, Volume 17, Issue 4, pp 851–866 | Cite as

Functional analysis reveals angiogenic potential of human mesenchymal stem cells from Wharton’s jelly in dermal regeneration

  • Sandra S. Edwards
  • Gabriela Zavala
  • Catalina P. Prieto
  • Matías Elliott
  • Samuel Martínez
  • Jose T. Egaña
  • María R. Bono
  • Verónica Palma
Original Paper


Disorders in skin wound healing are a major health problem that requires the development of innovative treatments. The use of biomaterials as an alternative of skin replacement has become relevant, but its use is still limited due to poor vascularization inside the scaffolds, resulting in insufficient oxygen and growth factors at the wound site. In this study, we have developed a cell-based wound therapy consisting of the application of collagen-based dermal scaffolds containing mesenchymal stem cells from Wharton’s jelly (WJ-MSC) in an immunocompetent mouse model of angiogenesis. From our comparative study on the secretion profile between WJ-MSC and adipose tissue-derived MSC, we found a stronger expression of several well-characterized growth factors, such as VEGF-A, angiopoietin-1 and aFGF, which are directly linked to angiogenesis, in the culture supernatant of WJ-MSC, both on monolayer and 3D culture conditions. WJ-MSC proved to be angiogenic both in vitro and in vivo, through tubule formation and CAM assays, respectively. Moreover, WJ-MSC consistently improved the healing response in vivo in a mouse model of human-like dermal repair, by triggering angiogenesis and further providing a suitable matrix for wound repair, without altering the inflammatory response in the animals. Since these cells can be easily isolated, cultured with high expansion rates and cryopreserved, they represent an attractive stem cell source for their use in allogeneic cell transplant and tissue engineering.


Angiogenesis and wound healing Growth factors Mesenchymal stem cells Scaffold Umbilical cord VEGF-A 



The authors thank Dr. Erices for important contributions to the initial characterization of WJ-MSC cultures. This research was achieved thanks to umbilical cord samples provided by VidaCel and AD-MSC by Mariana Cifuentes (Instituto de Nutrición y Tecnología de los Alimentos, INTA, Universidad de Chile). This project was funded by the projects FONDEF D09I1047 and FONDAP 15090007.

Ethical standard

All procedures performed to elaborate this manuscript comply with the Chilean legislation and were approved by Institutional and Bioethical Use Committees (University of Chile).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. 1.
    Singer A, Clark R (1999) Cutaneous wound healing. N Engl J Med 341:738–746PubMedCrossRefGoogle Scholar
  2. 2.
    Gottrup F (2004) A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg 187:S38–S43CrossRefGoogle Scholar
  3. 3.
    Maxson S, Lopez E, Yoo D, Danilkovitch-Miagkova E, LeRoux M (2012) Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med 1:142–149PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Mustoe T, O’Shaughnessy K, Kloeters O (2006) Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg 117:35–41CrossRefGoogle Scholar
  5. 5.
    Fife C, Walker D, Thomson B, Carter M (2007) Limitations of daily living activities in patients with venous stasis ulcers undergoing compression bandaging: problems with the concept of self-bandaging. Wounds 19:255–257Google Scholar
  6. 6.
    Burd A, Chiu T (2005) Allogenic skin in the treatment of burns. Clin Dermatol 23:376–387PubMedCrossRefGoogle Scholar
  7. 7.
    Grant I, Warwick K, Marshall J, Green C, Martin R (2002) The co-application of sprayed cultured autologous keratinocytes and autologous fibrin sealant in a porcine wound model. Br J Plast Surg 55:219–227PubMedCrossRefGoogle Scholar
  8. 8.
    Currie L, Martin R, Sharpe JR, James SE (2003) A comparison of keratinocyte cell sprays with and without fibrin glue. Burns 29:677–685PubMedCrossRefGoogle Scholar
  9. 9.
    Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ, Conget PA (2008) Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 14:631–640PubMedCrossRefGoogle Scholar
  10. 10.
    Ezquer ME, Ezquer FE, Ricca M, Allers C, Conget P (2011) Intravenous administration of multipotent stromal cells prevents the onset of non-alcoholic steatohepatitis in obese mice with metabolic syndrome. J Hepatol 55:1112–1120PubMedCrossRefGoogle Scholar
  11. 11.
