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

Erica L. Herzog^*,1, John Van Arnam, Buqu Hu, Jason Zhang, Qingsheng Chen^*, Ann M. Haberman and Diane S. Krause

Departments of
^* Internal Medicine,

Laboratory Medicine, and

Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

¹Correspondence: Yale University School of Medicine, Internal Medicine-Pulmonary and Critical Care Division, 333 Cedar St., TAC 441-S, New Haven CT 06511, USA. E-mail: erica.herzog{at}yale.edu

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 postengraftment 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 confocal 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.

Key Words: plasticity • fusion

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