Targeted Gene Correction in Osteopetrotic-Induced Pluripotent Stem Cells for the Generation of Functional Osteoclasts

Stem Cell Reports
Tui NeriFrancesca Ficara

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.

References

Aug 5, 2003·Nature Reviews. Genetics·Steven L Teitelbaum, F Patrick Ross
Jan 31, 2009·The New England Journal of Medicine·Alessandro AiutiMaria-Grazia Roncarolo
Jan 22, 2010·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Alfredo CapparielloAnna Teti
Jul 28, 2010·The New England Journal of Medicine·Salima Hacein-Bey-AbinaMarina Cavazzana-Calvo
Dec 16, 2010·Human Molecular Genetics·Raymond M AnchanRichard L Maas
Apr 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Sara E HowdenJames A Thomson
Jul 24, 2013·Nature Reviews. Endocrinology·Cristina SobacchiMiep H Helfrich
May 30, 2014·Nature·Pietro GenoveseLuigi Naldini

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Citations

May 18, 2020·Stem Cell Research & Therapy·Xiaojie XianIlana Moscatelli
Feb 13, 2021·Molecular Therapy. Methods & Clinical Development·Ilana MoscatelliJohan Richter
May 11, 2021·Disease Models & Mechanisms·Sara PennaValentina Capo
Apr 28, 2021·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Uta RösslerUwe Kornak

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Methods Mentioned

BETA
PCR
PCRs
fluorescence-activated cell sorting
flow cytometry
transfection
biopsy
FACS

Software Mentioned

Diva
CytoVision Master
CytoVision
FlowJo
Applied

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