    Li Q, Zhou X, Shi Y, Li J, Zheng L, Cui L et al (2013) In vivo tracking and comparison of the therapeutic effects of MSCs and HSCs for liver injury. PLoS ONE 8:e62363PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Lee J, Cuddihy MJ, Kotov NA (2008) Three-dimensional cell culture matrices: state of the art. Tissue Eng Part B Rev 14:61–86PubMedCrossRefGoogle Scholar
  13. 13.
    Macneil S (2008) Biomaterials for tissue engineering of skin. Mater Today 11:26–35CrossRefGoogle Scholar
  14. 14.
    Murphy CM, O’Brien FJ (2010) Understanding the effect of mean pore size on cell activity in collagen-glycosaminoglycan scaffolds. Cell Adh Migr 4:377–381PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Shi C, Li Q, Zhao Y, Chen W, Chen B, Xiao Z et al (2011) Stem-cell-capturing collagen scaffold promotes cardiac tissue regeneration. Biomaterials 32:2508–2515PubMedCrossRefGoogle Scholar
  16. 16.
    Moiemen NS, Vlachou E, Staiano JJ, Thawy Y, Frame JD (2006) Reconstructive surgery with Integra dermal regeneration template: histologic study, clinical evaluation, and current practice. Plast Reconstr Surg 117:160S–174SPubMedCrossRefGoogle Scholar
  17. 17.
    Heimbach D, Luterman A, Burke J, Cram A, Herndon D, Hunt J et al (1988) Artificial dermis for major burns. Ann Surg 208:313–320PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Machens H, Berger AC, Mailaender P (2000) Bioartificial skin. Cells Tissues Organs 167:88–94PubMedCrossRefGoogle Scholar
  19. 19.
    Pham C, Greenwood J, Cleland H, Woodruff P, Maddern G (2007) Bioengineered skin substitutes for the management of burns: a systematic review. Burns 33:946–957PubMedCrossRefGoogle Scholar
  20. 20.
    Vogt P, Lehnhardt M, Wagner D, Jansen V, Krieg M, Steinau H (1998) Determination of endogenous growth factors in human wound fluid: temporal presence and profiles of secretion. Plast Reconstr Surg 102:117–123PubMedCrossRefGoogle Scholar
  21. 21.
    Pollins AC, Friedman DB, Nanney LB (2007) Proteomic investigation of human burn wounds by 2D-difference gel electrophoresis and mass spectrometry. J Surg Res 142:143–152PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Taverna D, Nanney LB, Pollins AC, Sindona G, Caprioli R (2011) Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry. Wound Repair Regen 19:734–744PubMedCrossRefGoogle Scholar
  23. 23.
    Zisch AH, Lutolf MP, Ehrbar M, Raeber GP, Rizzi SC, Davies N (2003) Cell-demanded release of VEGF from synthetic, biointeractive cell-ingrowth matrices for vascularized tissue growth. FASEB J 17:2260–2262PubMedGoogle Scholar
  24. 24.
    Falanga V (2005) Wound healing and its impairment in the diabetic foot. Lancet 366:1736–1743PubMedCrossRefGoogle Scholar
  25. 25.
    Wilcke I, Lohmeyer JA, Liu S, Condurache A, Krüger S, Mailänder P, Machens HG (2007) VEGF(165) and bFGF protein-based therapy in a slow release system to improve angiogenesis in a bioartificial dermal substitute in vitro and in vivo. Langenbecks Arch Surg 392:305–314PubMedCrossRefGoogle Scholar
  26. 26.
    Eming S, Krieg T, Davidson J (2007) Gene therapy and wound healing. Clin Dermatol 25:79–92PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585–601PubMedCrossRefGoogle Scholar
  28. 28.
    Falanga V (2012) Stem cells in tissue repair and regeneration. J Invest Dermatol 132:1538–1541PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Robson M, Phillips LG, Lawrence WT, Bishop JB, Youngerman JS, Hayward PG et al (1992) The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 216:401–408PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Mast BA (1996) Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen 4:411–420PubMedCrossRefGoogle Scholar
  31. 31.
