TY - JOUR
T1 - Targeted gene correction in osteopetrotic-induced pluripotent stem cells for the generation of functional osteoclasts
AU - Neri, Tui
AU - Muggeo, Sharon
AU - Paulis, Marianna
AU - Caldana, Maria Elena
AU - Crisafulli, Laura
AU - Strina, Dario
AU - Focarelli, Maria Luisa
AU - Faggioli, Francesca
AU - Recordati, Camilla
AU - Scaramuzza, Samantha
AU - Scanziani, Eugenio
AU - Mantero, Stefano
AU - Buracchi, Chiara
AU - Sobacchi, Cristina
AU - Lombardo, Angelo
AU - Naldini, Luigi
AU - Vezzoni, Paolo
AU - Villa, Anna
AU - Ficara, Francesca
PY - 2015/10/13
Y1 - 2015/10/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stemcr.2015.08.005
DO - 10.1016/j.stemcr.2015.08.005
M3 - Article
AN - SCOPUS:84944441147
VL - 5
SP - 558
EP - 568
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 4
ER -