Skip to main content

Advertisement

Log in

Stem Cells, Including a Population of Very Small Embryonic-Like Stem Cells, are Mobilized Into Peripheral Blood in Patients After Skin Burn Injury

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Background

Developmentally early cells, including hematopoietic stem progenitor cells (HSPCs), as well as very small embryonic-like stem cells (VSELs), are mobilized into peripheral blood (PB) in response to tissue and organ injury (e.g., heart infarct or stroke).

Objective

We seek to determine whether these cells are also mobilized into PB in patients with skin burn injuries.

Methods

Forty-four (44) patients (33–57 years of age) with total body surface burn area of 30–60%, as well as 23 healthy control subjects, were recruited and PB samples were harvested during the first 24 hours, day +2, and day +5 after burn injury and compared to normal controls. The circulating human CD34+CD133+ cells enriched for HSPCs, as well as small CXCR4+CD34+CD133+ subsets of LinCD45 cells that correspond to the population of VSELs, were counted by FACS and evaluated by direct immunofluorescence staining for pluripotency markers (Oct-4, Nanog, and SSEA-4). In parallel, we also measured by ELISA the serum concentration of factors that regulate stem cell trafficking, such as SDF-1, VEGF, and HGF.

Results

Our data indicate that skin burn injury mobilizes cells expressing stem cell-associated markers, such as CD133, CD34, and CXCR4, into PB. More importantly, we found an increase in the number of circulating primitive, small Oct-4+Nanog+SSEA-4+CXCR4+linCD45 VSELs. All these changes were accompanied by increased serum concentrations of SDF-1 and VEGF.

Limitations

Further studies are needed to fully assess the role of mobilized stem cells in the healing process to see if they can contribute to skin regeneration.

Conclusion

Skin burn injury triggers the mobilization of HSPCs and CXCR4+ VSELs, while the significance and precise role of mobilized VSELs in skin repair requires further study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kucia, M., Dawn, B., Hunt, G., Guo, Y., Wysoczynski, M., Majka, M., et al. (2004). Cell expressing early cardiac marcers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infraction. Circulation Research, 95, 1191–9.

    Article  PubMed  CAS  Google Scholar 

  2. Kucia, M., Reca, R., Campbell, F. R., Zuba-Surma, E., Majka, M., Ratajczak, J., et al. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia, 20, 857–69.

    Article  PubMed  CAS  Google Scholar 

  3. Paczkowska, E., Kucia, M., Koziarska, D., Halasa, M., Safranow, K., Masiuk, M., et al. (2009). Clinical evidence that very small embryonic-like stem cells are mobilized into peripheral blood in patients after stroke. Stroke, 40, 1237–4.

    Article  PubMed  CAS  Google Scholar 

  4. Barrandon, Y., & Green, H. (1987). Three clonal types of keratinocyte with different capacities for multiplication. Proceedings of the National Academy of Sciences of the United States of America, 84, 2302–6.

    Article  PubMed  CAS  Google Scholar 

  5. Cotsarelis, G., Sun, T. T., & Lavker, R. M. (1990). Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell, 61, 1329–37.

    Article  PubMed  CAS  Google Scholar 

  6. Jones, P. H., Harper, S., & Watt, F. M. (1995). Stem cell pattering and fate in human epidermis. Cell, 80, 83–93.

    Article  PubMed  CAS  Google Scholar 

  7. Li, A., Simmons, P. J., & Kaur, P. (1998). Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proceedings of the National Academy of Sciences of the United States of America, 95, 3902–7.

    Article  PubMed  CAS  Google Scholar 

  8. Niemann, C., & Watt, F. M. (2002). Designer skin: lineage commitment in postnatal epidermis. Trends in Cell Biology, 12, 185–92.

    Article  PubMed  CAS  Google Scholar 

  9. Fuchs, E., Tumbar, T., & Guasch, G. (2004). Socializing with the neighbors: stem cells and their niche. Cell, 116, 769–78.

