Abstract
The replicative capacity of cultured human fibroblasts is discussed in relation to three areas, diabetes mellitus, expression of HL-A antigens, and interactions with polymerizing fibrin. The replicative capacity of cells is diminished in diabetes mellitus and certain related disorders such as progeria and Werner’s syndrome, all of which feature accelerated aging. Expression of HL-A antigens is reduced in progeria fibroblasts compared to normal cultures at corresponding stages of passage. Normal cells show more subtle alteration during aging in vitro probably related to clonal heterogeneity and/or selection within mass cultures. Early-passage fibroblasts interact rapidly with polymerizing fibrin to form a mature clot which is then retracted by a process dependent on cellular integrity and active metabolism. Late-passage cultures are less active in both parameters as are fibroblasts from a subject with progeria. These observations, in total, may relate to altered self-recognition and certain autoimmune concomitants of aging in vivo. They may also help to explain impaired wound healing and increased predisposition to atherothrombosis in aging and diabetic individuals. This system of cultured human fibroblasts should serve as an excellent model to investigate the cellular and molecular basis of diabetes mellitus, aging and related pathology.—Goldstein, S., S. Niewiarowski and D. P. Singal. Pathological implications of cell aging in vitro. Federation Proc. 34: 56–63, 1975.
From Session III, Finite versus infinite proliferative and functional capacities of cells, of the FASEB Conference on Biology of Development and Aging, presented at the 58th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, N. J., April 10, 1974.
Supported by grants from the Medical Research Council of Canada, the Canadian Diabetic Association Foundation Fund, and Hoechst Pharmaceuticals Limited of Canada and the U.S. during the tenure of a Medical Research Council Scholarship (S.G.).
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Abbreviations
- MPD:
-
mean population doublings
References
Adman, R., and D. A. Pious: Isoantigenic variants: isolation from human diploid cells in culture. Science 168: 370, 1970.
Amos, D. B., I. Cohen and W. J. Klein: Mechanisms of immunologic enhancement. Transplantation Proc. 2: 68, 1970.
Andres, R., T. Pozefsky, S. Swerdloff, et al.: Effect of aging on carbohydrate metabolism, early diabetes. In: Advances in Metabolic Disorders, Suppl. 1, edited by R. A. Camerini-Davalos and H. S. Cole New York: Academic, 1970, p. 349.
Astrup, T.: Blood coagulation and fibrinolysis in tissue culture and tissue repair. Biochem. Pharmacol. Suppl. 241, 1968.
Atkins, L.: Progeria: report of a case with post-mortem findings. New Engl. J. Med. 250: 1065, 1954.
Bernoco, D., S. Cullen, G. Scudeller, G. Trinchieri and R. Ceppellini: HL-A molecules at the cell surface. In: Histocompatibility Testing, edited by J. Dausset and J. Colombani. Copenhagen: Munksgaard, 1972, p. 527.
Brautbar, C., R. Payne and L. Hayflick: Fate of HL-A antigens in aging cultured human diploid cell strains. Exptl. Cell Res. 75: 31, 1972.
Brautbar, C., M. A. Pellegrino, S. Ferrone, R. A. Reisfeld, R. Payne and L. Hayflick: Fate of HL-A antigens in aging cultured human diploid cell strains. Exptl. Cell Res. 78: 367, 1973.
Cooper, J. T., and S. Goldstein. De novo synthesis of lipids and incorporation of oleic acid into cultured human fibroblasts from diabetics and nor-mals. Atherosclerosis 20: 41, 1974.
Cullen, S. E., D. Bernoco, A. O. Carbonara, H. Jaeot-Guillarmod, G. Trinchieri and R. Ceppellini: Fate of HL-A antigens and antibodies at the lymphocyte surface. Transplantation Proc. 5: 1835, 1973.
Danes, B. S.: Progeria: a cell culture study on aging. J. Clin. Intest. 50: 2000, 1971.
Epstein, C. J., G. M. Martin, A. S. Schultz and A. G. Motulsky: Werner’s syndrome. A review of its symptomatology, natural history, pathology features, genetics and relationship to the aging process. Medicine 45: 177, 1966.
Ganguly, P.: Binding of thrombin to human platelets. Nature 247: 306, 1974.
Gauldie, J., S. C. Bhandari and D. P. Singal: Non-involvement of carbohydrate in the HL-A antigenic site. Federation Proc. 33: 719, 1974.
Gavin, J. R., JR., J. Roth, D. M. Neville, JR., P. Meyts and D. N. Buell: Insulin-dependent regulation of insulin receptors concentrations: a direct demonstration in cell culture. Proc. Natl. Acad. Sci. U.S. 71: 84, 1974.
