Abstract
The delivery of biologically active factors to the developing mammalian embryo by in utero gene transfer has generated considerable interest but limited success. The chorioallantoic placenta is a potential alternative target for providing therapeutic transgenes to the fetus during gestation. We demonstrate that somatic gene transfer to the midgestation rat placenta may be efficiently accomplished in situ through the implantation of a variety of genetically modified cells with different antigenic and growth properties. Ex vivo-modified cells survived and retained transgene expression until term. Proteins secreted from the transplanted cells were detectable within the fetal trunk blood. These studies suggest that gene transfer to the placenta may be a useful tool for answering questions of both embryonic and placental development and providing therapeutic proteins during gestation for amelioration of diseases with onset during embryonic life.
Full Text
The Full Text of this article is available as a PDF (365.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adeniyi-Jones S. C., Ozato K. Transfer of antibodies directed to paternal major histocompatibility class I antigens from pregnant mice to the developing fetus. J Immunol. 1987 Mar 1;138(5):1408–1415. [PubMed] [Google Scholar]
- Bonham L., Palmer T., Miller A. D. Prolonged expression of therapeutic levels of human granulocyte colony-stimulating factor in rats following gene transfer to skeletal muscle. Hum Gene Ther. 1996 Aug 1;7(12):1423–1429. doi: 10.1089/hum.1996.7.12-1423. [DOI] [PubMed] [Google Scholar]
- Civin C. I., Almeida-Porada G., Lee M. J., Olweus J., Terstappen L. W., Zanjani E. D. Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo. Blood. 1996 Dec 1;88(11):4102–4109. [PubMed] [Google Scholar]
- Clapp D. W., Dumenco L. L., Hatzoglou M., Gerson S. L. Fetal liver hematopoietic stem cells as a target for in utero retroviral gene transfer. Blood. 1991 Aug 15;78(4):1132–1139. [PubMed] [Google Scholar]
- Coutelle C., Douar A. M., Colledge W. H., Froster U. The challenge of fetal gene therapy. Nat Med. 1995 Sep;1(9):864–866. doi: 10.1038/nm0995-864. [DOI] [PubMed] [Google Scholar]
- Cross J. C., Werb Z., Fisher S. J. Implantation and the placenta: key pieces of the development puzzle. Science. 1994 Dec 2;266(5190):1508–1518. doi: 10.1126/science.7985020. [DOI] [PubMed] [Google Scholar]
- Faria T. N., Soares M. J. Trophoblast cell differentiation: establishment, characterization, and modulation of a rat trophoblast cell line expressing members of the placental prolactin family. Endocrinology. 1991 Dec;129(6):2895–2906. doi: 10.1210/endo-129-6-2895. [DOI] [PubMed] [Google Scholar]
- Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
- Hall C. V., Jacob P. E., Ringold G. M., Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed] [Google Scholar]
- Heartlein M. W., Roman V. A., Jiang J. L., Sellers J. W., Zuliani A. M., Treco D. A., Selden R. F. Long-term production and delivery of human growth hormone in vivo. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10967–10971. doi: 10.1073/pnas.91.23.10967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoshimaru M., Ray J., Sah D. W., Gage F. H. Differentiation of the immortalized adult neuronal progenitor cell line HC2S2 into neurons by regulatable suppression of the v-myc oncogene. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1518–1523. doi: 10.1073/pnas.93.4.1518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jollie W. P. Development, morphology, and function of the yolk-sac placenta of laboratory rodents. Teratology. 1990 Apr;41(4):361–381. doi: 10.1002/tera.1420410403. [DOI] [PubMed] [Google Scholar]