    Article  PubMed  CAS  Google Scholar 

  10. Webb, A., Li, A., & Kaur, P. (2004). Location and phenotype of human adult keratinocyte stem cells of the skin. Differentiation, 72, 378–95.

    Article  Google Scholar 

  11. Moore, K. A., & Lemischka, I. R. (2006). Stem cells and their niches. Science, 311, 1880–5.

    Article  PubMed  CAS  Google Scholar 

  12. Bell, E., Ehrlich, H. P., Buttle, D. J., & Nakatsuji, T. (1988). Living tissue formed in vitro and accepted as skin equivalent tissue of full thickness. Science, 211, 1052–4.

    Article  Google Scholar 

  13. Boyce, S. T., & Hansbrough, J. F. (1988). Biologic attachment, growth, and differentiation of cultured human epidermal keratinocytes on a graftable collagen and chondroitin-6-sulfate substrate. Surgery, 103, 421–31.

    PubMed  CAS  Google Scholar 

  14. Parenteau, N. L., Hardin-Young, J., & Ross, R. N. (2000). Skin. In R. P. Lanza, R. S. Langer, & W. L. Chick (Eds.), Principles of the tissue engineering (pp. 879–890). San Diego: Academic.

    Chapter  Google Scholar 

  15. Compton, C. C. (1996). Cultured epithelial autografts for burn wound resurfacing: review of observations from an 11-year biopsy study. Wounds, 8, 125–33.

    Google Scholar 

  16. Horch, R. E., Bannasch, H., Kopp, J., Andree, C., & Stark, G. B. (1997). Single-cell suspension of cultured human keratinocytes in fibrin-glue reconstitute the epidermis. Cell Transplantation, 7, 309–17.

    Article  Google Scholar 

  17. Wood, F. (2003). Clinical potential of autologous epithelial suspension. Wounds, 15, 16–22.

    Google Scholar 

  18. Drukala, J., Bandura, L., Cieslik, K., & Korohoda, W. (2001). Locomotion of human skin keratinocytes on polystyrene, fibrin, and collagen substrata and its modification by cell-to-cell contacts. Cell Transplantation, 10, 765–71.

    PubMed  CAS  Google Scholar 

  19. Badiavas, E. V., & Falanga, V. (2003). Treatment of chronic wounds with bone marrow-derived cells. Archives of Dermatology, 139, 510–6.

    Article  PubMed  Google Scholar 

  20. Satoh, H., Kishi, K., Tanaka, T., Kubota, Y., Nakajima, T., Akasaka, Y., et al. (2004). Transplanted mesenchymal stem cells are effective for skin regeneration in acute cutaneous wounds. Cell Transplantation, 13, 405–12.

    Article  PubMed  Google Scholar 

  21. Sasaki, M., Abe, R., Fujita, Y., Ando, S., Inokuma, D., & Shimizu, H. (2008). Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. Journal of Immunology, 180, 2581–7.

    CAS  Google Scholar 

  22. Fu, X., & Li, H. (2009). Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions. Cell and Tissue Research, 335, 317–21.

    Article  PubMed  Google Scholar 

  23. Wojakowski, W., Tendera, M., Kucia, M., Zuba-Surma, E., Paczkowska, E., Ciosek, J., et al. (2009). Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. Journal of the American College of Cardiology, 53, 1–9.

    Article  PubMed  CAS  Google Scholar 

  24. Paczkowska, E., Larysz, B., Rzeuski, R., Karbicka, A., Jałowiński, R., Kornacewicz-Jach, Z., et al. (2005). Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. European Journal of Haematology, 75, 461–7.

    Article  PubMed  CAS  Google Scholar 

  25. Massberg, S., Schaerli, P., Knezevic-Maramica, I., Köllnberger, M., Tubo, N., Moseman, E. A., et al. (2007). Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell, 131, 994–1008.

    Article  PubMed  CAS  Google Scholar 

  26. Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I., & Littman, D. R. (1998). Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature, 393, 595–9.

