Chinese Science Bulletin

, Volume 58, Issue 23, pp 2820–2827 | Cite as

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

  • XiaoHua Jia
  • He Lü
  • Chen Li
  • GuoWei Feng
  • XinPeng Yao
  • LiNa Mao
  • TingYu Ke
  • YongZhe Che
  • Yong Xu
  • ZongJin Li
  • DeLing Kong
Open Access
Article Cell Biology


Endothelial cell therapy has been implicated to enhance tissue regeneration and vascularization in ischemic kidney. However, no published study has yet examined direct effects of endothelial cell treatment in kidney recovery. This study investigated the therapeutic efficacy of endothelial cells in a mouse model with acute kidney injury (AKI). Thus, human embryonic stem cells-derived endothelial cells (hESC-ECs) labeled with a reporter system encoding a double fusion reporter gene for firefly luciferase (Fluc) and green fluorescent protein (GFP) were characterized by Fluc imaging and immunofluoresence staining. Cultured hESC-ECs (1×106) were injected into ischemic kidney shortly after AKI. Survival of the transplanted hESC-ECs was monitored in vivo from day 1 to 14 after endothelial cell transplantation and potential impact of hESC-EC treatment on renal regeneration was assessed by histological analyses. We report that a substantial level of bioluminescence activity was detected 24 h after hESC-EC injection followed by a gradual decline from 1 to 14 d. Human ESC-ECs markedly accelerated kidney cell proliferation in response to ischaemia-induced damage, indicated by an elevated number of BrdU+ cells. Co-expression of Sca-1, a kidney stem cell proliferation marker, and BrdU further suggested that the observed stimulation in renal cell regeneration was, at least in part, due to increased proliferation of renal resident stem cells especially within the medullary cords and arteriole. Differentiation of hESC-ECs to smooth muscle cells was also observed at an early stage of kidney recovery. In summary, our results suggest that endothelial cell therapy facilitates kidney recovery by promoting vascularization, trans-differentiation and endogenous renal stem cell proliferation in AKI.


molecular imaging kidney ischemia renal stem cells endothelial cells cell transplantation 


