TY - JOUR
T1 - Liver from bone marrow in humans
AU - Theise, Neil D.
AU - Nimmakayalu, Manjunath
AU - Gardner, Rebekah
AU - Illei, Peter B.
AU - Morgan, Glyn
AU - Teperman, Lewis
AU - Henegariu, Octavian
AU - Krause, Diane S.
N1 - Funding Information:
Abbreviations: CK-19, cytokeratin 19; FISH, fluorescence in situ hybridization; PBS, phosphate-buffered saline; DAB, diaminiobenzidine; SSC, sodium saline citrate; FITC, fluorescein isothiocyanate; GVHD, graft-versus-host disease. From the Departments of 1Pathology and 4Surgery, New York University, School of Medicine, New York, NY; 2Genetics and5Laboratory Medicine, Yale University, School of Medicine, New Haven, CT; and 3Pathology, Memorial-Sloan Kettering Cancer Center, New York, NY. Received May 16, 2000; accepted May 18, 2000. Supported in part by a Primary Biliary Cirrhosis Seed Grant from the American Liver Foundation and an award from the Mary Lea Johnson Research Institute (N.D.T.) and by a grant from the National Institutes of Health (D.S.K.). Address reprint requests to: Neil Theise, M.D., New York University School of Medicine, Room 461, Department of Pathology, 560 First Avenue, New York, NY 10016. E-mail: Neil.Theise@med.nyu.edu; fax: 212-263-7916. Copyright r 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3201-0003$3.00/0 doi:10.1053/jhep.2000.9124
PY - 2000/7
Y1 - 2000/7
N2 - It has been shown in animal models that hepatocytes and cholangiocytes can derive from bone marrow cells. We have investigated whether such a process occurs in humans. Archival autopsy and biopsy liver specimens were obtained from 2 female recipients of therapeutic bone marrow transplantations with male donors and from 4 male recipients of orthotopic liver transplantations from female donors. Immunohistochemical staining with monoclonal antibody CAM5.2, specific for cytokeratins 8, 18, and 19, gave typical strong staining of hepatocytes, cholangiocytes, and ductular reactions in all tissues, to the exclusion of all nonepithelial cells. Slides were systematically photographed and then restained by fluorescence in situ hybridization (FISH) for X and Y chromosomes. Using morphologic criteria, field-by-field comparison of the fluorescent images with the prior photomicrographs, and persistence of the diaminiobenzidene (DAB) stain through the FISH protease digestion, Y-positive hepatocytes and cholangiocytes could be identified in male control liver tissue and in all study specimens. Cell counts were adjusted based on the number of Y-positive cells in the male control liver to correct for partial sampling of nuclei in the 3-micron thin tissue sections. Adjusted Y-positive hepatocyte and cholangiocyte engraftment ranged from 4% to 43% and from 4% to 38%, respectively, in study specimens, with the peak values being found in a case of fibrosing cholestatic recurrent hepatitis C in one of the liver transplant recipients. We therefore show that in humans, hepatocytes and cholangiocytes can be derived from extrahepatic circulating stem cells, probably of bone marrow origin, and such 'transdifferentiation' can replenish large numbers of hepatic parenchymal cells.
AB - It has been shown in animal models that hepatocytes and cholangiocytes can derive from bone marrow cells. We have investigated whether such a process occurs in humans. Archival autopsy and biopsy liver specimens were obtained from 2 female recipients of therapeutic bone marrow transplantations with male donors and from 4 male recipients of orthotopic liver transplantations from female donors. Immunohistochemical staining with monoclonal antibody CAM5.2, specific for cytokeratins 8, 18, and 19, gave typical strong staining of hepatocytes, cholangiocytes, and ductular reactions in all tissues, to the exclusion of all nonepithelial cells. Slides were systematically photographed and then restained by fluorescence in situ hybridization (FISH) for X and Y chromosomes. Using morphologic criteria, field-by-field comparison of the fluorescent images with the prior photomicrographs, and persistence of the diaminiobenzidene (DAB) stain through the FISH protease digestion, Y-positive hepatocytes and cholangiocytes could be identified in male control liver tissue and in all study specimens. Cell counts were adjusted based on the number of Y-positive cells in the male control liver to correct for partial sampling of nuclei in the 3-micron thin tissue sections. Adjusted Y-positive hepatocyte and cholangiocyte engraftment ranged from 4% to 43% and from 4% to 38%, respectively, in study specimens, with the peak values being found in a case of fibrosing cholestatic recurrent hepatitis C in one of the liver transplant recipients. We therefore show that in humans, hepatocytes and cholangiocytes can be derived from extrahepatic circulating stem cells, probably of bone marrow origin, and such 'transdifferentiation' can replenish large numbers of hepatic parenchymal cells.
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U2 - 10.1053/jhep.2000.9124
DO - 10.1053/jhep.2000.9124
M3 - Article
C2 - 10869283
AN - SCOPUS:0034235784
SN - 0270-9139
VL - 32
SP - 11
EP - 16
JO - Hepatology
JF - Hepatology
IS - 1
ER -