    Article  PubMed  CAS  Google Scholar 

  27. Lapidot, T., & Kollet, O. (2002). The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia, 16, 1992–2003.

    Article  PubMed  CAS  Google Scholar 

  28. Kmiecik, T. E., Keller, J. R., Rosen, E., & Vande Woude, G. F. (1992). Hepatocyte growth factor is a synergistic factor for the growth of hematopoietic progenitor cells. Blood, 80, 2454–7.

    PubMed  CAS  Google Scholar 

  29. Ma, Q., Jones, D., Borghesani, P. R., Segal, R. A., Nagasawa, T., Kishimoto, T., et al. (1998). Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 95, 9448–53.

    Article  PubMed  CAS  Google Scholar 

  30. Nagasawa, T. (2000). A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. International Journal of Hematology, 72, 408–11.

    PubMed  CAS  Google Scholar 

  31. Taichman, R. S., Wang, Z., Shiozawa, Y., Jung, Y., Song, J., Balduino, A., et al. (2010). Prospective identification and skeletal localization of cells capable of multilineage differentiation in vivo. Stem Cells and Development, 19, 1557–70.

    Article  PubMed  CAS  Google Scholar 

  32. LaBarge, M. A., & Blau, H. M. (2002). Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell, 111, 589–601.

    Article  PubMed  CAS  Google Scholar 

  33. Ratajczak, M. Z., Reca, R., Wysoczynski, M., Yan, J., & Ratajczak, J. (2006). Modulation of the SDF-1-CXCR4 axis by the third complement component (C3)–implications for trafficking of CXCR4+ stem cells. Experimental Hematology, 34, 986–95.

    Article  PubMed  CAS  Google Scholar 

  34. Ratajczak, M. Z., Lee, H., Wysoczynski, M., Wan, W., Marlicz, W., Laughlin, M. J., et al. (2010). Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia, 24, 976–85.

    Article  PubMed  CAS  Google Scholar 

  35. Ratajczak, M. Z., Kim, C. H., Wojakowski, W., Janowska-Wieczorek, A., Kucia, M., & Ratajczak, J. (2010). Innate immunity as orchestrator of stem cell mobilization. Leukemia, 24, 1667–75.

    Article  PubMed  CAS  Google Scholar 

  36. Petit, I., Szyper-Kravitz, M., Nagler, A., Lahav, M., Peled, A., Habler, L., et al. (2002). G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nature Immunology, 3, 687–94.

    Article  PubMed  CAS  Google Scholar 

  37. Stocum, D. L. (2001). Stem cells in regenerative biology and medicine. Wound Repair and Regeneration, 9, 429–42.

    Article  PubMed  CAS  Google Scholar 

  38. Wojakowski, W., Tendera, M., Michałowska, A., Majka, M., Kucia, M., Maślankiewicz, K., et al. (2004). Mobilization of CD34/CXCR4+, CD34/CD117+, c-met + stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation, 110, 3213–20.

    Article  PubMed  CAS  Google Scholar 

  39. Dawn, B., Tiwari, S., Kucia, M. J., Zuba-Surma, E. K., Guo, Y., Sanganalmath, S. K., et al. (2008). Transplantation of bone marrow-derived very small embryonic-like stem cells attenuates left ventricular dysfunction and remodeling after myocardial infarction. Stem Cells, 26, 1646–55.

    Article  PubMed  Google Scholar 

  40. Shyu, W. C., Lin, S. Z., Yang, H. I., Tzeng, Y. S., Pang, C. Y., Yen, P. S., et al. (2004). Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation, 110, 1847–54.

    Article  PubMed  CAS  Google Scholar 

  41. Kassirer, M., Zeltser, D., Gluzman, B., Leibovitz, E., Goldberg, Y., Roth, A., et al. (1999). The appearance of L-selectin(low) polymorphonuclear leukocytes in the circulating pool of peripheral blood during myocardial infarction correlates with neutrophilia and with the size of the infarct. Clinical Cardiology, 22, 721–6.

