Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia

  • Kang, Insung (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Byung-Chul (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Choi, Soon Won (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Jin Young (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Jae-Jun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Bo-Eun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Da-Hyun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Lee, Seung Eun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Shin, Nari (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Seo, Yoojin (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Hyung-Sik (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University) ;
  • Kim, Dong-Ik (Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kang, Kyung-Sun (Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University)
  • Received : 2017.08.07
  • Accepted : 2017.11.09
  • Published : 2018.04.30
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Abstract

With the rapidly growing demand for mesenchymal stem cell (MSC) therapy, numerous strategies using MSCs for different diseases have been studied and reported. Because of their immunosuppressive properties, MSCs are commonly used as an allogeneic treatment. However, for the many donors who could potentially be used, it is important to understand the capacity for therapeutic usage with donor-to-donor heterogeneity. In this study, we aimed to investigate MSCs as a promising therapeutic strategy for critical limb ischemia. We evaluated MSCs from two donors (#55 and #64) and analyzed the capacity for angiogenesis through in vivo and in vitro assays to compare the therapeutic effect between different donors. We emphasized the importance of intra-population heterogeneity of MSCs on therapeutic usage by evaluating the effects of hypoxia on activating cellular angiogenesis in MSCs. The precondition of hypoxia in MSCs is known to enhance therapeutic efficacy. Our study suggests that sensitivity to hypoxic conditions is different between cells originating from different donors, and this difference affects the contribution to angiogenesis. The bioinformatics analysis of different donors under hypoxic culture conditions identified intrinsic variability in gene expression patterns and suggests alternative potential genetic factors ANGPTL4, ADM, SLC2A3, and CDON as guaranteed general indicators for further stem cell therapy.

Keywords

Acknowledgement

Supported by : Korea Health Industry Development Institute (KHIDI), National Research Foundation of Korea, Seoul National University (SNU)

