Plastic and Reconstructive Surgery pp 593-603 | Cite as
Cellular Therapy Models: Ex Vivo Chimera Model by Cell Fusion
Abstract
Cell fusion is a ubiquitous process fundamental to physiological and pathophysiological events common to multiple cell types and species. Performed ex vivo, cell fusion is a versatile research and therapeutic tool for gene mapping, antibody production, discovering new mechanisms in biological processes, inventing alternative therapies for cell reprogramming, restoring organ function, and creating cellular therapeutics for cancer treatment.
Cell fusion can be successfully applied by creating cellular therapeutic of donor – recipient chimeric cell (DRCC) in the field of solid organ and vascularized composite allotransplantation (VCA). Immunomodulatory DRCC therapy has the potential to reduce or even eliminate the need for toxic, life-long immunosuppression and to prevent both acute and chronic rejection. This innovative VCA treatment is a combination of ex vivo created chimeric cell therapy with a short-term selective protocol of monoclonal antibody and Cyclosporine A. The utilization of short-term immunosuppressive protocol will provide the opportunity for chimeric cell engraftment, proliferation, and re-education of recipient’s immune system resulting in prolongation of allograft survival. The use of chimeric cells, as a supportive treatment for VCA, would improve the conditions of severely disfigured patients by offering safe alternative approach and providing better functional and aesthetic results compared to standard reconstructive procedures.
This chapter summarizes the phenomenon, current discoveries, and advancements in the field of cell fusion, as well as introduces ex vivo creation of chimeric cells and presents potential benefits of chimeric cell-based protocols. Successful application of chimeric cell protocol in VCA experimental models will advance the field of reconstructive transplantation towards clinical trials.
Keywords
Donor-recipient chimeric cells Ex vivo cell fusion Cellular therapy Fused cells Bone marrow Vascularized composite allotransplantation ChimerismReferences
- 1.Schwann T. Mikroskopische Untersuchungen uber die Ubereinstimmung in der Struktur und dem Wachsten der Thiere und Pflanzen. Berlin: Saunderschen Buchhandlung; 1839.Google Scholar
- 2.Dittmar T, Zanker KS. Cell fusion in health and disease. Volume II: cell fusion in disease. Introduction. Adv Exp Med Biol. 2011;714:1–3.PubMedGoogle Scholar
- 3.Chen EH, Olson EN. Unveiling the mechanisms of cell-cell fusion. Science. 2005;308(5720):369–73.PubMedCrossRefGoogle Scholar
- 4.Zhou X, Platt JL. Molecular and cellular mechanisms of mammalian cell fusion. Adv Exp Med Biol. 2011;713:33–64.PubMedCrossRefGoogle Scholar
- 5.Ramakrishnan M, Mathur SR, Mukhopadhyay A. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma. Cancer Res. 2013;73(17):5360–70.PubMedCrossRefGoogle Scholar
- 6.Silk AD, et al. Fusion between hematopoietic and epithelial cells in adult human intestine. PLoS ONE. 2013;8(1):e55572.PubMedCentralPubMedCrossRefGoogle Scholar
- 7.Barski G, Sorieul S, Cornefert F. “Hybrid” type cells in combined cultures of two different mammalian cell strains. J Natl Cancer Inst. 1961;26:1269–91.PubMedGoogle Scholar
- 8.Terada N, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416(6880):542–5.PubMedCrossRefGoogle Scholar
- 9.Ying QL, et al. Changing potency by spontaneous fusion. Nature. 2002;416(6880):545–8.PubMedCrossRefGoogle Scholar
- 10.Dittmar T, et al. Characterization of hybrid cells derived from spontaneous fusion events between breast epithelial cells exhibiting stem-like characteristics and breast cancer cells. Clin Exp Metastasis. 2011;28(1):75–90.PubMedCrossRefGoogle Scholar
- 11.Lu X, Kang Y. Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc Natl Acad Sci U S A. 2009;106(23):9385–90.PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7.PubMedCrossRefGoogle Scholar
- 13.Miller FR, Mohamed AN, McEachern D. Production of a more aggressive tumor cell variant by spontaneous fusion of two mouse tumor subpopulations. Cancer Res. 1989;49(15):4316–21.PubMedGoogle Scholar