    Robson M (1997) The role of growth factors in the healing of chronic wounds. Wound Repair Regen 5:12–17PubMedCrossRefGoogle Scholar
  32. 32.
    Vogt PM, Thompson S, Andree C, Liu P, Breuing K, Hatzis D et al (1994) Genetically modified keratinocytes transplanted to wounds reconstitute the epidermis. Proc Natl Acad Sci USA 91:9307–9311PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Nomi M, Atala A, Coppi PD, Soker S (2002) Principals of neovascularization for tissue engineering. Mol Aspects Med 23:463–483PubMedCrossRefGoogle Scholar
  34. 34.
    Park HJ, Yang F, Cho SW (2012) Nonviral delivery of genetic medicine for therapeutic angiogenesis. Adv Drug Deliv Rev 64:40–52PubMedCrossRefGoogle Scholar
  35. 35.
    Song SH, Lee MO, Lee JS, Jeong HC, Kim HG, Kim WS et al (2012) Genetic modification of human adipose-derived stem cells for promoting wound healing. J Dermatol Sci 66:98–107PubMedCrossRefGoogle Scholar
  36. 36.
    Kleinheinz J, Jung S, Wermker K, Fischer C, Joos U (2010) Release kinetics of VEGF 165 from a collagen matrix and structural matrix changes in a circulation model. Head Face Med 6:1–7CrossRefGoogle Scholar
  37. 37.
    Schultz GS, Davidson JM, Kirsner RS, Herman IM (2011) Dynamic reciprocity in the wound microenvironment. Wound Repair Regen 19:134–148PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Hocking AM, Gibran NS (2010) Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 316:2213–2219PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Wei L, Fraser JL, Lu ZY, Hu X, Yu S (2012) Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 46:635–645PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Salem HK, Thiemermann C (2010) Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28:585–596PubMedPubMedCentralGoogle Scholar
  41. 41.
    Li Q, Yao D, Ma J, Zhu J, Xu X, Ren Y et al (2011) Transplantation of MSCs in combination with netrin-1 improves neoangiogenesis in a rat model of hind limb ischemia. J Surg Res 166:162–169PubMedCrossRefGoogle Scholar
  42. 42.
    Lim JY, Jeong CH, Jun JA, Kim SM, Ryu CH, Hou Y et al (2011) Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther 2:1–47CrossRefGoogle Scholar
  43. 43.
    Sukpat S, Isarasena N, Wongphoom J, Patumraj S (2013) Vasculoprotective effects of combined endothelial progenitor cells and mesenchymal stem cells in diabetic wound care: their potential role in decreasing wound-oxidative stress. Biomed Res Int 1–8Google Scholar
  44. 44.
    Stewart MC, Stewart AA (2011) Mesenchymal stem cells: characteristics, sources, and mechanisms of action. Vet Clin North Am Equine Pract 27:243–261PubMedCrossRefGoogle Scholar
  45. 45.
    Mouiseddine M, François S, Semont A, Sache A, Allenet B, Mathieu N et al (2007) Human mesenchymal stem cells home specifically to radiation-injured tissues in a non-obese diabetes/severe combined immunodeficiency mouse model. Br J Radiol 80(1):S49–S55PubMedCrossRefGoogle Scholar
  46. 46.
    Pozzi S, Lisini D, Podestà M, Bernardo ME, Sessarego N, Piaggio G et al (2006) Donor multipotent mesenchymal stromal cells may engraft in pediatric patients given either cord blood or bone marrow transplantation. Exp Hematol 34:934–942PubMedCrossRefGoogle Scholar
  47. 47.
    Rojewski MT, Weber BM, Schrezenmeier H (2008) Phenotypic characterization of mesenchymal stem cells from various tissues. Transfus Med Hemother 35:168–184PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I et al (2008) Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells 26:2865–2874PubMedCrossRefGoogle Scholar
  49. 49.
    Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403PubMedGoogle Scholar
  50. 50.
    Chen MY, Lie PC, Li ZL, Wei X (2009) Endothelial differentiation of Wharton’s jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells. Exp Hematol 37:629–640PubMedCrossRefGoogle Scholar
  51. 51.
