Lung-specific nuclear reprogramming is accompanied by heterokaryon formation and Y chromosome loss following bone marrow transplantation and secondary inflammation.
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
Erica L
EL
Yale University School of Medicine, Internal Medicine-Pulmonary and Critical Care Division, 333 Cedar St., TAC 441-S, New Haven CT 06511, USA. erica.herzog@yale.edu
Van Arnam
John
J
Hu
Buqu
B
Zhang
Jason
J
Chen
Qingsheng
Q
Haberman
Ann M
AM
Krause
Diane S
DS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000473:pathology / Q000502:physiology*; D002872:Chromosome Deletion; D005260:Female; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency*; D011183:Postoperative Complications / Q000503:physiopathology; D037721:Pulmonary Surfactant-Associated Protein C; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation; D014998:Y Chromosome
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse