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Rescue of ATPa3-Deficient Murine Malignant Osteopetrosis by Hematopoietic Stem Cell Transplantation in utero

Annalisa Frattini, Harry C. Blair, Maria Grazia Sacco, Francesco Cerisoli, Francesca Faggioli, Enrica Mira Catò, Alessandra Pangrazio, Antonio Musio, Francesca Rucci, Cristina Sobacchi, Allison C. Sharrow, Sara E. Kalla, Maria Grazia Bruzzone, Roberto Colombo, Maria Cristina Magli, Paolo Vezzoni and Anna Villa
Proceedings of the National Academy of Sciences of the United States of America
Vol. 102, No. 41, Clonogenicity of Hair Follicle Stem Cells (Oct. 11, 2005), pp. 14629-14634
Stable URL: http://www.jstor.org/stable/4143368
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Rescue of ATPa3-Deficient Murine Malignant Osteopetrosis by Hematopoietic Stem Cell Transplantation in utero
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Abstract

Autosomal recessive osteopetrosis (ARO) is a paradigm for genetic diseases that cause severe, often irreversible, defects before birth. In ARO, osteoclasts cannot remove mineralized cartilage, bone marrow is severely reduced, and bone cannot be remodeled for growth. More than 50% of the patients show defects in the osteoclastic vacuolar-proton-pump subunit, ATP6a3. We treated ATP6a3-deficient mice by in utero heterologous hematopoietic stem cell (HSC) transplant from outbred GFP transgenic mice. Dramatic phenotype rescue by GFP osteoclasts was obtained with engraftment, which was observed in most cases. Engraftment survived for variable periods. Recipients were not immunosuppressed, and graft-versus-host disease was not observed in all pups born after in utero treatment. Thus, differentiation of unmatched HSC transplanted in utero is sufficient to prevent fatal defects in ARO and may prevent complications of ARO unresponsive to conventional bone marrow transplantation. The presence of defective cells is not a barrier to the rescue of the phenotype by donor HSC.

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