Do cells fuse in vivo?

Abstract

Spontaneous or virally induced fusion between somatic cells can occur in vitro (1, 2, 3) and has provided a new and important tool for analysis of gene expression. In some instances, nuclear "mating" or hybridization is achieved; in others, the nuclei remain separate within the fusion product and a heterokaryon is formed. Under appropriate culture conditions, fusion can even take place between cells of unrelated species (3). Many ingenious experimental systems are being devised in this rapidly developing area of investigation and the differences between donor cells have been variously chosen so as to furnish models for normal differentiation or for the etiology of disease states. In a multicellular organism such as a mammal, do cells also fuse in vivo? If so, what are the consequences? Does cell hybridization occur in hematopoietic tissue, as some studies (4, 5, 6) have suggested? Are syncytia (e.g., skeletal muscle) formed by cell fusion? Do polyploidy and binucleation (e.g., in liver) ever arise by means of cell fusion, or only by endoreduplication? Cells in the body may be phagocytosed; does any of their DNA or RNA become incorporated and remain functional in the host cell? Do aneuploid cancer cells sometimes originate from cell "matings", and is this a significant factor in conversion of cells from normalcy to malignancy? In order to answer these and related questions in vivo, unequivocal genetic markers are required to distinguish the putative cellular contributors in a way that would be comparable to the tests of fusion in vitro. Moreover, it would be desirable to have the genotypically dissimilar cells associated throughout development of the intact organism, to learn what role any cell hybridization or heterokaryonization might play in differentiation, aging, or disease, as these processes ordinarily occur in situ. The allophenic mouse is a laboratory creation that fulfills these ground rules (7, 8, 9, 10, 11, 12, 13). As the name suggests, each animal contains phenotypically different subpopulations of cells within any or all tissues as a result of genotypic cellular differences. Allophenic mice in a sense owe their existence to the many innovations of modern tissue culture methodology, since each individual is produced by artificially aggregating very early embryo cells of different genotypes into one composite embryo in vitro. The aggregate, after a short culture period, is then returned to a uterine environment. The projected purpose in thus establishing genetic mosaicism throughout life was to allow complex developmental events at supracellular levels of organization to become decipherable. Owen's discovery (14) of two genetic populations of erythrocytes in dizygotic cattle co-twins with a shared placental circulation suggested to me that genetic mosaicism in all functional systems might be a useful experimental device for examining many sorts of problems in mammals. The embryologists of the nineteenth century had shown that blastomeres could be recombined in invertebrate or amphibian embryos. If cells of diverse constitution could be introduced into an early mammalian embryo, their eventual inclusion in all organs and tissues might be expected. The laboratory mouse, with its profus1 These investigations were supported by U.S.P.H.S. grants No. HD 01646 (formerly CA 05201) and CA 06927, and by an appropriation from the Commonwealth of Pennsylvania.