Goldstein, S.: Lifespan of cultured cells in progeria. Lancet 1: 424, 1969.
Goldstein, S.: On the pathogenesis of diabetes mellitus and its relationship to biological aging. Humangenetik 12: 83, 1971.
Goldstein, S.: The biology of aging. New Engl. J. Med. 285: 1120, 1971.
Goldstein, S., and R. Haslam: Cyclic AMP levels in young and senescent fibroblasts: effects of epinephrine and prostaglandin E,. J. Clin. Invest. 52: 35a, 1973.
Goldstein, S., J. W. Littlefield and J. S. Soeldner: Diabetes mellitus and aging: diminished plating efficiency of cultured human fibroblasts. Proc. Natl. Acad. Sci. U.S. 64: 155, 1969.
Goldstein, S., E. J. Moerman, J. S. Soeldner, R. E. Gleason and D. M. Barnett: Diabetes mellitus and pre-diabetes: decreased replicative capacity of cultured fibroblasts. J. Clin. Invest. 53: 27a, 1974.
Goldstein, S., and D. P. Singal: Loss of reactivity of HL-A antigens in clonal populations of cultured human fibroblasts during aging in vitro. Exptl. Cell Res. 75: 278, 1972.
Goldstein, S., and D. P. Singal: Senescence of cultured human fibroblasts: mitotic versus metabolic time. Exptl. Cell Res. In a press.
Goldstein, S., and D. P. Singal: Alteration of fibroblast gene products in vitro from a subject with Werner’s syndrome. Nature in a press.
Graham, A. F., J. S. Schroeder, R. B. Griepp, E. B. Stinson and D. C. Harrison: Does cardiac transplantation significantly prolong life and improve its quality? Circulation 48: Suppl. III, 116, 1973.
Grothaus, E. A., M. W. Flye, E. Yunis and D. B. Amos: Human lymphocyte antigen reactivity modified by neuraminidase. Science 173: 542, 1971.
Haimovici, H: Peripheral arterial disease in diabetes mellitus. In: Diabetes Mellitus: Theory and Practice, edited by M. Ellenberg and H. Rifkin. New York: McGraw-Hill, 1970.
Hayflick, L: The limited in vitro lifetime of human diploid cell strains. Exptl. Cell Res. 37: 614, 1965.
Holliday, R., and G. M. Tarrant: Altered enzymes in aging human fibroblasts. Nature 238: 26, 1972.
Holliday, R., J. S. Porterfield and D. D. Gibbs: Werner’s syndrome: premature aging in vivo and in vitro. 248: 762, 1974.
Klein, G., S. Friberg, JR. and H. Harris: Two kinds of antigen suppression in tumor cells revealed by cell fusion. Exptl. Med. 135: 839, 1972.
Lewis, M., and G. M. Tarrant: Error theory and ageing in human diploid fibroblasts. Nature 239: 316, 1972.
Manganiello, V., J. Breslow and M. Vaughan: An effect of dexamethasone on the cyclic AMP content of human fibroblasts stimulated by catecholamines and prostaglandin E,. J. Clin., invest. 51: 60a, 1972.
Mann, D. L., G. N. Rogentine, J. L. Fahey and S. G. Nathenson: Solubilization of human leukocyte membrane isoantigens. Nature 217: 1180, 1968.
Martin, G. M., C. A. Sprague and C. J. Epstein: Replicative lifespan of cultivated human cells. Effects of donor’s age, tissue, and genotype. Lab. Invest. 23: 86, 1970.
Mckusick, V. A.: Mendelian Inheritance in Man. Baltimore: Johns Hopkins Press, 1968.
Menkes, J. H., and N. Stein: Fibroblast cultures in Huntington’s disease. New Engl. J. Med. 288: 856, 1973.
Miggiano, V. C., M. Nabholz and W. F. Bodmer: Detection of HL-A and other antigens on fibroblast micro monolayers using a fluorochromatic cytotoxicity assay. In: Histocompatibility Testing, edited by P. I. Terasaki. Copenhagen: Munksgaard. 1970, p. 623.
Mittal, K. K., M. R. Mickey, D. P. Singal and P. I. Terasaki: Serotyping for homotransplantation XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6: 913, 1968.
Miyajima, T., A. A. Hirata and P. I. Terasaki: Escape from sensitization to HL-A antibodies. Tissue Antigens 2: 64, 1972.
Niewiarowski, S., and S. Gold-Stein: Interaction of cultured human fibroblasts with fibrin: modification by drugs and aging in vitro. J. Lab. Clin. Med. 82: 605, 1973.
Niewiarowski, S., E. Regoeczi and J. F. Mustard: Platelet interaction with fibrinogen and fibrin: comparison of the interaction of platelets with that of fibroblasts, leukocytes, and erythrocytes. Ann. N.Y. Acad. Sci. 201: 72, 1972.
