Experimental study on the effect of desferrioxamine on targeted homing and angiogenesis of bone marrow mesenchymal stem cells_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHENG Shengwu ¹ , DU Zijing ² ^△ , HUANG Xiongmei ¹ , ZHUANG Jing ¹ , LIN Genhui ¹ , YANG Yu ¹ , DING Xin ¹ ,  ZAN Tao ²

1. Department of Plastic Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou Fujian, 350001, P.R.China;
2. Department of Plastic Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, P.R.China;

Corresponding author：

ZAN Tao, Email: zantaodoctor@yahoo.com

Keywords：

Hypoxia mimetic agent; desferrioxamine; bone marrow mesenchymal stem cells; homing; neovascularization

DOI：

10.7507/1002-1892.201809065

Video：

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Objective To investigate whether desferrioxamine (DFO) can enhance the homing of bone marrow mesenchymal stem cells (BMSCs) and improve neovascularization in random flaps of rats.Methods BMSCs and fibroblasts (FB) of luciferase transgenic Lewis rats were isolated and cultured. Forty 4-week-old Lewis male rats were used to form a 10 cm×3 cm rectangular flap on their back. The experimental animals were randomly divided into 4 groups with 10 rats in each group: in group A, 200 μL PBS were injected through retrobulbar venous plexus; in group B, 200 μL FB with a concentration of 1×10⁶ cells/mL were injected; in group C, 200 μL BMSCs with a concentration of 1×10⁶ cells/mL were injected; in group D, cells transplantation was the same as that in group C, after cells transplantation, DFO [100 mg/(kg·d)] were injected intraperitoneally for 7 days. On the 7th day after operation, the survival rate of flaps in each group was observed and calculated; the blood perfusion was observed by laser speckle imaging. Bioluminescence imaging was used to detect the distribution of transplanted cells in rats at 30 minutes and 1, 4, 7, and 14 days after operation. Immunofluorescence staining was performed at 7 days after operation to observe CD31 staining and count capillary density under 200-fold visual field and to detect the expressions of stromal cell derived factor 1 (SDF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF), and Ki67. Transplanted BMSCs were labeled with luciferase antibody and observed by immunofluorescence staining whether they participated in the repair of injured tissues.Results The necrosis boundary of ischemic flaps in each group was clear at 7 days after operation. The survival rate of flaps in groups C and D was significantly higher than that in groups A and B, and in group D than in group C (P<0.05). Laser speckle imaging showed that the blood perfusion units of flaps in groups C and D was significantly higher than that in groups A and B, and in group D than in group C (P<0.05). Bioluminescence imaging showed that BMSCs gradually migrated to the ischemia and hypoxia area and eventually distributed to the ischemic tissues. The photon signal of group D was significantly stronger than that of other groups at 14 days after operation (P<0.05). CD31 immunofluorescence staining showed that capillary density in groups C and D was significantly higher than that in groups A and B, and in group D than in group C (P<0.05). The expressions of SDF-1, EGF, FGF, and Ki67 in groups C and D were significantly stronger than those in groups A and B, and in group D than in group C. Luciferase-labeled BMSCs were expressed in the elastic layer of arteries, capillaries, and hair follicles at 7 days after transplantation.Conclusion DFO can enhance the migration and homing of BMSCs to the hypoxic area of random flap, accelerate the differentiation of BMSCs in ischemic tissue, and improve the neovascularization of ischemic tissue.

Citation： ZHENG Shengwu, DU Zijing, HUANG Xiongmei, ZHUANG Jing, LIN Genhui, YANG Yu, DING Xin, ZAN Tao. Experimental study on the effect of desferrioxamine on targeted homing and angiogenesis of bone marrow mesenchymal stem cells. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(1): 85-92. doi: 10.7507/1002-1892.201809065 Copy