    Shetty P, Thakur AM, Ravindran G, Viswanathan C (2010) Directed therapeutic angiogenesis by mesenchymal stem cells from umbilical cord matrix in preclinical model of ischemic limb disease. Stem Cell Stud 1(e16):97–104Google Scholar
  52. 52.
    Troyer DL, Weiss ML (2008) Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 26:591–599PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Hsieh JY, Wang HW, Chang SJ, Liao KH, Lee IH, Lin WS et al (2013) Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS ONE 8:e72604PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Carvalho MM, Teixeira FG, Reis RL, Sousa N, António J (2011) Mesenchymal stem cells in the umbilical cord: phenotypic characterization, secretome and applications in central nervous system regenerative medicine. Curr Stem Cell Res Ther 6:221–228PubMedCrossRefGoogle Scholar
  55. 55.
    Ribeiro CA, Fraga JS, Grãos M, Neves NM, Reis RL, Gimble JM et al (2012) The secretome of stem cells isolated from the adipose tissue and Wharton jelly acts differently on central nervous system derived cell populations. Stem Cell Res Ther 3:1–17CrossRefGoogle Scholar
  56. 56.
    Burlacu A, Grigorescu G, Rosca AM, Preda MB, Simionescu M (2013) Factors secreted by mesenchymal stem cells and endothelial progenitor cells have complementary effects on angiogenesis in vitro. Stem Cells Dev 22:643–653PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Truong ATN, Kowal-Vern A, Latenser BA, Wiley DE, Walter RJ (2005) Comparison of dermal substitutes in wound healing utilizing a nude mouse model. J Burns Wounds 4:e4PubMedPubMedCentralGoogle Scholar
  58. 58.
    Egaña JT, Danner S, Kremer M, Rapoport DH, Lohmeyer JA, Dye JF et al (2009) The use of glandular-derived stem cells to improve vascularization in scaffold-mediated dermal regeneration. Biomaterials 30:5918–5926PubMedCrossRefGoogle Scholar
  59. 59.
    Egaña JT, Fierro FA, Krüger S, Bornhäuser M, Huss R, Lavandero S, Machens HG (2009) Use of human mesenchymal cells to improve vascularization in a mouse model for scaffold-based dermal regeneration. Tissue Eng Part A15:1191–1200CrossRefGoogle Scholar
  60. 60.
    Danner S, Kremer M, Petschnik AE, Nagel S, Zhang Z, Hopfner U et al (2012) The use of human sweat gland-derived stem cells for enhancing vascularization during dermal regeneration. J Invest Dermatol 132:1707–1716PubMedCrossRefGoogle Scholar
  61. 61.
    Cuadra A, Correa G, Roa R, Piñeros JL, Norambuena H, Searle S et al (2012) Functional results of burned hands treated with Integra®. J Plast Reconstr Aesthet Surg 65:228–234PubMedCrossRefGoogle Scholar
  62. 62.
    Yao M, Attalla K, Ren Y, French MA, Driver VR (2013) Ease of use, safety, and efficacy of integra bilayer wound matrix in the treatment of diabetic foot ulcers in an outpatient clinical setting. A prospective pilot study. J Am Podiatr Med Assoc 103:274–280PubMedCrossRefGoogle Scholar
  63. 63.
    Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB (2010) Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS ONE 5:e9016PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Prieto C, Krause B, Quezada C, San Martin R, Sobrevia L, Casanello P (2011) Hypoxia-reduced nitric oxide synthase activity is partially explained by higher arginase-2 activity and cellular redistribution in human umbilical vein endothelium. Placenta 32:932–940PubMedCrossRefGoogle Scholar
  65. 65.
    Mosna F, Sensebé L, Krampera M (2010) Human bone marrow and adipose tissue mesenchymal stem cells: a user’s guide. Stem Cells Dev 19:1449–1470PubMedCrossRefGoogle Scholar
  66. 66.
    Elsdale T, Bard J (1972) Collagen substrata for studies on cell behavior. J Cell Biol 54:626–637PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Shohara R, Yamamoto A, Takikawa S, Iwase A, Hibi H, Kikkawa F, Ueda M (2012) Mesenchymal stromal cells of human umbilical cord Wharton’s jelly accelerate wound healing by paracrine mechanisms. Cytotherapy 14:1171–1181PubMedCrossRefGoogle Scholar
  68. 68.
    Dunn LK, Gruenloh SK, Dunn BE, Reddy DS, Falck JR, Jacobs ER, Medhora M (2005) Chick chorioallantoic membrane as an in vivo model to study vasoreactivity: characterization of development-dependent hyperemia induced by epoxyeicosatrienoic acids (EETs). Anat Rec A Discov Mol Cell Evol Biol 285:771–780PubMedCrossRefGoogle Scholar
  69. 69.
    Jones I, Currie L, Martin R (2002) A guide to biological skin substitutes. Br J Plast Surg 55:185–193PubMedCrossRefGoogle Scholar
  70. 70.
    Böttcher-Haberzeth S, Biedermann T, Reichmann E (2010) Tissue engineering of skin. Burns 36:450–460PubMedCrossRefGoogle Scholar
  71. 71.
    Wong VW, Gurtner GC (2012) Tissue engineering for the management of chronic wounds: current concepts and future perspectives. Exp Dermatol 21:729–734PubMedGoogle Scholar
  72. 72.
    Wu Y, Chen L, Scott PG, Tredget EE (2007) Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 25:2648–2659PubMedCrossRefGoogle Scholar
  73. 73.
    Maharlooei MK, Bagheri M, Solhjou Z, Jahromi BM, Akrami M, Rohani L et al (2011) Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats. Diabetes Res Clin Pract 93:228–234PubMedCrossRefGoogle Scholar
  74. 74.
    Azari O, Babaei H, Derakhshanfar A, Nematollahi-Mahani SN, Poursahebi R, Moshrefi M (2011) Effects of transplanted mesenchymal stem cells isolated from Wharton’s jelly of caprine umbilical cord on cutaneous wound healing; histopathological evaluation. Vet Res Commun 35:211–222PubMedCrossRefGoogle Scholar
  75. 75.
    Choi M, Lee HS, Naidansaren P, Kim HK, Cha JH, Ahn HY, Yang PI, Shin JC, Joe YA (2013) Proangiogenic features of Wharton’s jelly-derived mesenchymal stromal/stem cells and their ability to form functional vessels. Int J Biochem Cell Biol 45:560–570PubMedCrossRefGoogle Scholar
  76. 76.
    Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y et al (2009) Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol 259:150–156PubMedCrossRefGoogle Scholar
  77. 77.
    Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369–3376PubMedCrossRefGoogle Scholar
  78. 78.
    Lin X, Guo C, Gu L, Deuel T (1993) Site-specific methylation inhibits transcriptional activity of platelet-derived growth factor A-chain promoter. J Biol Chem 268:17334–17340PubMedGoogle Scholar
  79. 79.
    Schneider L, Cammer M, Lehman J, Nielsen S, Guerra C, Veland I et al (2010) Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell Physiol Biochem 25:279–292PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Shikada Y, Yonemitsu Y, Koga T, Onimaru M, Nakano T, Okano S et al (2005) Platelet-derived growth factor-AA is an essential and autocrine regulator of vascular endothelial growth factor expression in non-small cell lung carcinomas. Cancer Res 65:7241–7248PubMedCrossRefGoogle Scholar
  81. 81.
    Kagiwada H, Yashiki T, Ohshima A, Tadokoro M, Nagaya N, Ohgushi H (2008) Human mesenchymal stem cells as a stable source of VEGF-producing cells. J Tissue Eng Regen Med 2:184–189PubMedCrossRefGoogle Scholar
  82. 82.
    Bao P, Kodra A, Tomic-Canic M, Golinko M, Ehrlich H, Brem H (2008) The role of vascular endothelial growth factor in wound healing. J Surg Res 153:347–358PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321PubMedCrossRefGoogle Scholar
  84. 84.
    Formigli L, Benvenuti S, Mercatelli R, Quercioli F, Tani A, Mirabella C et al (2012) Dermal matrix scaffold engineered with adult mesenchymal stem cells and platelet-rich plasma as a potential tool for tissue repair and regeneration. J Tissue Eng Regen Med 6:125–134PubMedCrossRefGoogle Scholar
  85. 85.
    Ponce L, Kleinman H (2003) The Chick Chorioallantoic Membrane as an In Vivo Angiogenesis Model. Curr Protoc Cell Biol Chapter 19:Unit 19.5:22–39Google Scholar
  86. 86.
    Ribatti D, Nico B, Vacca A, Presta M (2006) The gelatin sponge-chorioallantoic membrane assay. Nat Protoc 1:85–91PubMedCrossRefGoogle Scholar
  87. 87.
    Herbert S, Stainier D (2011) Molecular control of endothelial cell behavior during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12:551–564PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Stefanini MO, Wu FTH, Mac Gabhann F, Popel AS (2008) A compartment model of VEGF distribution in blood, healthy and diseased tissues. BMC Syst Biol 2:1–15CrossRefGoogle Scholar
  89. 89.
    Oskowitz A, McFerrin H, Gutschow M, Carter M, Pochampally R (2011) Serum-deprived human multipotent mesenchymal stromal cells (MSCs) are highly angiogenic. Stem Cell Res 6:215–225PubMedCrossRefGoogle Scholar
  90. 90.
    Martínez C, Cornejo VH, Lois P, Ellis T, Solis NP, Wainwright BJ, Palma V (2013) Proliferation of murine midbrain neural stem cells depends upon an endogenous sonic hedgehog (Shh) source. PLoS ONE 8:e65818PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Landman KA, Cai AQ (2007) Cell proliferation and oxygen diffusion in a vascularising scaffold. Bull Math Biol 69:2405–2428PubMedCrossRefGoogle Scholar
  92. 92.
    Fraisl P, Mazzone M, Schmidt T, Carmeliet P (2009) Regulation of angiogenesis by oxygen and metabolism. Dev Cell 16:167–179PubMedCrossRefGoogle Scholar
  93. 93.
    Hass R, Kasper C, Böhm S, Jacobs R (2011) Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 9:1–14CrossRefGoogle Scholar
  94. 94.
    Lavrentieva A, Majore I, Kasper C, Hass R (2010) Effects of hypoxic culture conditions on umbilical cord-derived human mesenchymal stem cells. Cell Commun Signal 8:1–9CrossRefGoogle Scholar
  95. 95.
    Ma T, Grayson WL, Fröhlich M, Vunjak-Novakovic G (2009) Hypoxia and stem cell-based engineering of mesenchymal tissues. Biotechnol Prog 25:32–42PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Bizzarri A, Koehler H, Cajlakovic M, Pasic A, Schaupp L, Klimant I, Ribitsch V (2006) Continuous oxygen monitoring in subcutaneous adipose tissue using microdialysis. Anal Chim Acta 573–574:48–56PubMedCrossRefGoogle Scholar
  97. 97.
    Schäffler A, Büchler C (2007) Concise review: adipose tissue-derived stromal cells–basic and clinical implications for novel cell-based therapies. Stem Cells 25:818–827PubMedCrossRefGoogle Scholar
  98. 98.
    Jackson WM, Nesti LJ, Tuan RS (2012) Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med. 1:44–50PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Miyazaki S, Ishikawa F, Fujikawa T, Nagata S, Yamaguchi K (2004) Intraperitoneal injection of lipopolysaccharide induces dynamic migration of Gr-1high polymorphonuclear neutrophils in the murine abdominal cavity. Clin Diagn Lab Immunol 11:452–457PubMedPubMedCentralGoogle Scholar
  100. 100.
    Parekkadan B, Milwid JM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng 12:87–117PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Sandra S. Edwards
    • 1
  • Gabriela Zavala
    • 1
  • Catalina P. Prieto
    • 1
  • Matías Elliott
    • 1
  • Samuel Martínez
    • 1
  • Jose T. Egaña
    • 2
  • María R. Bono
    • 3
  • Verónica Palma
    • 1
  1. 1.FONDAP Center for Genome Regulation, Laboratory of Stem Cells and Development, Faculty of SciencesUniversidad de ChileSantiagoChile
  2. 2.Laboratory of Tissue Engineering and RegenerationTechnical University of MunichMunichGermany
  3. 3.Laboratory of Inmunology, Faculty of SciencesUniversidad de ChileSantiagoChile

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