Autosomal recessive osteopetrosis (ARO) is a group of genetic disorders that involve defects that preclude the normal function of osteoclasts, which differentiate from hematopoietic precursors. In half of human cases, ARO is the result of mutations in the TCIRG1 gene, which codes for a subunit of the vacuolar proton pump that plays a fundamental role in the acidification of the cell-bone interface. Functional mutations of this pump severely impair the resorption of bone mineral. Although postnatal hematopoietic stem cell transplantation can partially rescue the hematological phenotype of ARO, other stigmata of the disease, such as secondary neurological and growth defects, are not reversed. For this reason, ARO is a paradigm for genetic diseases that would benefit from effective prenatal treatment. Using the oc/oc mutant mouse, a murine model whose osteopetrotic phenotype closely recapitulates human TCIRG1-dependent ARO, we report that in utero transplantation of adult bone marrow hematopoietic stem cells can correct the ARO phenotype in a limited number of mice. Here we report that in utero injection of allogeneic fetal liver cells, which include hematopoietic stem cells, into oc/oc mouse fetuses at 13.5 days post coitum produces a high level of engraftment, and the oc/oc phenotype is completely rescued in a high percentage of these mice. Therefore, oc/oc pathology appears to be particularly sensitive to this form of early treatment of the ARO genetic disorder.

Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse / B. Tondelli, H.C. Blair, M. Guerrini, K.D. Patrene, B. Cassani, P. Vezzoni, F. Lucchini. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 174:3(2009 Mar 23), pp. 727-735. [10.2353/ajpath.2009.080688]

Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse

M. Guerrini;B. Cassani;
2009

Abstract

Autosomal recessive osteopetrosis (ARO) is a group of genetic disorders that involve defects that preclude the normal function of osteoclasts, which differentiate from hematopoietic precursors. In half of human cases, ARO is the result of mutations in the TCIRG1 gene, which codes for a subunit of the vacuolar proton pump that plays a fundamental role in the acidification of the cell-bone interface. Functional mutations of this pump severely impair the resorption of bone mineral. Although postnatal hematopoietic stem cell transplantation can partially rescue the hematological phenotype of ARO, other stigmata of the disease, such as secondary neurological and growth defects, are not reversed. For this reason, ARO is a paradigm for genetic diseases that would benefit from effective prenatal treatment. Using the oc/oc mutant mouse, a murine model whose osteopetrotic phenotype closely recapitulates human TCIRG1-dependent ARO, we report that in utero transplantation of adult bone marrow hematopoietic stem cells can correct the ARO phenotype in a limited number of mice. Here we report that in utero injection of allogeneic fetal liver cells, which include hematopoietic stem cells, into oc/oc mouse fetuses at 13.5 days post coitum produces a high level of engraftment, and the oc/oc phenotype is completely rescued in a high percentage of these mice. Therefore, oc/oc pathology appears to be particularly sensitive to this form of early treatment of the ARO genetic disorder.
Osteopetrosis ; in utero transplantation ; fetal tissue transplantation ; genetics ; Vacuolar Proton-Translocating ATPases;
Settore BIO/17 - Istologia
23-mar-2009
Article (author)
File in questo prodotto:
File Dimensione Formato  
AJP 2009.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 871.25 kB
Formato Adobe PDF
871.25 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/61590
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 18
social impact