Niewiarowski, S., E. Regoeczi and J. F. Mustard: Adhesion of fibro-blasts to polymerizing fibrin and retraction of fibrin induced by fibroblasts. Proc. Soc. Exptl. Biol. Med. 140: 199, 1972.
Niewiarowski, S., E. Regoeczi, G. J. Stewart et al: Platelet interaction with polymerizing fibrin. J. Clin. Invest. 51: 685, 1972.
Podolsky, S., N. A. Leopold and D. S. Sax: Increased frequency of diabetes mellitus in patients with Huntington’s chorea. Lancet 1. 1356, 1972.
Reichel, W., and R. Garciabunuel: Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment. Am. J. Clin. Pathol. 53: 243, 1970.
Reisfeld, R. A., M. A. Pellegrino, S. Ferrone and B. D. Kahau: Chemical and molecular nature of HL-A antigens. Transplantation Proc. 5: 447, 1973.
Renold, A. D., W. Stauffacher and G. F. Cahill: Diabetes mellitus. In: The Metabolic Basis of Inherited Disease, edited by J. B. Stanbury, J. B. Wyngaarden and D. S. Fredrickson. New York: McGraw-Hill, 1972, p. 83.
Rimoin, D. L., and N. Schimke: Genetic Disorders of the Endocrine Glands. St. Louis: Mosby, 1971, p. 163.
Sanderson, A. R.: HL-A substances from human spleens. Nature 220: 192, 1968.
Sasportes, M., C. Dehay and M. Fellous: Variations of the expression of HL-A antigens on human diploid fibroblasts in vitro. Nature 233: 332, 1971.
Schneider, E. L., and C. J. Epstein: Replication rate and lifespan of. cultured fibroblasts in Down’s syndrome. Proc. Soc. Exptl. Biol. Med. 141: 1092, 1972.
Segal, D. J., and E. E. Mccoy: Studies on Down’s syndrome in tissue culture. I. Growth rate and protein contents of fibroblast cultures. J. Cellular Physiol. 83: 85, 1974.
Singal, D. P: Tissue typing and organ transplantation. Can. J. Surg. 15: 295, 1972.
Singal, D. P., and S. Goldstein: Absence of detectable HL-A antigens on cultured fibroblasts in progeria. J. Clin. Invest. 52: 2259, 1973.
Singal, D. P., V. R. Villanueva and N. Naipaul: Effect of phytohemagglutinin on expression of human histocompatibility antigens. J. Immunol. 112: 852, 1974.
Swim, H. E., and R. F. Parker: Culture characteristics of human fibroblasts propagated serially. Am. J. Hyg. 66: 235, 1957.
Tao, L. C., E. Stecker and H. A. Gardner: Werner’s syndrome and acute myeloid leukemia. Can. Med. Assoc. J. 105: 951, 1971.
Taylor, H. E.: Pathology of organ transplantation in man. Pathology Annual7: 1973, 1972.
Thorsby, E., and S. Lie: Antigens on human fibroblasts demonstrated with HL-A antisera and anti-human lymphocytic sera. Vox Sanguinis 15: 44, 1968.
Ungar, B., A. E. Stocks, F. I. R. Martin, S. Whittingham and I. R. Mackay: Intrinsic factor antibody, parietal-cell antibody, and latent pernicious anemia in diabetes mellitus. Lancet 2: 415, 1968.
Villee, D. B., G. Nichols, JR. and N. B. Talbot: Metabolic studies in two boys with classical progeria. Pediatrics 43: 207, 1969.
Vracko, R.: Basal lamina layering in diabetes mellitus. Evidence for accelerated rate of cell death and cell regeneration. Diabetes 23: 94, 1974.
Vracko, R., and E. P. Benditt: Replicative life-span of diabetic fibroblasts. Federation Proc. 33: 607, 1974.
Walford, R. L.: The Immunologic Theory of Aging. Copenhagen: Munksgaard, 1969.
Walford, R. L.: Immunologic theory of aging: current status. Federation Proc. 33: 2020, 1974.
Zacharksi, L. R., and O. R. Mcintyre: Membrane-mediated synthesis of tissue factor (thromboplastin in cultured fibroblasts. Blood 41: 679, 1973.
Zacharski, L. R., and O. R. Mcintyre: Tisue factor (thromboplastin, Factor-III) synthesis by cultured cells. J. Med. Exptl. Clin. 4: 118, 1973.
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Goldstein, S., Niewiarowski, S., Singal, D.P. (1975). Pathological implications of cell aging in vitro. In: Thorbecke, G.J. (eds) Biology of Aging and Development. Faseb Monographs, vol 3. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-2631-1_12
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