Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver
Orit Kollet, … , David A. Shafritz, Tsvee Lapidot
Orit Kollet, … , David A. Shafritz, Tsvee Lapidot
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):160-169. https://doi.org/10.1172/JCI17902.
View: Text | PDF
Article

HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver

  • Text
  • PDF
Abstract

Hematopoietic stem cells rarely contribute to hepatic regeneration, however, the mechanisms governing their homing to the liver, which is a crucial first step, are poorly understood. The chemokine stromal cell–derived factor-1 (SDF-1), which attracts human and murine progenitors, is expressed by liver bile duct epithelium. Neutralization of the SDF-1 receptor CXCR4 abolished homing and engraftment of the murine liver by human CD34+ hematopoietic progenitors, while local injection of human SDF-1 increased their homing. Engrafted human cells were localized in clusters surrounding the bile ducts, in close proximity to SDF-1–expressing epithelial cells, and differentiated into albumin-producing cells. Irradiation or inflammation increased SDF-1 levels and hepatic injury induced MMP-9 activity, leading to both increased CXCR4 expression and SDF-1–mediated recruitment of hematopoietic progenitors to the liver. Unexpectedly, HGF, which is increased following liver injury, promoted protrusion formation, CXCR4 upregulation, and SDF-1–mediated directional migration by human CD34+ progenitors, and synergized with stem cell factor. Thus, stress-induced signals, such as increased expression of SDF-1, MMP-9, and HGF, recruit human CD34+ progenitors with hematopoietic and/or hepatic-like potential to the liver of NOD/SCID mice. Our results suggest the potential of hematopoietic CD34+/CXCR4+cells to respond to stress signals from nonhematopoietic injured organs as an important mechanism for tissue targeting and repair.

Authors

Orit Kollet, Shoham Shivtiel, Yuan-Qing Chen, Jenny Suriawinata, Swan N. Thung, Mariana D. Dabeva, Joy Kahn, Asaf Spiegel, Ayelet Dar, Sarit Samira, Polina Goichberg, Alexander Kalinkovich, Fernando Arenzana-Seisdedos, Arnon Nagler, Izhar Hardan, Michel Revel, David A. Shafritz, Tsvee Lapidot

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
SDF-1 expression and engrafting cell accumulation within the liver. (a–d...
SDF-1 expression and engrafting cell accumulation within the liver. (a–d) NOD/SCID mice transplanted with CB CD34+ cells. (a) Hematoxylin and eosin staining 5–6 weeks after transplantation shows a bile duct (large arrow) adjacent to a large portal vein (pv) with cells surrounding the duct (dashed arrow) that are not observed in normal mouse liver. (b) Identification of SDF-1 in the bile ducts of NOD/SCID mouse liver. All epithelial cells in the bile ducts are strongly positive for SDF-1 (large arrow); scattered bile ductule cells (arrowheads) are also SDF-1–positive. (c) Human CD45+ hematopoietic cells (small arrows) are present in large numbers surrounding the bile ducts (large arrows) and accumulate to very high density between the ducts and the adjacent portal veins. (d) Human CD45+ cells are also observed as single cells or small clusters in random distribution in the hepatic sinusoids. Original magnification for a–d, ×400. (e and f) SDF-1 expression in normal adult human liver and in the liver of a patient with chronic hepatitis resulting from HCV infection was detected by immunohistochemistry. (e) Normal liver shows a single mature bile duct stained positive for SDF-1 (arrow) and absence of SDF-1 expression in endothelial cells lining a venous channel (arrowheads). (f) Liver from a patient with chronic liver disease from HCV infection shows extensive proliferation of bile ducts positive for SDF-1 expression (arrows) as well as expression of SDF-1 in bile ductule epithelium and/or canal of Hering or oval cells (arrowheads). Magnification for e and f, ×200.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts