Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stem Cells

Organ-injury-induced reactivation of hemangioblastic precursor cells

Leukemia volume 22, pages 103–113 (2008)Cite this article

Abstract

Early in mammalian development, the stem cell leukemia (SCL/TAL1) gene and its distinct 3′ enhancer (SCL 3′En) specify bipotential progenitor cells that give rise to blood and endothelium, thus termed hemangioblasts. We have previously detected a minor population of SCL (+) cells in the postnatal kidney. Here, we demonstrate that cells expressing the SCL 3′En in the adult kidney are comprised of CD45+CD31− hematopoietic cells, CD45−CD31+ endothelial cells and CD45−CD31− interstitial cells. Creation of bone marrow chimeras of SCL 3′En transgenic mice into wild-type hosts shows that all three types of SCL 3′En-expressing cells in the adult kidney can originate from the bone marrow. Ischemia/reperfusion injury to the adult kidney of SCL 3′En transgenic mice results in the intrarenal elevation of SCL and FLK1 mRNA levels and of cells expressing hem-endothelial progenitor markers (CD45, CD34, c-Kit and FLK1). Furthermore, analysis of SCL 3′En in the ischemic kidneys reveals an increase in the abundance of SCL 3′En-expressing cells, predominantly within the CD45 (+) hematopoietic fraction and to a lesser extent in the CD45 (−) fraction. Our results suggest organ-injury-induced reactivation of bone marrow-derived hemangioblasts and possible local angioblastic progenitors expressing SCL and SCL 3′En.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Risau W, Flamme I . Vasculogenesis. Annu Rev Cell Dev Biol 1995; 11: 73–91.

    Article  CAS  Google Scholar 

  2. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422–3427.

    Article  CAS  Google Scholar 

  3. Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Eguchi H et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 2000; 105: 1527–1535.

    Article  CAS  Google Scholar 

  4. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 965–967.

    Article  Google Scholar 

  5. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85: 221–228.

    Article  CAS  Google Scholar 

  6. Begley CG, Green AR . The SCL gene: from case report to critical hematopoietic regulator. Blood 1999; 93: 2760–2770.

    CAS  Google Scholar 

  7. Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH . The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 1996; 86: 47–57.

    Article  CAS  Google Scholar 

  8. Robb L, Lyons I, Li R, Hartley L, Köntgen F, Harvey RP et al. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci USA 1995; 92: 7075–7079.

    Article  CAS  Google Scholar 

  9. Shivdasani RA, Mayer EL, Orkin SH . Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 1995; 373: 432–434.

    Article  CAS  Google Scholar 

  10. Visvader JE, Fujiwara Y, Orkin SH . Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev 1998; 12: 473–479.

    Article  CAS  Google Scholar 

  11. Drake CJ, Brandt SJ, Trusk TC, Little CD . TAL1/SCL is expressed in endothelial progenitor cells/angioblasts and defines a dorsal- to-ventral gradient of vasculogenesis. Dev Biol 1997; 192: 17–30.

    Article  CAS  Google Scholar 

  12. Drake CJ, Fleming PA . Vasculogenesis in the day 6.5–9.5 mouse embryo. Blood 2000; 95: 1671–1679.

    CAS  Google Scholar 

  13. Gering M, Rodaway ARF, Gottgens B, Patient RK, Green AR . The SCL gene specifies haemangioblast development from early mesoderm. EMBO J 1998; 17: 4029–4045.

    Article  CAS  Google Scholar 

  14. Murayama E, Kissa K, Zapata A, Mordelet E, Briolat V, Lin HF et al. Tracing hematopoietic precursor migration to successive hematopoietic organs during zebrafish development. Immunity 2006; 25: 963–975.

    Article  CAS  Google Scholar 

  15. Lugus JJ, Park C, Choi K . Developmental relationship between hematopoietic and endothelial cells. Immunol Res 2005; 32: 57–74.

    Article  CAS  Google Scholar 

  16. Chung YS, Zhang WJ, Arentson E, Kingsley PD, Palis J, Choi K . Lineage analysis of the hemangioblast as defined by FLK1 and SCL expression. Development 2002; 129: 5511–5520.

    Article  CAS  Google Scholar 

  17. Kappel A, Schlaeger TM, Flamme I, Orkin SH, Risau W, Breier G . Role of SCL/Tal-1, GATA, and ets transcription factor binding sites for the regulation of flk-1 expression during murine vascular development. Blood 2000; 96: 3078–3085.

