The ploidy conveyor of mature hepatocytes as a source of genetic variation.
Mononucleated and binucleated polyploid hepatocytes (4n, 8n, 16n and higher) are found in all mammalian species, but the functional significance of this conserved phenomenon remains unknown. Polyploidization occurs through failed cytokinesis, begins at weaning in rodents and increases with age. Previously, we demonstrated that the opposite event, ploidy reversal, also occurs in polyploid hepatocytes generated by artificial cell fusion. This raised the possibility that somatic 'reductive mitoses' can also happen in normal hepatocytes. Here we show that multipolar mitotic spindles form frequently in mouse polyploid hepatocytes and can result in one-step ploidy reversal to generate offspring with halved chromosome content. Proliferating hepatocytes produce a highly diverse population of daughter cells with multiple numerical chromosome imbalances as well as uniparental origins. Our findings support a dynamic model of hepatocyte polyploidization, ploidy reversal and aneuploidy, a phenomenon that we term the 'ploidy conveyor'. We propose that this mechanism evolved to generate genetic diversity and permits adaptation of hepatocytes to xenobiotic or nutritional injury.
Duncan
Andrew W
AW
Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon 97239, USA. duncanan@ohsu.edu
Taylor
Matthew H
MH
Hickey
Raymond D
RD
Hanlon Newell
Amy E
AE
Lenzi
Michelle L
ML
Olson
Susan B
SB
Finegold
Milton J
MJ
Grompe
Markus
M
D000222:Adaptation, Physiological; D000782:Aneuploidy; D000818:Animals; D020090:Chromosome Segregation; D005434:Flow Cytometry; D014644:Genetic Variation; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008297:Male; D051379:Mice; D008938:Mitosis; D008957:Models, Genetic; D011123:Polyploidy; D008941:Spindle Apparatus / Q000378:metabolism