Rescue of ATPa3-deficient murine malignant osteopetrosis by hematopoietic stem cell transplantation in utero.
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.
Frattini
Annalisa
A
Human Genome Department, Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, 20090 Segrate, Milan, Italy.
Blair
Harry C
HC
Sacco
Maria Grazia
MG
Cerisoli
Francesco
F
Faggioli
Francesca
F
Catò
Enrica Mira
EM
Pangrazio
Alessandra
A
Musio
Antonio
A
Rucci
Francesca
F
Sobacchi
Cristina
C
Sharrow
Allison C
AC
Kalla
Sara E
SE
Bruzzone
Maria Grazia
MG
Colombo
Roberto
R
Magli
Maria Cristina
MC
Vezzoni
Paolo
P
Villa
Anna
A
D000818:Animals; D001857:Bone Matrix / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D046128:Fetal Therapies / Q000379:methods*; D049452:Green Fluorescent Proteins; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism*; D010022:Osteopetrosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy*; D011247:Pregnancy; D011859:Radiography; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
D049452:Green Fluorescent Proteins; D025262:Vacuolar Proton-Translocating ATPases