    CAS  Google Scholar 

  18. Ema M, Faloon P, Zhang WJ, Hirashima M, Reid T, Stanford WL et al. Combinatorial effects of Flk-1 and Tal1 (SCL) on vascular and hematopoietic development in the mouse. Genes Dev 2003; 17: 380–393.

    Article  CAS  Google Scholar 

  19. Abrahamson DR, Robert B, Hyink DP, St John PL, Daniel TO . Origins and formation of microvasculature in the developing kidney. Kidney Int Suppl 1998; 67: S7–S11.

    Article  Google Scholar 

  20. Sanchez M, Gottgens B, Sinclair AM, Stanley M, Begley CG, Hunter S et al. An SCL 3′ enhancer targets developing endothelium together with embryonic and adult haematopoietic progenitors. Development 1999; 126: 3891–3904.

    CAS  Google Scholar 

  21. Sanchez MJ, Bockamp EO, Miller J, Gambardella L, Green AR . Selective rescue of early haematopoietic progenitors in SCL(−/−) mice by expressing SCL under the control of a stem cell enhancer. Development 2001; 128: 4815–4827.

    CAS  Google Scholar 

  22. Göttgens B, Nastos A, Kinston S, Piltz S, Delabesse EC, Stanley M et al. Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J 2002; 21: 3039–3050.

    Article  Google Scholar 

  23. Silberstein L, Sanchez MJ, Socolovsky M, Liu Y, Hoffman G, Kinston S et al. Transgenic analysis of the stem cell leukemia +19 stem cell enhancer in adult and embryonic hematopoietic and endothelial cells. Stem Cells 2005; 23: 1378–1388.

    Article  CAS  Google Scholar 

  24. Dekel B, Hochman E, Sanchez MJ, Maharshak N, Amariglio N, Green AR et al. Kidney, blood, and endothelium: developmental expression of stem cell leukemia during nephrogenesis. Kidney Int 2004; 65: 1162–1169.

    Article  Google Scholar 

  25. Dekel B, Biton S, Yerushalmi GM, Altstock RT, Mittelman L, Faletto D et al. In situ activation pattern of Met docking site following renal injury and hypertrophy. Nephrol Dial Transplant 2003; 18: 1493–1504.

    Article  CAS  Google Scholar 

  26. Dekel B, Metsuyanim S, Schmidt-Ott KM, Fridman E, Jacob-Hirsch J, Simon A et al. Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res 2006; 66: 6040–6049.

    Article  CAS  Google Scholar 

  27. Rookmaaker MB, Smits AM, Tolboom H, Van ‘t Wout K, Martens AC, Goldschmeding R et al. Bone-marrow-derived cells contribute to glomerular endothelial repair in experimental glomerulonephritis. Am J Pathol 2003; 163: 553–562.

    Article  Google Scholar 

  28. Dekel B, Shezen E, Even-Tov-Friedman S, Katchman H, Margalit R, Nagler A et al. Transplantation of human hematopoietic stem cells into ischemic and growing kidneys suggests a role in vasculogenesis but not tubulogenesis. Stem Cells 2006; 24: 1185–1193.

    Article  CAS  Google Scholar 

  29. Johnson SA, Yoder MC . Reconstitution of hematopoiesis following transplantation into neonatal mice. Methods Mol Med 2005; 105: 95–106.

    Google Scholar 

  30. Sands MS, Barker JE . Percutaneous intravenous injection in neonatal mice. Lab Anim Sci 1999; 49: 328–330.

    CAS  Google Scholar 

  31. Dekel B, Zangi L, Shezen E, Reich-Zeliger S, Eventov-Friedman S, Katchman H et al. Isolation and characterization of nontubular Sca-1+Lin- multipotent stem/progenitor cells from adult mouse kidney. J Am Soc Nephrol 2006; 17: 3300–3314.

    Article  Google Scholar 

  32. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161: 1163–1177.

    Article  CAS  Google Scholar 

  33. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002; 8: 831–840.

    Article  CAS  Google Scholar 

  34. Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T et al. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest 2005; 115: 1743–1755.

    Article  CAS  Google Scholar 

  35. Cogle CR, Scott EW . The hemangioblast: cradle to clinic. Exp Hematol 2004; 32: 885–890.

    Article  Google Scholar 

  36. Hristov M, Weber C . Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance. J Cell Mol Med 2004; 8: 498–508.

    Article  Google Scholar 

  37. Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH et al. Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci USA 2006; 103: 13156–13161.

