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

Tui Neri, Sharon Muggeo, Marianna Paulis, Maria Elena Caldana, Laura Crisafulli, Dario Strina, Maria Luisa Focarelli, Francesca Faggioli, Camilla Recordati, Samantha Scaramuzza, Eugenio Scanziani, Stefano Mantero, Chiara Buracchi, Cristina Sobacchi, Angelo Lombardo, Luigi Naldini, Paolo Vezzoni, Anna Villa, Francesca Ficara

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)558-568
Number of pages11
JournalStem Cell Reports
Issue number4
Publication statusPublished - Oct 13 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics


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