Andrew R. Cuddihy, Batul T. Suterwala, Shundi Ge, Lisa A

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Rapid Thymic Reconstitution Following Bone Marrow Transplantation in Neonatal Mice is VEGF-Dependent Andrew R. Cuddihy, Batul T. Suterwala, Shundi Ge, Lisa A. Kohn, Julie Jang, Jacob Andrade, Xiaoyan Wang, Gay M. Crooks Biology of Blood and Marrow Transplantation Volume 18, Issue 5, Pages 683-689 (May 2012) DOI: 10.1016/j.bbmt.2012.01.006 Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Neonatal mice show rapid and robust thymic reconstitution after HSCT. (A) Frequency of CD45.2+ donor cells in the bone marrow of nonirradiated (−, black bars) or irradiated (+, grey bars) neonates or adult NSG mice analyzed 6 weeks posttransplantation (neonates: no radiation therapy [XRT] n = 22 versus XRT n = 16; adults: no XRT n = 13 versus XRT n = 18). All numbers are mean ± SEM. (B) Thymocyte numbers, 6 weeks posttransplantation (neonates: no XRT n = 13 versus XRT n = 14; adults: no XRT n = 9 versus XRT n = 8). (C) Fluorescent activated cell sorter (FACS) plot comparing thymic and bone marrow reconstitution with donor (CD45.2+) cells at 1 and 2 weeks posttransplantation in NSG neonates. (D) FACS plots showing de novo generation of double positive (CD4+CD8+) thymocytes 2 weeks posttransplantation in nonirradiated neonatal NSG mice (right panel); isotype control for CD4 and CD8 (left panel). ∗P < .01, ∗∗P < .001. Biology of Blood and Marrow Transplantation 2012 18, 683-689DOI: (10.1016/j.bbmt.2012.01.006) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Immature vascular architecture and robust thymic reconstitution are lost during the first week of postnatal life. (A) In vivo tomato lectin staining comparing vasculature between newborn (left panel) and adult (right panel) immune-competent (C57Bl/6) and immune-deficient (NOD/SCID/β2m–/–) mice. (B) Vascular endothelial growth factor (VEGF)-Trap reduces vascular density of newborn thymi in immune-competent (C57Bl/6) and immune-deficient (NSG) mice. Control mice were treated with hFc. (C, D) Effect of host age on bone marrow (C) and thymic reconstitution (D). NSG neonatal mice were transplanted with CD45.2+ bone marrow (BM) without irradiation at day 1, 4, 7, and 10 of life, (n = 4, 7, 7, and 9 mice, respectively) and analyzed at 3 weeks post–bone marrow transplantation (BMT). All numbers are mean ± SEM. Biology of Blood and Marrow Transplantation 2012 18, 683-689DOI: (10.1016/j.bbmt.2012.01.006) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Vascular endothelial growth factor (VEGF) inhibition impairs early thymic engraftment of donor cells in mice transplanted as neonates, but not adults. (A) Number of thymocytes in nonirradiated neonates harvested at 3 weeks (hFc [black bars] n = 9; VEGF-Trap [grey bars] n = 11; *P < .01) and 6 weeks (hFc n = 14; VEGF-Trap n = 11; P = .30). (B) Number of thymocytes in irradiated neonates harvested at 3 weeks (hFc n = 6; VEGF-Trap n = 5; P = .14) and 6 weeks (hFc n = 5; VEGF-Trap n = 4; P = .5). (C) Number of thymocytes in irradiated adults harvested at 3 weeks (hFc n = 8; VEGF-Trap n = 6; P = .48) or 6 weeks (hFc n = 7; VEGF-Trap n = 6; P = .84). P values were unchanged when thymocyte numbers were normalized to body weight, to account for the smaller size of the VEGF-Trap treated mice. (D-I) Percentage of CD4−CD8−; double-negative (DN) (D-F) and CD4+CD8+; double-positive (DP) (G-I) thymocytes from mice treated with hFc (black bars) and VEGF-Trap (grey bars) before transplantation. (D, G) Nonirradiated neonates harvested 3 weeks (hFc n = 9; VEGF-Trap n = 5) and 6 weeks (hFc n = 8; VEGF-Trap n = 6) posttransplantation. (E, H) Irradiated neonates harvested 3 weeks (hFc n = 5; VEGF-Trap n = 3, *P < .01) and 6 weeks (hFc n = 5; VEGF-Trap n = 4) posttransplantation. (F, I), Irradiated adults harvested 3 weeks (hFc n = 4; VEGF-Trap n = 2) and 6 weeks (hFc n = 6; VEGF-Trap n = 6) posttransplantation. (J-L) H&E stains of thymi from NSG mice treated as described in (A-C) harvested at 3 and 6 weeks. All images shown are at original magnification ×4. (J) Nonirradiated NSG mice transplanted as neonates. (K) Irradiated NSG mice transplanted as neonates. (L) Irradiated NSG mice transplanted as adults. In (L), the largest examples of tissue from the 3-week adult cohorts are shown because, in most cases, the thymus was not detected. Biology of Blood and Marrow Transplantation 2012 18, 683-689DOI: (10.1016/j.bbmt.2012.01.006) Copyright © 2012 American Society for Blood and Marrow Transplantation Terms and Conditions