- Kantoff P. W., Flake A. W., Eglitis M. A., Scharf S., Bond S., Gilboa E., Erlich H., Harrison M. R., Zanjani E. D., Anderson W. F. In utero gene transfer and expression: a sheep transplantation model. Blood. 1989 Mar;73(4):1066–1073. [PubMed] [Google Scholar]
- Kawaja M. D., Gage F. H. Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J Comp Neurol. 1992 Mar 1;317(1):102–116. doi: 10.1002/cne.903170108. [DOI] [PubMed] [Google Scholar]
- Letterio J. J., Geiser A. G., Kulkarni A. B., Roche N. S., Sporn M. B., Roberts A. B. Maternal rescue of transforming growth factor-beta 1 null mice. Science. 1994 Jun 24;264(5167):1936–1938. doi: 10.1126/science.8009224. [DOI] [PubMed] [Google Scholar]
- McCray P. B., Jr, Armstrong K., Zabner J., Miller D. W., Koretzky G. A., Couture L., Robillard J. E., Smith A. E., Welsh M. J. Adenoviral-mediated gene transfer to fetal pulmonary epithelia in vitro and in vivo. J Clin Invest. 1995 Jun;95(6):2620–2632. doi: 10.1172/JCI117964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pitt B. R., Schwarz M. A., Pilewski J. M., Nakayama D., Mueller G. M., Robbins P. D., Watkins S. A., Albertine K. H., Bland R. D. Retrovirus-mediated gene transfer in lungs of living fetal sheep. Gene Ther. 1995 Jul;2(5):344–350. [PubMed] [Google Scholar]
- Popliker M., Shatz A., Avivi A., Ullrich A., Schlessinger J., Webb C. G. Onset of endogenous synthesis of epidermal growth factor in neonatal mice. Dev Biol. 1987 Jan;119(1):38–44. doi: 10.1016/0012-1606(87)90204-1. [DOI] [PubMed] [Google Scholar]
- Sekhon H. S., Larson J. E. In utero gene transfer into the pulmonary epithelium. Nat Med. 1995 Nov;1(11):1201–1203. doi: 10.1038/nm1195-1201. [DOI] [PubMed] [Google Scholar]
- Senut M. C., Tuszynski M. H., Raymon H. K., Suhr S. T., Liou N. H., Jones K. R., Reichardt L. F., Gage F. H. Regional differences in responsiveness of adult CNS axons to grafts of cells expressing human neurotrophin 3. Exp Neurol. 1995 Sep;135(1):36–55. doi: 10.1006/exnr.1995.1064. [DOI] [PubMed] [Google Scholar]
- Shimohama S., Rosenberg M. B., Fagan A. M., Wolff J. A., Short M. P., Breakefield X. O., Friedmann T., Gage F. H. Grafting genetically modified cells into the rat brain: characteristics of E. coli beta-galactosidase as a reporter gene. Brain Res Mol Brain Res. 1989 Jun;5(4):271–278. doi: 10.1016/0169-328x(89)90061-2. [DOI] [PubMed] [Google Scholar]
- Snider W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 1994 Jun 3;77(5):627–638. doi: 10.1016/0092-8674(94)90048-5. [DOI] [PubMed] [Google Scholar]
- Soares M. J., Chapman B. M., Rasmussen C. A., Dai G., Kamei T., Orwig K. E. Differentiation of trophoblast endocrine cells. Placenta. 1996 Jul-Aug;17(5-6):277–289. doi: 10.1016/s0143-4004(96)90051-x. [DOI] [PubMed] [Google Scholar]
- Story C. M., Mikulska J. E., Simister N. E. A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus. J Exp Med. 1994 Dec 1;180(6):2377–2381. doi: 10.1084/jem.180.6.2377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsukamoto M., Ochiya T., Yoshida S., Sugimura T., Terada M. Gene transfer and expression in progeny after intravenous DNA injection into pregnant mice. Nat Genet. 1995 Mar;9(3):243–248. doi: 10.1038/ng0395-243. [DOI] [PubMed] [Google Scholar]
- Vincent M. C., Trapnell B. C., Baughman R. P., Wert S. E., Whitsett J. A., Iwamoto H. S. Adenovirus-mediated gene transfer to the respiratory tract of fetal sheep in utero. Hum Gene Ther. 1995 Aug;6(8):1019–1028. doi: 10.1089/hum.1995.6.8-1019. [DOI] [PubMed] [Google Scholar]