    Article  CAS  Google Scholar 

  38. Pimanda JE, Silberstein L, Dominici M, Dekel B, Bowen M, Oldham S et al. Transcriptional link between blood and bone: the stem cell leukemia gene and its +19 stem cell enhancer are active in bone cells. Mol Cell Biol 2006; 26: 2615–2625.

    Article  CAS  Google Scholar 

  39. Dreyfus PA, Chretien F, Chazaud B, Kirova Y, Caramelle P, Garcia L et al. Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. Am J Pathol 2004; 164: 773–779.

    Article  Google Scholar 

  40. Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG . Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest 2003; 112: 42–49.

    Article  CAS  Google Scholar 

  41. Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol 2003; 14: 1188–1199.

    Article  Google Scholar 

  42. Li J, Deane JA, Campanale NV, Bertram JF, Ricardo SD . Blockade of p38 mitogen-activated protein kinase and TGF-beta1/Smad signaling pathways rescues bone marrow-derived peritubular capillary endothelial cells in adriamycin-induced nephrosis. J Am Soc Nephrol 2006; 17: 2799–2811.

    Article  CAS  Google Scholar 

  43. Uchimura H, Marumo T, Takase O, Kawachi H, Shimizu F, Hayashi M 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: 997–1004.

    Article  Google Scholar 

  44. Grant MB, Caballero S, Brown GA, Guthrie SM, Mames RN, Vaught T et al. The contribution of adult hematopoietic stem cells to retinal neovascularization. Adv Exp Med Biol 2003; 522: 37–45.

    Article  Google Scholar 

  45. Botta R, Gao E, Stassi G, Bonci D, Pelosi E, Zwas D et al. Heart infarct in NOD-SCID mice: therapeutic vasculogenesis by transplantation of human CD34+ cells and low dose CD34+KDR+ cells. FASEB J 2004; 18: 1392–1394.

    Article  CAS  Google Scholar 

  46. Togel F, Isaac J, Hu Z, Weiss K, Westenfelder C . Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int 2005; 67: 1772–1784.

    Article  Google Scholar 

  47. Brunet de la Grange P, Armstrong F, Duval V, Rouyez MC, Goardon N, Romeo PH et al. Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells. Blood 2006; 108: 2998–3004.

    Article  CAS  Google Scholar 

  48. Ruiz de Almodovar C, Luttun A, Carmeliet P . An SDF-1 trap for myeloid cells stimulates angiogenesis. Cell 2006; 124: 18–21.

    Article  CAS  Google Scholar 

  49. Huss R, Heil M, Moosmann S, Sagebiel S, Seliger C, Kinston S et al. Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL(+) multipotent adult progenitor cell clones from peripheral blood. J Vasc Res 2004; 41: 422–431.

    Article  Google Scholar 

  50. Gottgens B, Broccardo C, Sanchez MJ, Deveaux S, Murphy G, Gothert JR et al. The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5′ bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol 2004; 24: 1870–1883.

    Article  Google Scholar 

Download references

Acknowledgements

This study was partially supported by grants from the Israel Scientific Foundation Physician-Scientist Grant Award, Sheba Career Development Award and Moriss Kahn Career Development Award (BD); The Israel Cancer Research Foundation and the Recannati foundation (SI); The Spanish Ministry of Education and Science Grant SAF07241; Junta de Andalucia grant PAI-CVI 295, fellowship CONACYT179065 to AMG and fellowship I3P-CSIC to CQ.

Author information

Author notes

  1. M J Sanchez and S Izraeli: These authors equally contributed to this paper.

Authors and Affiliations

  1. Department of Pediatrics and Laboratory of Regenerative Nephrology, Edmond and Lili Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel

    B Dekel & S Metsuyanim

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    B Dekel & S Izraeli

  3. Centro Andaluz de Biologia del Desarrollo (CABD), Consejo Superior de Investigaciones Cientificas, Universidad Pablo de Olavide, Seville, Spain

    A M Garcia, C Quintero & M J Sanchez

  4. Department of Pediatric Hemato-Oncology and the Cancer Research Center, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel

    S Izraeli

Authors
  1. B Dekel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Metsuyanim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A M Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Quintero
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M J Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Izraeli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Dekel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dekel, B., Metsuyanim, S., Garcia, A. et al. Organ-injury-induced reactivation of hemangioblastic precursor cells. Leukemia 22, 103–113 (2008). https://doi.org/10.1038/sj.leu.2404941

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404941

Keywords

This article is cited by

Search

Advanced search

Quick links