- 14.Nagler C, et al. Co-cultivation of murine BMDCs with 67NR mouse mammary carcinoma cells give rise to highly drug resistant cells. Cancer Cell Int. 2011;11(1):21.PubMedCentralPubMedCrossRefGoogle Scholar
- 15.LaBarge MA, Blau HM. Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell. 2002;111(4):589–601.PubMedCrossRefGoogle Scholar
- 16.Alvarez-Dolado M, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425(6961):968–73.PubMedCrossRefGoogle Scholar
- 17.Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422(6934):901–4.PubMedCrossRefGoogle Scholar
- 18.Wang X, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422(6934):897–901.PubMedCrossRefGoogle Scholar
- 19.Weimann JM, et al. Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A. 2003;100(4):2088–93.PubMedCentralPubMedCrossRefGoogle Scholar
- 20.Nygren JM, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 2004;10(5):494–501.PubMedCrossRefGoogle Scholar
- 21.Rizvi AZ, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci U S A. 2006;103(16):6321–5.PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Johansson CB, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol. 2008;10(5):575–83.PubMedCentralPubMedCrossRefGoogle Scholar
- 23.Camargo FD, Finegold M, Goodell MA. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest. 2004;113(9):1266–70.PubMedCentralPubMedCrossRefGoogle Scholar
- 24.Willenbring H, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med. 2004;10(7):744–8.PubMedCrossRefGoogle Scholar
- 25.Powell AE, et al. Fusion between Intestinal epithelial cells and macrophages in a cancer context results in nuclear reprogramming. Cancer Res. 2011;71(4):1497–505.PubMedCentralPubMedCrossRefGoogle Scholar
- 26.Dales S, Siminovitch L. The development of vaccinia virus in Earle’s L strain cells as examined by electron microscopy. J Biophys Biochem Cytol. 1961;10:475–503.PubMedCentralPubMedCrossRefGoogle Scholar
- 27.Okada Y, Hosokawa Y. Isolation of a new variant of HVJ showing low cell fusion activity. Biken J. 1961;4:217–20.PubMedGoogle Scholar
- 28.Okada Y. Analysis of giant polynuclear cell formation caused by HVJ virus from Ehrlich’s ascites tumor cells. III. Relationship between cell condition and fusion reaction or cell degeneration reaction. Exp Cell Res. 1962;26:119–28.PubMedCrossRefGoogle Scholar
- 29.Yeheskely-Hayon D, et al. Optically induced cell fusion using bispecific nanoparticles. Small. 2013;9(22):3771–7.PubMedCrossRefGoogle Scholar
- 30.Gottesman A, Milazzo J, Lazebnik Y. V-fusion: a convenient, nontoxic method for cell fusion. Biotechniques. 2010;49(4):747–50.PubMedCrossRefGoogle Scholar
- 31.Golestani R, Pourfathollah AA, Moazzeni SM. Cephalin as an efficient fusogen in hybridoma technology: can it replace poly ethylene glycol? Hybridoma (Larchmt). 2007;26(5):296–301.CrossRefGoogle Scholar
- 32.Cheong SC, et al. Generation of cell hybrids via a fusogenic cell line. J Gene Med. 2006;8(7):919–28.PubMedCrossRefGoogle Scholar
- 33.Pedrazzoli F, et al. Cell fusion in tumor progression: the isolation of cell fusion products by physical methods. Cancer Cell Int. 2011;11:32.PubMedCentralPubMedCrossRefGoogle Scholar
- 34.Norwood TH, Zeigler CJ, Martin GM. Dimethyl sulfoxide enhances polyethylene glycol-mediated somatic cell fusion. Somatic Cell Genet. 1976;2(3):263–70.PubMedCrossRefGoogle Scholar
- 35.Gurtovenko AA, Anwar J. Modulating the structure and properties of cell membranes: the molecular mechanism of action of dimethyl sulfoxide. J Phys Chem B. 2007;111(35):10453–60.PubMedCrossRefGoogle Scholar
- 36.Guo-Parke H, et al. Configuration of electrofusion-derived human insulin-secreting cell line as pseudoislets enhances functionality and therapeutic utility. J Endocrinol. 2012;214(3):257–65.PubMedCrossRefGoogle Scholar
- 37.Schwaber J, Cohen EP. Human x mouse somatic cell hybrid clone secreting immunoglobulins of both parental types. Nature. 1973;244(5416):444–7.PubMedCrossRefGoogle Scholar
- 38.Tesarik J, et al. Chemically and mechanically induced membrane fusion: non-activating methods for nuclear transfer in mature human oocytes. Hum Reprod. 2000;15(5):1149–54.PubMedCrossRefGoogle Scholar
- 39.Bhutani N, et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature. 2010;463(7284):1042–7.PubMedCentralPubMedCrossRefGoogle Scholar