References

  1. Hirsch, A. T. et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 113, e463-e654 (2006). https://doi.org/10.1161/circ.113.4.463
  2. Perin, E. C. et al. Evaluation of cell therapy on exercise performance and limb perfusion in peripheral artery disease. Circulation 135, 1417-1428 (2017). https://doi.org/10.1161/CIRCULATIONAHA.116.025707
  3. Ikegame, Y. et al. Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy 13, 675-685 (2011). https://doi.org/10.3109/14653249.2010.549122
  4. Li, S. et al. Advances in the treatment of ischemic diseases by mesenchymal stem cells. Stem Cells Int. 2016, 5896061 (2016).
  5. Raval, Z. & Losordo, D. W. Cell therapy of peripheral arterial disease. Circ. Res. 112, 1288-1302 (2013). https://doi.org/10.1161/CIRCRESAHA.113.300565
  6. Kim, H. S. et al. Human umbilical cord blood mesenchymal stem cells reduce colitis in mice by activating NOD2 signaling to COX2. Gastroenterology 145, 1392-1403 (2013). https://doi.org/10.1053/j.gastro.2013.08.033
  7. Lee, B. C. et al. PGE2 maintains self-renewal of human adult stem cells via EP2-mediated autocrine signaling and its production is regulated by cell-to-cell contact. Sci. Rep. 6, 26298 (2016). https://doi.org/10.1038/srep26298
  8. Kim, S. W. et al. Successful stem cell therapy using umbilical cord bloodderived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells 24, 1620-1626 (2006). https://doi.org/10.1634/stemcells.2005-0365
  9. Kyurkchiev, D. et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J. Stem Cells 6, 552-570 (2014). https://doi.org/10.4252/wjsc.v6.i5.552
  10. Chang, H.-K. et al. Inducible HGF-secreting human umbilical cord bloodderived MSCs produced via TALEN-mediated genome editing promoted angiogenesis. Mol. Ther. 24, 1644-1654 (2016). https://doi.org/10.1038/mt.2016.120
  11. Siegel, G. et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Med. 11, 146 (2013). https://doi.org/10.1186/1741-7015-11-146
  12. Phinney, D. G. et al. Donor variation in the growth properties and osteogenic potential of human marrow stromal cells. J. Cell Biochem. 75, 424-436 (1999). https://doi.org/10.1002/(SICI)1097-4644(19991201)75:3<424::AID-JCB8>3.0.CO;2-8
  13. Siddappa, R., Licht, R., van Blitterswijk, C. & de Boer, J. Donor variation and loss of multipotency during in vitro expansion of human mesenchymal stem cells for bone tissue engineering. J. Orthop. Res. 25, 1029-1041 (2007). https://doi.org/10.1002/jor.20402
  14. Brenes, R. A. et al. Toward a mouse model of hindlimb ischemia to test therapeutic angiogenesis. J. Vasc. Surg. 56, 1669-1679 (2012). https://doi.org/10.1016/j.jvs.2012.04.067
  15. Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010). https://doi.org/10.1186/gb-2010-11-3-r25
  16. Mi, H. et al. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 45, D183-D189 (2017). https://doi.org/10.1093/nar/gkw1138
  17. Rosova, I., Dao, M., Capoccia, B., Link, D. & Nolta, J. A. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26, 2173-2182 (2008). https://doi.org/10.1634/stemcells.2007-1104
  18. Beegle, J. et al. Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. Stem Cells 33, 1818-1828 (2015). https://doi.org/10.1002/stem.1976
  19. Leroux, L. et al. Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a Wnt4-dependent pathway. Mol. Ther. 18, 1545-1552 (2010). https://doi.org/10.1038/mt.2010.108
  20. Liu, L. et al. Hypoxia preconditioned human adipose derived mesenchymal stem cells enhance angiogenic potential via secretion of increased VEGF and bFGF. Cell Biol. Int. 37, 551-560 (2013). https://doi.org/10.1002/cbin.10097
  21. Yang, F. et al. Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles. Proc. Natl Acad. Sci. USA 107, 3317-3322 (2010). https://doi.org/10.1073/pnas.0905432106
  22. Huang, W. H. et al. Hypoxic mesenchymal stem cells engraft and ameliorate limb ischaemia in allogeneic recipients. Cardiovasc. Res. 101, 266-276 (2014). https://doi.org/10.1093/cvr/cvt250
  23. Rishi, M. T. et al. Deletion of prolyl hydroxylase domain proteins (PHD1, PHD3) stabilizes hypoxia inducible factor-1 alpha, promotes neovascularization, and improves perfusion in a murine model of hind-limb ischemia. Microvasc. Res. 97, 181-188 (2015). https://doi.org/10.1016/j.mvr.2014.10.009
  24. Masferrer, J. L. et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 60, 1306-1311 (2000).
  25. Mi, H., Muruganujan, A., Casagrande, J. T. & Thomas, P. D. Large-scale gene function analysis with the PANTHER classification system. Nat. Protoc. 8, 1551-1566 (2013). https://doi.org/10.1038/nprot.2013.092
  26. Wang, Z., Fang, B., Tan, Z., Zhang, D. & Ma, H. Hypoxic preconditioning increases the protective effect of bone marrow mesenchymal stem cells on spinal cord ischemia/reperfusion injury. Mol. Med. Rep. 13, 1953-1960 (2016). https://doi.org/10.3892/mmr.2016.4753
  27. Saraswati, S., Guo, Y., Atkinson, J. & Young, P. P. Prolonged hypoxia induces monocarboxylate transporter-4 expression in mesenchymal stem cells resulting in a secretome that is deleterious to cardiovascular repair. Stem Cells 33, 1333-1344 (2015). https://doi.org/10.1002/stem.1935
  28. Hu, X. et al. Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning. Stem Cells 32, 2702-2713 (2014). https://doi.org/10.1002/stem.1784
  29. Boyette, L. B., Creasey, O. A., Guzik, L., Lozito, T. & Tuan, R. S. Human bone marrow-derived mesenchymal stem cells display enhanced clonogenicity but impaired differentiation with hypoxic preconditioning. Stem Cells Transl. Med. 3, 241-254 (2014). https://doi.org/10.5966/sctm.2013-0079
  30. HoWangYin, K.-Y. et al. HIF-prolyl hydroxylase 2 inhibition enhances the efficiency of mesenchymal stem cell-based therapies for the treatment of critical limb ischemia. Stem Cells 32, 231-243 (2014). https://doi.org/10.1002/stem.1540
  31. Hung, S. C. et al. Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo. PLoS ONE 2, e416 (2007). https://doi.org/10.1371/journal.pone.0000416
  32. Saller, M. M. et al. Increased stemness and migration of human mesenchymal stem cells in hypoxia is associated with altered integrin expression. Biochem. Biophys. Res. Commun. 423, 379-385 (2012). https://doi.org/10.1016/j.bbrc.2012.05.134
  33. Beegle, J. R. et al. Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia. Mol. Ther. Methods Clin. Dev. 3, 16053 (2016). https://doi.org/10.1038/mtm.2016.53
  34. Pai, R. et al. PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Biochem. Biophys. Res. Commun. 286, 923-928 (2001). https://doi.org/10.1006/bbrc.2001.5494
  35. Camacho, M. et al. Hypoxia upregulates PGI-synthase and increases PGI(2) release in human vascular cells exposed to inflammatory stimuli. J. Lipid Res. 52, 720-731 (2011). https://doi.org/10.1194/jlr.M011007
  36. Phinney, D. G. Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. J. Cell Biochem. 113, 2806-2812 (2012). https://doi.org/10.1002/jcb.24166
  37. La Paglia, L. et al. Potential role of ANGPTL4 in the cross talk between metabolism and cancer through PPAR signaling pathway. PPAR Res 2017, 8187235 (2017).
  38. Nagaya, N., Mori, H., Murakami, S., Kangawa, K. & Kitamura, S. Adrenomedullin: angiogenesis and gene therapy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R1432-R1437 (2005). https://doi.org/10.1152/ajpregu.00662.2004
  39. Mimura, I. et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol. Cell Biol. 32, 3018-3032 (2012). https://doi.org/10.1128/MCB.06643-11
  40. Mathew, E. et al. Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling. Cell Rep. 9, 484-494 (2014). https://doi.org/10.1016/j.celrep.2014.09.010

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