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.

Neri, T., Muggeo, S., Paulis, M., Elena Caldana, M., Crisafulli, L., Strina, D., et al. (2015). Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts. STEM CELL REPORTS, 5(4), 558-568 [10.1016/j.stemcr.2015.08.005].

Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts

Buracchi, C;Villa, A
;
2015

Abstract

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.
Articolo in rivista - Articolo scientifico
stem cells
English
2015
5
4
558
568
none
Neri, T., Muggeo, S., Paulis, M., Elena Caldana, M., Crisafulli, L., Strina, D., et al. (2015). Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts. STEM CELL REPORTS, 5(4), 558-568 [10.1016/j.stemcr.2015.08.005].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/402799
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