  1. 1.
    Patschan D, Patschan S, Muller G A. Endothelial progenitor cells in acute ischemic kidney injury: Strategies for increasing the cells’ renoprotective competence. Int J Nephrol, 2011, 828369Google Scholar
  2. 2.
    Munshi R, Hsu C, Himmelfarb J. Advances in understanding ischemic acute kidney injury. BMC Med, 2011, 9: 11CrossRefGoogle Scholar
  3. 3.
    Strauer B E, Kornowski R. Stem cell therapy in perspective. Circulation, 2003, 107: 929–934CrossRefGoogle Scholar
  4. 4.
    Brodsky S V, Gao S, Li H, et al. Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol, 2002, 283: H2130–2139Google Scholar
  5. 5.
    Yamamoto T, Tada T, Brodsky S V, et al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am J Physiol Renal Physiol, 2002, 282: F1150–1155Google Scholar
  6. 6.
    Kumar A H, Caplice N M. Clinical potential of adult vascular progenitor cells. Arterioscler Thromb Vasc Biol, 2010, 30: 1080–1087CrossRefGoogle Scholar
  7. 7.
    Cheung C, Sinha S. Human embryonic stem cell-derived vascular smooth muscle cells in therapeutic neovascularisation. J Mol Cell Cardiol, 2011, 51: 651–664CrossRefGoogle Scholar
  8. 8.
    Morigi M, Rota C, Montemurro T, et al. Life-sparing effect of human cord blood-mesenchymal stem cells in experimental acute kidney injury. Stem Cells, 2010, 28: 513–522Google Scholar
  9. 9.
    Liu Y, Ye Z, Wang Y, et al. Induction-dependent neural marker expression and electrophysiological characteristics of bone marrow mesenchymal stem cells that naturally express high levels of nestin. Chin Sci Bull, 2011, 56: 640–646CrossRefGoogle Scholar
  10. 10.
    Li D, Wang W, Guo R, et al. Restoration of rat calvarial defects by poly(lactide-do-glycolide)/hydroxyapatite scaffolds loaded with bone mesenchymal stem cells and DNA complexes. Chin Sci Bull, 2012, 57: 435–444CrossRefGoogle Scholar
  11. 11.
    Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med, 2005, 353: 999–1007CrossRefGoogle Scholar
  12. 12.
    Levenberg S, Zoldan J, Basevitch Y, et al. Endothelial potential of human embryonic stem cells. Blood, 2007, 110: 806–814CrossRefGoogle Scholar
  13. 13.
    Li Z, Han Z, Wu J C. Transplantation of human embryonic stem cell-derived endothelial cells for vascular diseases. J Cell Biochem, 2009, 106: 194–199CrossRefGoogle Scholar
  14. 14.
    Li Z, Wilson K D, Smith B, et al. Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS One, 2009, 4: e844Google Scholar
  15. 15.
    Huang N F, Niiyama H, Peter C, et al. Embryonic stem cell-derived endothelial cells engraft into the ischemic hindlimb and restore perfusion. Arterioscler Thromb Vasc Biol, 2010, 30: 984–991CrossRefGoogle Scholar
  16. 16.
    Oyamada N, Itoh H, Sone M, et al. Transplantation of vascular cells derived from human embryonic stem cells contributes to vascular regeneration after stroke in mice. J Transl Med, 2008, 6: 54CrossRefGoogle Scholar
  17. 17.
    Li Z, Wu J C, Sheikh A Y, et al. Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation, 2007, 116: I46–54Google Scholar
  18. 18.
    Cho S W, Moon S H, Lee S H, et al. Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation, 2007, 116: 2409–2419CrossRefGoogle Scholar
  19. 19.
    Uchimura H, Marumo T, Takase O, et al. Intrarenal injection of bone marrow-derived angiogenic cells reduces endothelial injury and mesangial cell activation in experimental glomerulonephritis. J Am Soc Nephrol, 2005, 16: 997–1004CrossRefGoogle Scholar
  20. 20.
    Gnecchi M, Zhang Z, Ni A, et al. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res, 2008, 103: 1204–1219CrossRefGoogle Scholar
  21. 21.
    Sangidorj O, Yang S H, Jang H R, et al. Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model. Am J Physiol Renal Physiol, 2010, 299: F325–335CrossRefGoogle Scholar
  22. 22.
    Li Z, Suzuki Y, Huang M, et al. Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells, 2008, 26: 864–873CrossRefGoogle Scholar
  23. 23.
    Li Z, Lee A, Huang M, et al. Imaging survival and function of transplanted cardiac resident stem cells. J Am Coll Cardiol, 2009, 53: 1229–1240CrossRefGoogle Scholar
  24. 24.
    Yu J, Huang N F, Wilson K D, et al. nAChRs mediate human embryonic stem cell-derived endothelial cells: Proliferation, apoptosis, and angiogenesis. PLoS One, 2009, 4: e7040CrossRefGoogle Scholar
  25. 25.
    Kwon O, Miller S, Li N, et al. Bone marrow-derived endothelial progenitor cells and endothelial cells may contribute to endothelial repair in the kidney immediately after ischemia-reperfusion. J Histochem Cytochem, 2010, 58: 687–694CrossRefGoogle Scholar
  26. 26.
    Brodsky S V, Yamamoto T, Tada T, et al. Endothelial dysfunction in ischemic acute renal failure: Rescue by transplanted endothelial cells. Am J Physiol Renal Physiol, 2002, 282: F1140–1149Google Scholar
  27. 27.
    Kofidis T, Lebl D R, Martinez E C, et al. Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation, 2005, 112: I173–177Google Scholar
  28. 28.
    Frid M G, Kale V A, Stenmark K R. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: In vitro analysis. Circ Res, 2002, 90: 1189–1196CrossRefGoogle Scholar
  29. 29.
    Liebner S, Cattelino A, Gallini R, et al. Beta-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol, 2004, 166: 359–367CrossRefGoogle Scholar
  30. 30.
    Sallustio F, De Benedictis L, Castellano G, et al. TLR2 plays a role in the activation of human resident renal stem/progenitor cells. FASEB J, 2010, 24: 514–525CrossRefGoogle Scholar
  31. 31.
    Parikh C R, Lu J C, Coca S G, et al. Tubular proteinuria in acute kidney injury: A critical evaluation of current status and future promise. Ann Clin Biochem, 2010, 47: 301–312CrossRefGoogle Scholar
  32. 32.
    Yeagy B A, Cherqui S. Kidney repair and stem cells: A complex and controversial process. Pediatr Nephrol, 2011, 26: 1427–1434CrossRefGoogle Scholar
  33. 33.
    Dekel B, Zangi L, Shezen E, et al. Isolation and characterization of nontubular sca-1+lin-multipotent stem/progenitor cells from adult mouse kidney. J Am Soc Nephrol, 2006, 17: 3300–3314CrossRefGoogle Scholar
  34. 34.
    Burchfield J S, Dimmeler S. Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis. Fibrogenesis Tissue Repair, 2008, 1: 4CrossRefGoogle Scholar

Copyright information

© The Author(s) 2013

Authors and Affiliations

  • XiaoHua Jia
    • 1
    • 2
  • He Lü
    • 3
  • Chen Li
    • 4
  • GuoWei Feng
    • 5
  • XinPeng Yao
    • 1
  • LiNa Mao
    • 1
  • TingYu Ke
    • 1
  • YongZhe Che
    • 1
    • 2
  • Yong Xu
    • 5
  • ZongJin Li
    • 1
    • 2
  • DeLing Kong
    • 1
  1. 1.State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of EducationNankai UniversityTianjinChina
  2. 2.School of MedicineNankai UniversityTianjinChina
  3. 3.College of Basic MedicineYanbian UniversityYanjiChina
  4. 4.Diabetes Research GroupKing’s College LondonLondonUK
  5. 5.Department of UrologySecond Hospital of Tianjin Medical University, Tianjin Institute of UrologyTianjinChina

Personalised recommendations