cell Therapy
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Encephalomyelitis
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The results of recent clinical trials using mesenchymal stem cells (MSCs) have been unsatisfactory, indicating that current MSC-based therapies need to be improved. We and others have previously demonstrated that MSCs activate complement by unknown mechanisms after infusion, leading to damaged MSCs. In the study reported here, we found that incorporation of N-glycolylneuraminic acid onto MSCs during in vitro culture was a factor in the activation of complement by MSCs. In addition, we developed a way to "paint" heparin onto MSCs. This novel method improved the viability of MSCs and enhanced their function after infusion by directly inhibiting complement and by recruiting factor H, another potent complement inhibitor in serum, onto the surface of the MSCs. These data suggest that cell-surface engineering of MSCs with heparin to locally inhibit complement activation on MSCs might be a straightforward and effective method for improving the outcome of current MSC-based therapies.
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