Autosomal recessive osteopetrosis is a human bone disease mainly caused by TCIRG1 gene mutations that prevent osteoclasts resorbing activity, recapitulated by the oc/oc mouse model. Bone marrow transplantation is the only available treatment, limited by the need for a matched donor. The use of induced pluripotent stem cells (iPSCs) as an unlimited source of autologous cells to generate gene corrected osteoclasts might represent a powerful alternative. We generated iPSCs from oc/oc mice, corrected the mutation using a BAC carrying the entire Tcirg1 gene locus as a template for homologous recombination, and induced hematopoietic differentiation. Similarly to physiologic fetal hematopoiesis, iPSC-derived CD41+ cells gradually gave rise to CD45+ cells, which comprised both mature myeloid cells and high proliferative potential colony-forming cells. Finally, we differentiated the gene corrected iPSC-derived myeloid cells into osteoclasts with rescued bone resorbing activity. These results are promising for a future translation into the human clinical setting.
Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts / T. Neri, S. Muggeo, M. Paulis, M.E. Caldana, L. Crisafulli, D. Strina, M.L. Focarelli, F. Faggioli, C. Recordati, S. Scaramuzza, E. Scanziani, S. Mantero, C. Buracchi, C. Sobacchi, A. Lombardo, L. Naldini, P. Vezzoni, A. Villa, F. Ficara. - In: STEM CELL REPORTS. - ISSN 2213-6711. - 5:4(2015), pp. 558-568.
|Titolo:||Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts|
MUGGEO, SHARON (Secondo)
|Parole Chiave:||Animals; Cell Differentiation; Cell Line; Hematopoiesis; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cells; Osteoclasts; Osteopetrosis; Targeted Gene Repair; Vacuolar Proton-Translocating ATPases; Biochemistry; Genetics; Developmental Biology; Cell Biology|
|Settore Scientifico Disciplinare:||Settore VET/03 - Patologia Generale e Anatomia Patologica Veterinaria|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.stemcr.2015.08.005|
|Appare nelle tipologie:||01 - Articolo su periodico|