1.	Granero-Moltó F, Weis JA, Miga MI, et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells, 2009, 27(8): 1887-1898.
2.	Falanga V. Wound healing and its impairment in the diabetic foot. Lancet, 2005, 366(9498): 1736-1743.
3.	Misao Y, Takemura G, Arai M, et al. Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation. Cardiovasc Res, 2006, 69(2): 476-490.
4.	Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411): 143-147.
5.	Javazon EH, Keswani SG, Badillo AT, et al. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen, 2007, 15(3): 350-359.
6.	McFarlane RM, Deyoung G, Henry RA. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg, 1965, 35: 177-182.
7.	Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol, 2007, 211(1): 27-35.
8.	邓蓉蓉, 谢伊旻, 谢林. 间充质干细胞归巢的研究与进展. 中国组织工程研究, 2016, 20(19): 2879-2888.
9.	Liu N, Tian J, Cheng J, et al. Migration of CXCR4 gene-modified bone marrow-derived mesenchymal stem cells to the acute injured kidney. J Cell Biochem, 2013, 114(12): 2677-2689.
10.	Chiang KH, Cheng WL, Shih CM, et al. Statins, HMG-CoA reductase inhibitors, improve neovascularization by increasing the expression density of CXCR4 in endothelial progenitor cells. PLoS One, 2015, 10(8): e0136405.
11.	Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med, 2004, 10(8): 858-864.
12.	Oladipupo S, Hu S, Kovalski J, et al. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proc Natl Acad Sci U S A, 2011, 108(32): 13264-13269.
13.	Hou Z, Nie C, Si Z, et al. Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1α. Diabetes Res Clin Pract, 2013, 101(1): 62-71.
14.	Mehrabani M, Najafi M, Kamarul T, et al. Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell Prolif, 2015, 48(5): 532-549.
15.	Ikeda Y, Tajima S, Yoshida S, et al. Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. Atherosclerosis, 2011, 215(2): 339-347.
16.	Du Z, Zan T, Huang X, et al. DFO enhances the targeting of CD34-positive cells and improves neovascularization. Cell Transplant, 2015, 24(11): 2353-2366.
17.	Ichioka S, Kudo S, Shibata M, et al. Bone marrow cell implantation improves flap viability after ischemia-reperfusion injury. Ann Plast Surg, 2004, 52(4): 414-418.
18.	Zheng Y, Yi C, Xia W, et al. Mesenchymal stem cells transduced by vascular endothelial growth factor gene for ischemic random skin flaps. Plast Reconstr Surg, 2008, 121(1): 59-69.
19.	Wu Y, Chen L, Scott PG, et al. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells, 2007, 25(10): 2648-2659.
20.	Chen L, Tredget EE, Wu PY, et al. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One, 2008, 3(4): e1886.
21.	Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 2006, 20(6): 661-669.
22.	Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 2004, 109(12): 1543-1549.
23.	Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res, 2004, 94(5): 678-685.

1. Granero-Moltó F, Weis JA, Miga MI, et al. Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells, 2009, 27(8): 1887-1898.
2. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet, 2005, 366(9498): 1736-1743.
3. Misao Y, Takemura G, Arai M, et al. Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation. Cardiovasc Res, 2006, 69(2): 476-490.
4. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411): 143-147.
5. Javazon EH, Keswani SG, Badillo AT, et al. Enhanced epithelial gap closure and increased angiogenesis in wounds of diabetic mice treated with adult murine bone marrow stromal progenitor cells. Wound Repair Regen, 2007, 15(3): 350-359.
6. McFarlane RM, Deyoung G, Henry RA. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg, 1965, 35: 177-182.
7. Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol, 2007, 211(1): 27-35.
8. 邓蓉蓉, 谢伊旻, 谢林. 间充质干细胞归巢的研究与进展. 中国组织工程研究, 2016, 20(19): 2879-2888.
9. Liu N, Tian J, Cheng J, et al. Migration of CXCR4 gene-modified bone marrow-derived mesenchymal stem cells to the acute injured kidney. J Cell Biochem, 2013, 114(12): 2677-2689.
10. Chiang KH, Cheng WL, Shih CM, et al. Statins, HMG-CoA reductase inhibitors, improve neovascularization by increasing the expression density of CXCR4 in endothelial progenitor cells. PLoS One, 2015, 10(8): e0136405.
11. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med, 2004, 10(8): 858-864.
12. Oladipupo S, Hu S, Kovalski J, et al. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proc Natl Acad Sci U S A, 2011, 108(32): 13264-13269.
13. Hou Z, Nie C, Si Z, et al. Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1α. Diabetes Res Clin Pract, 2013, 101(1): 62-71.
14. Mehrabani M, Najafi M, Kamarul T, et al. Deferoxamine preconditioning to restore impaired HIF-1α-mediated angiogenic mechanisms in adipose-derived stem cells from STZ-induced type 1 diabetic rats. Cell Prolif, 2015, 48(5): 532-549.
15. Ikeda Y, Tajima S, Yoshida S, et al. Deferoxamine promotes angiogenesis via the activation of vascular endothelial cell function. Atherosclerosis, 2011, 215(2): 339-347.
16. Du Z, Zan T, Huang X, et al. DFO enhances the targeting of CD34-positive cells and improves neovascularization. Cell Transplant, 2015, 24(11): 2353-2366.
17. Ichioka S, Kudo S, Shibata M, et al. Bone marrow cell implantation improves flap viability after ischemia-reperfusion injury. Ann Plast Surg, 2004, 52(4): 414-418.
18. Zheng Y, Yi C, Xia W, et al. Mesenchymal stem cells transduced by vascular endothelial growth factor gene for ischemic random skin flaps. Plast Reconstr Surg, 2008, 121(1): 59-69.
19. Wu Y, Chen L, Scott PG, et al. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells, 2007, 25(10): 2648-2659.
20. Chen L, Tredget EE, Wu PY, et al. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One, 2008, 3(4): e1886.
21. Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 2006, 20(6): 661-669.
22. Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 2004, 109(12): 1543-1549.
23. Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res, 2004, 94(5): 678-685.

Chinese Journal of Reparative and Reconstructive Surgery

Experimental study on the effect of desferrioxamine on targeted homing and angiogenesis of bone marrow mesenchymal stem cells

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