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

Barbara Tondelli, Harry C. Blair, Matteo Guerrini, Kenneth D. Patrene, Barbara Cassani, Paolo Vezzoni, Franco Lucchini

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)727-735
Number of pages9
JournalAmerican Journal of Pathology
Volume174
Issue number3
DOIs
Publication statusPublished - Mar 2009

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Osteopetrosis
Phenotype
Liver
Inborn Genetic Diseases
Hematopoietic Stem Cells
Christianity
Proton Pumps
Mutation
Hematopoietic Stem Cell Transplantation
Osteoclasts
Bone Resorption
Bone Marrow Transplantation
Minerals
Fetus
Pathology
Bone and Bones
Injections
Therapeutics
Growth

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse. / Tondelli, Barbara; Blair, Harry C.; Guerrini, Matteo; Patrene, Kenneth D.; Cassani, Barbara; Vezzoni, Paolo; Lucchini, Franco.

In: American Journal of Pathology, Vol. 174, No. 3, 03.2009, p. 727-735.

Research output: Contribution to journalArticle

Tondelli, Barbara ; Blair, Harry C. ; Guerrini, Matteo ; Patrene, Kenneth D. ; Cassani, Barbara ; Vezzoni, Paolo ; Lucchini, Franco. / Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse. In: American Journal of Pathology. 2009 ; Vol. 174, No. 3. pp. 727-735.
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