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.

  • Research Article
  • Published:

Human CD34loCD133lo fetal liver cells support the expansion of human CD34hiCD133hi hematopoietic stem cells

Cellular & Molecular Immunology volume 13, pages 605–614 (2016)Cite this article

Abstract

We have recently discovered a unique CD34loCD133lo cell population in the human fetal liver (FL) that gives rise to cells in the hepatic lineage. In this study, we further characterized the biological functions of FL CD34loCD133lo cells. Our findings show that these CD34loCD133lo cells express markers of both endodermal and mesodermal lineages and have the capability to differentiate into hepatocyte and mesenchymal lineage cells by ex vivo differentiation assays. Furthermore, we show that CD34loCD133lo cells express growth factors that are important for human hematopoietic stem cell (HSC) expansion: stem cell factor (SCF), insulin-like growth factor 2 (IGF2), C-X-C motif chemokine 12 (CXCL12), and factors in the angiopoietin-like protein family. Co-culture of autologous FL HSCs and allogenic HSCs derived from cord blood with CD34loCD133lo cells supports and expands both types of HSCs.These findings are not only essential for extending our understanding of the HSC niche during the development of embryonic and fetal hematopoiesis but will also potentially benefit adult stem cell transplantations in clinics because expanded HSCs demonstrate the same capacity as primary cells to reconstitute the human immune system and mediate long-term hematopoiesis in vivo. Together, CD34loCD133lo cells not only serve as stem/progenitor cells for liver development but are also an essential component of the HSC niche in the human FL.

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.
Figure 6.

Similar content being viewed by others

References

  1. Martinez-Agosto JA, Mikkola HKA, Hartenstein V, Banerjee U . The hematopoietic stem cell and its niche: a comparative view . Genes Dev 2007 ; 21 : 3044 – 3060.

    Article  CAS  Google Scholar 

  2. Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C et al . Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells . Nat Med 2006 ; 12 : 240 – 245.

    Article  Google Scholar 

  3. Chou S, Lodish HF . Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells . PNAS 2010 ; 107 : 7799 – 7804.

    Article  CAS  Google Scholar 

  4. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I et al . Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy . Science 2009 ; 326 : 818 – 823.

    Article  CAS  Google Scholar 

  5. Le Blanc K, Ringdén O . Mesenchymal stem cells: properties and role in clinical bone marrow transplantation . Curr Opin Immunol 2006 ; 18 : 586 – 591.

    Article  CAS  Google Scholar 

  6. Ishii T, Eto K . Fetal stem cell transplantation: past, present, and future . World J Stem Cells 2014 ; 6 : 404 – 420.

    Article  Google Scholar 

  7. Rehman K, Iqbal MJ, Zahra N, Akash MSH . Liver stem cells: from preface to advancements . Curr Stem Cell Res Ther 2014 ; 9 : 10 – 21.

    Article  CAS  Google Scholar 

  8. Herrmann RP, Sturm MJ . Adult human mesenchymal stromal cells and the treatment of graft versus host disease . Stem Cells and Cloning 2014 : 7 : 45 – 52.

    PubMed  Google Scholar 

  9. Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C et al . Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival . Blood 2002 ; 100 : 1611 – 1618.

    CAS  PubMed  Google Scholar 

  10. Colter DC, Class R, DiGirolamo CM, Prockop DJ . Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow . PNAS 2000 ; 97 : 3213 – 3218.

    Article  CAS  Google Scholar 

  11. Drake AC, Khoury M, Leskov I, Iliopoulou BP, Fragoso M, Lodish H et al . Human CD34+ CD133+ hematopoietic stem cells cultured with growth factors including Angptl5 efficiently engraft adult NOD-SCID Il2rc2/2 (NSG) mice . PLoS One 2011 ; 6 : 1 – 9.

    Article  Google Scholar 

  12. Khoury M, Drake A, Chen Q, Dong D, Leskov I, Fragoso MF et al . Mesenchymal stem cells secreting angiopoietin-like-5 support efficient expansion of human hematopoietic stem cells without compromising their repopulating potential . Stem Cells Dev 2011 ; 20 : 1371 – 1381.

    Article  CAS  Google Scholar 

  13. Walasek MA, Os Rv, Haan Gd . Hematopoietic stem cell expansion: challenges and opportunities . Ann New York Acad Sci 2012 ; 1266 : 138 – 150.

    Article  CAS  Google Scholar 

  14. Chen Q, Khoury M, Limmon G, Choolani M, Chan JKY, Chen J . Human fetal hepatic progenitor cells are distinct from, but closely related to, hematopoetic stem/progenitor cells . Stem Cells 2013 ; 31 : 1160 – 1169.

    Article  CAS  Google Scholar 

  15. Sugiyama T, Kohara H, Noda M, Nagasawa T . Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches . Immunity 2006 ; 25 : 977 – 988.

