Murine Rankl−/− Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector

Autor: Valentina Capo, Marco Gattorno, Cristina Sobacchi, Ileana Bortolomai, Ciro Menale, Anna Tampieri, Elisabetta Traggiai, Lorenzo Diomede, Camilla Recordati, Francesca Schena, Monica Sandri, Emanuela Caci, Eleonora Palagano, Arinna Bertoni, Alberto Martini, Claudia Pastorino, Anna Villa
Přispěvatelé: Schena, F., Menale, C., Caci, E., Diomede, L., Palagano, E., Recordati, C., Sandri, M., Tampieri, A., Bortolomai, I., Capo, V., Pastorino, C., Bertoni, A., Gattorno, M., Martini, A., Villa, A., Traggiai, E., Sobacchi, C.
Rok vydání: 2017
Předmět:
0301 basic medicine
Cellular differentiation
Lentiviral transduction
Inbred C57BL
Mice
0302 clinical medicine
Osteopetrosi
Transduction
Genetic
Osteogenesis
Mesenchymal stromal cell
Rankl
Cell Differentiation
Mesenchymal Stem Cell
medicine.anatomical_structure
RANKL
Differentiation
Osteopetrosis
030220 oncology & carcinogenesis
Molecular Medicine
Genetic Vector
Stem cell
Signal Transduction
musculoskeletal diseases
Stromal cell
Genetic Vectors
Biology
Lentiviru
Immunophenotyping
Clone Cell
Transduction
03 medical and health sciences
Genetic
Bone
Animals
Biomarkers
Clone Cells
Lentivirus
Mesenchymal Stem Cells
Mice
Inbred C57BL
RANK Ligand
Osteoclast
medicine
Animal
Mesenchymal stem cell
Biomarker
Cell Biology
medicine.disease
030104 developmental biology
Immunology
Cancer research
biology.protein
Bone marrow
Developmental Biology
Zdroj: Stem Cells. 35:1365-1377
ISSN: 1549-4918
1066-5099
DOI: 10.1002/stem.2574
Popis: Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl−/− mice, and found that Rankl−/− BM-MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl−/− BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics.
Databáze: OpenAIRE
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