In Vivo Angiogenic Capacity of Stem Cells from Human Exfoliated Deciduous Teeth with Human Umbilical Vein Endothelial Cells

다국어 초록 (Multilingual Abstract)

Dental pulp is a highly vascularized tissue requiring ade-quate blood supply for successful regeneration. In this study, we investigated the functional role of stem cells from human exfoliated deciduous teeth (SHEDs) as a perivascular source for in vivo formation of vessel-like structures. Primarily isolated SHEDs showed mesenchymal stem cell (MSC)-like characteristics including the expression of surface antigens and in vitro osteogenic and adipogenic differentiation potentials. Moreover, SHEDs were positive for NG2, -smooth muscle actin (SMA), platelet-derived growth factor receptor beta (PDGFR), and CD146 as pericyte markers. To prove feasibility of SHEDs as perivascular source, SHEDs were transplanted into immunodeficient mouse using Matrigel with or without human umbilical vein endothelial cells (HUVECs). Transplantation of SHEDs alone or HUVECs alone resulted in no formation of vessel-like structures with enough red blood cells. However, when SHEDs and HUVECs were transplanted together, extensive vessel-like structures were formed. The presence of murine erythrocytes within lumens sug-gested the formation of anastomoses between newly formed vessel-like structures in Matrigel plug and the host circulatory system. To understand underlying mechanisms of in vivo angiogenesis, the expression of angiogenic cytokine and chemokine, their receptors, and MMPs was compared between SHEDs and HUVECs. SHEDs showed higher expression of VEGF, SDF-1, and PDGFRthan HUVECs. On the contrary, HUVECs showed higher ex-pression of VEGF receptors, CXCR4, and PDGF-BB than SHEDs. This differential expression pattern suggested reciprocal interactions between SHEDs and HUVECs and their involvement during in vivo angiogenesis. In conclusion, SHEDs could be a feasible source of perivascular cells for in vivo angiogenesis.

참고문헌 (Reference)

1 Beck, L.Jr., "Vascular development : cellular and molecular regulation" 11 : 365-373, 1997

2 Petit, I., "The SDF-1-CXCR4 signaling pathway : a molecular hub modulating neo-angiogenesis" 28 : 299-307, 2007

3 Volponi, A. A., "Stem cell-based biological tooth repair and regeneration" 20 : 715-722, 2010

4 Miura, M., "SHED : stem cells from human exfoliated deciduous teeth" 100 : 5807-5812, 2003

5 Andrae, J., "Role of plateletderived growth factors in physiology and medicine" 22 : 1276-1312, 2008

6 Itoh, T., "Reduced angiogenesis and tumor progression in gelatinase A-deficient mice" 58 : 1048-1051, 1998

7 Schmalz, G., "Pulp development, repair, and regeneration : challenges of the transition from traditional dentistry to biologically based therapies" 40 : 2-5, 2014

8 Gronthos, S., "Postnatal human dental pulp stem cells(DPSCs)in vitro and in vivo" 97 : 13625-13630, 2000

9 Barnett, J. M., "Pharmacologic and genetic manipulation of MMP-2 and-9affects retinal neovascularization in rodent models of OIR" 48 : 907-915, 2007

10 Shi, S., "Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp" 18 : 696-704, 2003

11 Ren, S., "Pericytes in kidney fibrosis" 22 : 471-480, 2013

12 Huang, G. T., "Mesenchymal stem cells derived from dental tissues vs. those from other sources : their biology and role in regenerative medicine" 88 : 792-806, 2009

13 Cheng, X. W., "Mechanisms underlying the impairment of ischemia-induced neovascularization in matrix metalloproteinase 2-deficient mice" 100 : 904-913, 2007

14 Rundhaug, J. E, "Matrix metalloproteinases, angiogenesis, and cancer: commentary re: A.C. Lockhart et al., Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin.Cancer Res. 9: 00-00, 2003" 9 : 551-554, 2003

15 Fang, J., "Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model" 97 : 3884-3889, 2000

16 Vu, T. H., "MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes" 93 : 411-422, 1998

17 Kinnaird, T., "Local delivery of marrowderived stromal cells augments collateral perfusion through paracrine mechanisms" 109 : 1543-1549, 2004

18 Seo, B. M., "Investigation of multipotent postnatal stem cells from human periodontal ligament" 364 : 149-155, 2004

19 Melero-Martin, J. M., "In vivo vasculogenic potential of human blood-derived endothelial progenitor cells" 109 : 4761-4768, 2007

20 Zhou, Z., "Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinaseI" 97 : 4052-4057, 2000

21 Tomic, S., "Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists" 20 : 695-708, 2011

22 Li, Z., "Immunomodulatory properties of dental tissue-derived mesenchymal stem cells" 20 : 25-34, 2014

23 남현, "Establishment of Hertwig’s Epithelial Root Sheath/ Epithelial Rests of Malassez Cell Line from Human Periodontium" 한국분자세포생물학회 37 (37): 562-567, 2014

24 Ishii, M., "Enhanced angiogenesis by transplantation of mesenchymal stem cell sheet created by a novel magnetic tissue engineering method" 31 : 2210-2215, 2011

25 Jain, R. K., "Engineering vascularized tissue" 23 : 821-823, 2005

26 Melero-Martin, J. M., "Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells" 103 : 194-202, 2008

27 Armulik, A., "Endothelial/pericyte interactions" 97 : 512-523, 2005

28 Gaengel, K., "Endothelial-mural cell signaling in vascular development and angiogenesis" 29 : 630-638, 2009

29 Bento, L. W., "Endothelial differentiation of SHED requires MEK1/ERK signaling" 92 : 51-57, 2013

30 Liu, J., "Concise reviews : characteristics and potential applications of human dental tissue-derived mesenchymal stem cells" 33 : 627-638, 2015

31 Rumman, M., "Concise review : quiescence in adult stem cells : biological significance and relevance to tissue regeneration" 33 : 2903-2912, 2015

32 Isner, J. M., "Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb" 348 : 370-374, 1996

33 Bronckaers, A., "Angiogenic properties of human dental pulp stem cells" 8 : 71104-, 2013

34 Isner, J. M., "Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization" 103 : 1231-1236, 1999

35 Caplan, A. I., "All MSCs are pericytes?" 3 : 229-230, 2008

36 Crisan, M., "A perivascular origin for mesenchymal stem cells in multiple human organs" 3 : 301-313, 2008