title: Xenotransplanted embryonic kidney provides a niche for endogenous mesenchymal stem cell differentiation into erythropoietin-producing tissue.
abstract: Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide-inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long-lasting immunosuppression and help mitigate ethical concerns.
authors.affiliation: Project Laboratory for Kidney Regeneration, Institute of DNA Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoo
authors.forename: Hitomi
authors.initials: H
authors.lastname: Matsunari
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwai
authors.forename: Shinya
authors.initials: S
authors.lastname: Yokote
authors.forename: Takumi
authors.initials: T
authors.lastname: Teratani
authors.forename: Yousof
authors.initials: Y
authors.lastname: Gheisari
authors.forename: Osahiko
authors.initials: O
authors.lastname: Tsuji
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Utsunomiya
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Hirotaka James
authors.initials: HJ
authors.lastname: Okano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D002415:Cats; D002454:Cell Differentiation / Q000502:physiology; D046528:Chimerism; D004921:Erythropoietin / Q000097:blood*; D006801:Humans; D007668:Kidney / Q000196:embryology* / Q000378:metabolism / Q000601:surgery; D016030:Kidney Transplantation / Q000379:methods*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D051381:Rats; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D004921:Erythropoietin