- 40.Duelli DM, et al. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr Biol. 2007;17(5):431–7.PubMedCrossRefGoogle Scholar
- 41.Lu X, Kang Y. Cell fusion hypothesis of the cancer stem cell. Adv Exp Med Biol. 2011;714:129–40.PubMedCrossRefGoogle Scholar
- 42.Blau HM, Blakely BT. Plasticity of cell fate: insights from heterokaryons. Semin Cell Dev Biol. 1999;10(3):267–72.PubMedCrossRefGoogle Scholar
- 43.Duelli DM, Lazebnik YA. Primary cells suppress oncogene-dependent apoptosis. Nat Cell Biol. 2000;2(11):859–62.PubMedCrossRefGoogle Scholar
- 44.Malka F, et al. The mitochondria of cultured mammalian cells: I. Analysis by immunofluorescence microscopy, histochemistry, subcellular fractionation, and cell fusion. Methods Mol Biol. 2007;372:3–16.PubMedCrossRefGoogle Scholar
- 45.Rao PN, Johnson RT. Mammalian cell fusion. IV. Regulation of chromosome formation from interphase nuclei by various chemical compounds. J Cell Physiol. 1971;78(2):217–23.PubMedCrossRefGoogle Scholar
- 46.Park SU, et al. Effects of chromosomal polyploidy on survival of colon cancer cells. Korean J Gastroenterol. 2011;57(3):150–7.PubMedCrossRefGoogle Scholar
- 47.Walter MA, Goodfellow PN. Irradiation and fusion gene transfer. Mol Biotechnol. 1995;3(2):117–28.PubMedCrossRefGoogle Scholar
- 48.Upender MB, et al. Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells. Cancer Res. 2004;64(19):6941–9.PubMedCrossRefGoogle Scholar
- 49.Waid TH, et al. Treatment of acute cellular rejection with T10B9.1A-31 or OKT3 in renal allograft recipients. Transplantation. 1992;53(1):80–6.PubMedCrossRefGoogle Scholar
- 50.Kovarik J, et al. Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts. Transplantation. 1997;64(12):1701–5.PubMedCrossRefGoogle Scholar
- 51.Koido S, et al. Regulation of tumor immunity by tumor/dendritic cell fusions. Clin Dev Immunol. 2010;2010:516768.PubMedCentralPubMedCrossRefGoogle Scholar
- 52.Weise JB, et al. A dendritic cell based hybrid cell vaccine generated by electrofusion for immunotherapy strategies in HNSCC. Auris Nasus Larynx. 2004;31(2):149–53.PubMedCrossRefGoogle Scholar
- 53.Kanamoto A, Maki T. Chimeric donor cells play an active role in both induction and maintenance phases of transplantation tolerance induced by mixed chimerism. J Immunol. 2004;172(3):1444–8.PubMedCrossRefGoogle Scholar
- 54.Siemionow M, et al. Development and maintenance of donor-specific chimerism in semi-allogenic and fully major histocompatibility complex mismatched facial allograft transplants. Transplantation. 2005;79(5):558–67.PubMedCrossRefGoogle Scholar
- 55.Ayala R, et al. Long-term follow-up of donor chimerism and tolerance after human liver transplantation. Liver Transpl. 2009;15(6):581–91.PubMedCrossRefGoogle Scholar
- 56.Muramatsu K, Kuriyama R, Taguchi T. Intragraft chimerism following composite tissue allograft. J Surg Res. 2009;157(1):129–35.PubMedCrossRefGoogle Scholar
- 57.Rahhal DN, et al. Dissociation between peripheral blood chimerism and tolerance to hindlimb composite tissue transplants: preferential localization of chimerism in donor bone. Transplantation. 2009;88(6):773–81.PubMedCentralPubMedCrossRefGoogle Scholar
- 58.Bonde S, et al. Cell fusion of bone marrow cells and somatic cell reprogramming by embryonic stem cells. FASEB J. 2010;24(2):364–73.PubMedCentralPubMedCrossRefGoogle Scholar
- 59.Cwykiel J, Klimczak A. Therapeutic Potential of Ex-vivo Fused Chimeric Cells in Prolonging Vascularized Skin Allograft Survival. PRS. 2011; 127:26.Google Scholar
- 60.Li LH, et al. Electrofusion between heterogeneous-sized mammalian cells in a pellet: potential applications in drug delivery and hybridoma formation. Biophys J. 1996;71(1):479–86.PubMedCentralPubMedCrossRefGoogle Scholar
- 61.Chow T, et al. The transfer of host MHC class I protein protects donor cells from NK cell and macrophage-mediated rejection during hematopoietic stem cell transplantation and engraftment in mice. Stem Cells. 2013;31(10):2242–52.PubMedCrossRefGoogle Scholar
- 62.Lentz BR. PEG as a tool to gain insight into membrane fusion. Eur Biophys J. 2007;36(4–5):315–26.PubMedCrossRefGoogle Scholar
- 63.Lentz BR. Polymer-induced membrane fusion: potential mechanism and relation to cell fusion events. Chem Phys Lipids. 1994;73(1–2):91–106.PubMedCrossRefGoogle Scholar