A depleting antibody toward sca-1 mitigates a surge of CD34+/c-kit+ progenitors and reduces vascular restenosis in a murine vascular injury model Bryan.

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Presentation transcript:

A depleting antibody toward sca-1 mitigates a surge of CD34+/c-kit+ progenitors and reduces vascular restenosis in a murine vascular injury model Bryan W. Tillman, MD, PhD, Jeremy Kelly, PhD, Tara D. Richards, BS, Alex F. Chen, MD, PhD, Albert D. Donnenberg, PhD, Vera S. Donnenberg, PhD, Edith Tzeng, MD Journal of Vascular Surgery Volume 64, Issue 4, Pages 1084-1092 (October 2016) DOI: 10.1016/j.jvs.2015.05.002 Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 1 Wire injury of the murine femoral artery injures endothelium of the femoral segment. A, Representative image of murine femoral wire injury with ligation of the saphenous artery (arrow) and wire dilation of the common femoral artery (arrowhead). B and C, Confocal fluorescent microscopy of lectin (red) and Hoechst (blue) staining revealed an en face intact endothelial monolayer of a control vessel (B) that was absent on a wire-injured vessel (C). Scale bar is shown. Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 2 Stromal cell-derived factor 1α (sdf1α) increases after vascular injury. Compared with nonsurgical controls or mice with a sham surgery, mice with distal femoral artery ligation revealed a significant increase of sdf1α expression by enzyme-linked immunosorbent assay (ELISA; P = .001), whereas mice with femoral wire injury revealed a similar 2.2-fold increase in sdf1α (P = .003; n = 6 per condition). Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 3 Wire injury of the femoral artery increased circulating CD34+/c-kit+ cells (short-term hematopoietic stem cells [ST-HSCs]). Flow cytometry included (A) exclusion of debris followed by (B) gating of DAPI-positive events. Lineage-positive and CD45-positive events were then excluded. Shown are representative gating of CD34+/c-kit+ events among nonsurgical (C) and wire-injured (D) animals. Compared with mice with no surgery, animals after wire injury of the femoral artery revealed a statistically significant 2.3-fold increase among CD34+/c-kit+ cells (P = .005; E). Sham surgery and vessel ligation did not result in a significant rise in progenitors. Shown are percentage of cells with standard error bars (n = 6 per condition). Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 4 Antibody treatment does not prevent increases in plasma stromal cell-derived factor 1α (sdf1α) 1 day after vascular injury. Vascular wire injury among isotype (Wi cIg) or sca-treated (Wi sca) mice increased plasma sdf1α relative to nonsurgical, non-antibody-treated controls (naive) and to nonsurgical isotype (cIg, treated with control antibody without injury) on day 1. The sdf1α levels in Wi sca mice were not significantly different from those of Wi cIg animals. Means with standard error are shown (n = 8 per condition). Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 5 Stromal cell-derived factor 1α (sdf1α) levels remain elevated over 9 days after wire injury and are not affected by sca-1 treatment (Wi sca). The sdf1α levels at extended time points of 3 and 9 days after wire injury remained significantly elevated compared with either naive nonsurgical or nonsurgical isotype (cIg) controls. Treatment with sca-1 antibody did not affect sdf1α levels (P = NS relative to wire injury with control antibody [Wi cIg]; n = 8 per condition for naive and postoperative day 1; n = 6 for all other time points). Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 6 Sca-1 antibody treatment reduced a surge among short-term hematopoietic stem cells (ST-HSCs) 1 day after wire injury. Compared with naive nonsurgical mice (n = 6) or nonsurgical isotype controls (cIg, n = 8), wire injury after isotype treatment (Wi cIg, n = 8) increased progenitor cells by more than threefold (P = .004 and .0001, respectively). Animals treated with sca-1 antibody (Wi sca, n = 8) prevented the surge among progenitors relative to naive animals (P = NS). Shown are mean percentage of CD34+/c-kit+/Lin− cells with standard error. Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 7 Sca-1 antibody mitigates surge of CD34+/c-kit+ short-term hematopoietic stem cells (ST-HSCs) out to 9 days. Whereas the surge of CD34+/c-kit+ cells remained elevated through postoperative day (POD) 9, CD34+/c-kit+ cells among sca-1-treated wire-injured animals (Wi sca) were nonsignificant relative to naive nonsurgical animals at all time points. Shown are mean percentage CD34+/c-kit+/Lin− with standard error. cIg, Isotype control immunoglobulin; Wi, wire injured. Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 8 Murine bone marrow is preserved after sca antibody at late time points. By flow cytometric analysis, sca-1 cells in sca-treated mice were significantly reduced at day 3 of therapy relative to isotype (cIg) animals. By day 11, despite ongoing antibody treatment, there was no difference in sca+ cells between cIg- and sca-treated mice (n = 6 per condition on day 3, n = 9 on day 11). Shown are mean percentage with standard error. Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions

Fig 9 Depletion of short-term hematopoietic stem cells (ST-HSCs) reduces restenosis after wire injury. Compared with mice treated with control immunoglobulin G (Wi cIg) at the time of wire injury (A), mice treated with sca-1-depleting antibody (Wi sca) revealed reduced restenosis at 28 days (B; hematoxylin and eosin, ×400). Compared with either control mice with saline (n = 8) or mice with treatment of isotype control Ig (cIg, n = 5), mice treated with sca-1-depleting antibody (n = 8) revealed a significant decrease in the intima/media ratio. C, Means with standard error bars are shown. IEL, Internal elastic lamina; L, lumen; I, intima; M, media; Wi, wire injury. Journal of Vascular Surgery 2016 64, 1084-1092DOI: (10.1016/j.jvs.2015.05.002) Copyright © 2016 Society for Vascular Surgery Terms and Conditions