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Fate and Effects of Adult Bone Marrow Cells in Lungs of Normoxic and Hyperoxic Newborn Mice

Departments of ¹ Pathology and ² Pediatrics, Women and Infants Hospital; the ³ Division of Hematology and Oncology, and the ⁴ Division of Surgical Research, Rhode Island Hospital, Providence, Rhode Island; and Departments of ⁵ Pathology and Laboratory Medicine, ⁶ Pediatrics, and ⁷ Surgery, the Warren Alpert Medical School of Brown University, Providence, Rhode Island

Correspondence and requests for reprints should be addressed to Monique E. De Paepe, M.D., Women and Infants Hospital, Dept. of Pathology, 101 Dudley Street, Providence, RI 02905. E-mail: mdepaepe{at}wihri.org

Cell-based therapy in adult lung injury models is associated with highly variable donor cell engraftment and epithelial reconstitution. The role of marrow-derived cell therapy in neonatal lung injury is largely unknown. In this study, we determined the fate and effects of adult bone marrow cells in a model of neonatal lung injury. Wild-type mice placed in a normoxic or hyperoxic (95% O₂) environment received bone marrow cells from animals expressing green fluorescent protein (GFP) at Postnatal Day (P)5. Controls received vehicle buffer. Lungs were analyzed between Post-Transplantation (TPX) Day 2 and Week 8. The volume of GFP-immunoreactive donor cells, monitored by stereologic volumetry, remained constant between Post-TPX Weeks 1 and 8 and was similar in normoxic and hyperoxia-exposed recipients. Virtually all marrow-derived cells showed colocalization of GFP and the pan-macrophage marker, F4/80, by double immunofluorescence studies. Epithelial transdifferentiation was not seen. Marrow cell administration had adverse effects on somatic growth and alveolarization in normoxic mice, while no effects were discerned in hyperoxia-exposed recipients. Reexposure of marrow-treated animals to hyperoxia at P66 resulted in significant expansion of the donor-derived macrophage population. In conclusion, intranasal administration of unfractionated bone marrow cells to newborn mice does not achieve epithelial reconstitution, but establishes persistent alveolar macrophage chimerism. The predominantly adverse effects of marrow treatment in newborn lungs are likely due to macrophage-associated paracrine effects. While this model and route of cell therapy may not achieve epithelial reconstitution, the role of selected stem cell populations and/or alternate routes of administration for cell-based therapy in injured newborn lungs deserve further investigation.

Key Words: stem cells • cell therapy • lung injury • newborns • BPD

CLINICAL RELEVANCE The role of marrow-derived cell therapy in neonatal lung injury is largely unknown. We demonstrate that unfractionated adult marrow cells, administered intratracheally to newborn mice, result in a persistent pulmonary macrophage chimerism, without evidence of epithelial or mesenchymal transdifferentiation. Other cell-based therapy models remain to be investigated.