    Article  PubMed  CAS  Google Scholar 

  42. Ratajczak, J., Reca, R., Kucia, M., Majka, M., Allendorf, D. J., Baran, J. T., et al. (2004). Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood, 103(6), 2071–8. Epub 2003 Nov 6.

    Article  PubMed  CAS  Google Scholar 

  43. Reca, R., Mastellos, D., Majka, M., Marquez, L., Ratajczak, J., Franchini, S., et al. (2003). Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1. Blood, 101, 3784–93.

    Article  PubMed  CAS  Google Scholar 

  44. Lapidot, T., Dar, A., & Kollet, O. (2005). How do stem cells find their way home? Blood, 106, 1901–10.

    Article  PubMed  CAS  Google Scholar 

  45. Lévesque, J. P., Takamatsu, Y., Nilsson, S. K., Haylock, D. N., & Simmons, P. J. (2000). Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood, 98, 1289–97.

    Article  Google Scholar 

  46. Lee, H., & Ratajczak, M. Z. (2009). Innate immunity: a key player in the mobilization of hematopoietic stem/progenitor cells. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 57, 269–78.

    Article  CAS  Google Scholar 

  47. Sweeney, E. A., Lortat-Jacob, H., Priestley, G. V., Nakamoto, B., & Papayannopoulou, T. (2002). Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood, 99, 44–51.

    Article  PubMed  CAS  Google Scholar 

  48. Hänel, P., Andréani, P., & Gräler, M. H. (2007). Erythrocytes store and release sphingosine 1-phosphate in blood. The FASEB Journal, 21, 1202–9.

    Article  Google Scholar 

  49. Ohkawa, R., Nakamura, K., Okubo, S., Hosogaya, S., Ozaki, Y., Tozuka, M., et al. (2008). Plasma sphingosine-1-phosphate measurement in healthy subjects: close correlation with red blood cell parameters. Annals of Clinical Biochemistry, 45, 356–63.

    Article  PubMed  CAS  Google Scholar 

  50. Gronthos, S., Zannettino, A. C., Hay, S. J., Shi, S., Graves, S. E., Kortesidis, A., et al. (2003). Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. Journal of Cell Science, 116, 1827–35.

    Article  PubMed  CAS  Google Scholar 

  51. Aliotta, J. M., Pereira, M., Johnson, K. W., de Paz, N., Dooner, M. S., Puente, N., et al. (2010). Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Experimental Hematology, 38, 233–45.

    Article  PubMed  CAS  Google Scholar 

  52. Rodgerson DO, Harris AG (2011). A Comparison of Stem Cells for Therapeutic Use. Stem Cells Review 2011; (in press): doi: 10.1007/s12015-011-9241-y.

  53. Kucia, M., Ratajczak, J., & Ratajczak, M. Z. (2005). Are bone marrow stem cells plastic or heterogenous–that is the question. Experimental Hematology, 33, 613–23.

    Article  PubMed  Google Scholar 

  54. Ratajczak, M. Z., Shin, D. M., Liu, R., Marlicz, W., Tarnowski, M., Ratajczak, J., et al. (2010). Epiblast/germ line hypothesis of cancer development revisited: lesson from the presence of Oct-4+ cells in adult tissues. Stem Cell Reviews, 6, 307–16.

    Article  PubMed  Google Scholar 

Download references

Disclosures

The authors indicate no potential conflicts of interest.

Founding source

This research was supported by EU structural funds, Innovative Economy Operational Program POIG.01.01.01-00-109/09-01.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Justyna Drukała or Mariusz Z. Ratajczak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drukała, J., Paczkowska, E., Kucia, M. et al. Stem Cells, Including a Population of Very Small Embryonic-Like Stem Cells, are Mobilized Into Peripheral Blood in Patients After Skin Burn Injury. Stem Cell Rev and Rep 8, 184–194 (2012). https://doi.org/10.1007/s12015-011-9272-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-011-9272-4

Keywords

Navigation