    Article  CAS  Google Scholar 

  16. Christ B, Stock P . Mesenchymal stem cell-derived hepatocytes for functional liver replacement . Front Immunol 2012 ; 3 : 1 – 10.

    Article  Google Scholar 

  17. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T et al . Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells . J Clin Investig 2002 ; 109 : 1291 – 1302.

    Article  CAS  Google Scholar 

  18. Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS et al . Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages . PNAS 2006 ; 103 : 9912 – 9917.

    Article  CAS  Google Scholar 

  19. Rodaway A, Patient R . Mesendoderm: an ancient germ layer? Cell 2001 ; 105 : 169 – 172.

    Article  CAS  Google Scholar 

  20. Noll JE, Williams SA, Purton LE, Zannettino ACW . Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche? Blood Cancer J 2012 ; 2 : 1 – 10 .

    Article  Google Scholar 

  21. Walenda T, Bork S, Horn P, Wein F, Saffrich R, Diehlmann A et al . Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord . J Cell Mol Med 2010 ; 14 : 337 – 350.

    Article  CAS  Google Scholar 

  22. Wang H-S, Hung S-C, Peng S-T, Huang C-C, Wei H-M, Guo Y-J et al . Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord . Stem Cells 2004 ; 22 : 1330 – 1337.

    Article  Google Scholar 

  23. Bakhshi T, Zabriskie RC, Bodie S, Kidd S, Ramin S, Paganessi LA et al . Mesenchymal stem cells from the Wharton’s jelly of umbilical cord segments provide stromal support for the maintenance of cord blood hematopoietic stem cells during long-term ex vivo culture . Transfusion 2008 ; 48 : 2638 – 2644.

    Article  Google Scholar 

  24. Lee OK, Kuo TK, Chen W-M, Lee K-D, Hsieh S-L, Chen T-H . Isolation of multipotent mesenchymal stem cells from umbilical cord blood . Blood 2004 ; 103 : 1669 – 1675.

    Article  CAS  Google Scholar 

  25. Huang G-P, Pan Z-J, Jia B-B, Zheng Q, Xie C-G, Gu J-H et al . Ex vivo expansion and transplantation of hematopoietic stem/progenitor cells supported by mesenchymal stem cells from human umbilical cord blood . Cell Transplant 2007 ; 16 : 579 – 585.

    Article  CAS  Google Scholar 

  26. Campagnoli C, Roberts IAG, Kumar S, Bennett PR, Bellantuono I, Fisk NM . Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow . Blood 2001 ; 98 : 2396 – 2402.

    Article  CAS  Google Scholar 

  27. Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A . Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region . J Exp Med 2011 ; 208 : 2417 – 2427.

    Article  CAS  Google Scholar 

  28. Isern J, Martín-Antonio B, Ghazanfari R, Martín AM, López JA, Toro Rd et al . Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion . Cell 2013 ; 3 : 1714 – 1724.

    CAS  Google Scholar 

  29. Dzierzak EA, Harvey KN . Cell-cell contact and anatomical compatibility in stromal cell-mediated HSC support during development . Stem Cells 2004 ; 22 : 253 – 258.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Sue Yee Tan and Jessica Jie Ying Ong for providing excellent technical support. This study was supported by the Institute of Molecular and Cell Biology, the Agency for Science, Technology and Research (A*STAR), Singapore and A*STAR Joint Council Office Development Programme 1334k00082.

Author information

Author notes

  1. Qingfeng Chen, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673, Singapore. E-mail: qchen@imcb.a-star.edu.sg

Authors and Affiliations

  1. Humanized Mouse Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore

    Kylie Su Mei Yong, Choong Tat Keng, Wanjin Hong & Qingfeng Chen

  2. Department of Obstetrics & Gynaecology, KK Women’s and Children’s Hospital, Singapore, 229899, Singapore

    Shu Qi Tan & Thiam Chye Tan

  3. Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, 229899, Singapore

    Eva Loh & Kenneth TE Chang

  4. Duke-NUS Graduate Medical School, Singapore, 169857, Singapore

    Kenneth TE Chang & Thiam Chye Tan

  5. Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore, 138602, Singapore

    Qingfeng Chen

  6. Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

    Qingfeng Chen

Authors
  1. Kylie Su Mei Yong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Choong Tat Keng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu Qi Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Loh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth TE Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thiam Chye Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wanjin Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qingfeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors have no financial conflict of interest.

Additional information

Supplementary information accompanies the manuscript on Cellular & Molecular Immunology's website (http://www.nature.com/cmi/)

Supplementary Information accompanies the paper on Cellular & Molecular Immunology website.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yong, K., Keng, C., Tan, S. et al. Human CD34loCD133lo fetal liver cells support the expansion of human CD34hiCD133hi hematopoietic stem cells. Cell Mol Immunol 13, 605–614 (2016). https://doi.org/10.1038/cmi.2015.40

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2015.40

Keywords

This article is cited by

Search

Advanced search

Quick links