Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity
| العنوان: | Bone marrow stromal cells from β-thalassemia patients have impaired hematopoietic supportive capacity |
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| المؤلفون: | Marco Zecca, Maria Ester Bernardo, Luca Basso-Ricci, Alessandro Aiuti, Annamaria Aprile, Sarah Marktel, Giuliana Ferrari, Stefania Crippa, Maria Antonietta Avanzini, Raisa Jofra Hernandez, Fabio Ciceri, Laura Silvestri, Valeria Rossella, Stefania Pirroni, Silvia Rivis, Samantha Scaramuzza |
| المساهمون: | Crippa, Stefania, Rossella, Valeria, Aprile, Annamaria, Silvestri, Laura, Rivis, Silvia, Scaramuzza, Samantha, Pirroni, Stefania, Avanzini, Maria Antonietta, Basso-Ricci, Luca, Hernandez, Raisa Jofra, Zecca, Marco, Marktel, Sarah, Ciceri, Fabio, Aiuti, Alessandro, Ferrari, Giuliana, Bernardo, Maria Ester |
| المصدر: | The Journal of Clinical Investigation |
| بيانات النشر: | American Society for Clinical Investigation, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Stromal cell, Population, CD34, Bone Marrow Cells, Stem cells, Biology, 03 medical and health sciences, Cell stre, Mice, 0302 clinical medicine, medicine, Animals, Humans, Bone marrow, education, education.field_of_study, Transplantation, Stem cell, Medicine (all), Mesenchymal stem cell, beta-Thalassemia, Stem cell transplantation, Hematopoietic stem cell, General Medicine, Cell stress, Hematopoietic Stem Cells, Coculture Techniques, Hematopoiesis, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Clinical Medicine, Stromal Cells |
| الوصف: | BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche–associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente. |
| اللغة: | English |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d8737c2d3e2b3f67e0dda0c018bababe http://europepmc.org/articles/PMC6436882 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d8737c2d3e2b3f67e0dda0c018bababe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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