Abstract:
:Loss-of-function mutation in the heme oxygenase 1 (Hmox1) gene causes a rare and lethal disease in children, characterized by severe anemia and intravascular hemolysis, with damage to endothelia and kidneys. Previously, we found that macrophages engaged in recycling of red cells were depleted from the tissues of Hmox1(-/-) mice, which resulted in intravascular hemolysis and severe damage to the endothelial system, kidneys, and other organs. Here, we report that subablative bone marrow transplantation (BMT) has a curative effect for disease in Hmox1(-/-) animals as a result of restoration of heme recycling by repopulation of the tissues with wild-type macrophages. Although engraftment was transient, BMT reversed anemia, normalized blood chemistries and iron metabolism parameters, and prevented renal damage. The largest proportion of donor-derived cells was observed in the livers of transplanted animals. These cells, identified as Kupffer cells with high levels of Hmox1 expression, persisted months after transient engraftment of the donor bone marrow and were responsible for the full restoration of heme-recycling ability in Hmox1(-/-) mice and reversing Hmox1-deficient phenotype. Our findings suggest that BMT or the development of specific cell therapies to repopulate patients' tissues with wild-type or reengineered macrophages represent promising approaches for HMOX1 deficiency treatment in humans.
journal_name
Bloodjournal_title
Bloodauthors
Kovtunovych G,Ghosh MC,Ollivierre W,Weitzel RP,Eckhaus MA,Tisdale JF,Yachie A,Rouault TAdoi
10.1182/blood-2014-02-554162subject
Has Abstractpub_date
2014-08-28 00:00:00pages
1522-30issue
9eissn
0006-4971issn
1528-0020pii
blood-2014-02-554162journal_volume
124pub_type
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