Lung‐specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation

Abstract

ABSTRACT Cell fusion is one mechanism by which bone marrow‐derived cells (BMDCs) take on the gene expression pattern of nonhematopoietic cells. This process occurs in a number of organs with posten‐graftment injury but has never been found in the lung. We performed bone marrow (BM) transplant in a murine model of lung inflammation to test whether transplanted BMDCs develop lung‐specific gene expression by fusing with diseased pneumocytes. Mice lacking the lung‐specific protein surfactant protein C (Sp‐C) were lethally irradiated, transplanted with sex mismatched wild‐type marrow, and sacrificed 6 months later. Nineteen/38 recipients exhibited Sp‐C mRNA (RT‐PCR) and/or protein (mean 0.95±1.18 Sp‐C+ cells per 1000 type II pneumocytes by confo‐cal microscopy). In male recipients of female BM, 65% of Sp‐C + cells contained the Y chromosome, indicating their origin from fusion. Only 28% of Sp‐C+ cells in female recipients of male BMDCs contained the Y chromosome, suggesting that 72% of Sp‐C‐expressing cells lost the Y chromosome. In the setting of post‐transplant inflammation, pneumocyte‐specific reprogramming of transplanted BMDCs predominantly derives from heterokaryon formation. This process does not reverse inflammation caused by Sp‐C deficiency;nevertheless, further investigation may identify phenotypes benefiting from such an approach.—Herzog, E. L., Van Arnam, J., Hu, B., Zhang, J., Chen, Q., Haberman, A. M., Krause, D. S. Lung‐specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation. FASEB J. 21, 2592–2601 (2007)