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PLoS Biol. 2004 Mar;2(3):E75. Epub 2004 Mar 16.

Circulation and chemotaxis of fetal hematopoietic stem cells.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. jchristensen@cellerant.com

Abstract

The major site of hematopoiesis transitions from the fetal liver to the spleen and bone marrow late in fetal development. To date, experiments have not been performed to evaluate functionally the migration and seeding of hematopoietic stem cells (HSCs) during this period in ontogeny. It has been proposed that developmentally timed waves of HSCs enter the bloodstream only during distinct windows to seed the newly forming hematopoietic organs. Using competitive reconstitution assays to measure HSC activity, we determined the localization of HSCs in the mid-to-late gestation fetus. We found that multilineage reconstituting HSCs are present at low numbers in the blood at all timepoints measured. Seeding of fetal bone marrow and spleen occurred over several days, possibly while stem cell niches formed. In addition, using dual-chamber migration assays, we determined that like bone marrow HSCs, fetal liver HSCs migrate in response to stromal cell-derived factor-1alpha (SDF-1alpha); however, unlike bone marrow HSCs, the migratory response of fetal liver HSCs to SDF-1alpha is greatly increased in the presence of Steel factor (SLF), suggesting an important role for SLF in HSC homing to and seeding of the fetal hematopoietic tissues. Together, these data demonstrate that seeding of fetal organs by fetal liver HSCs does not require large fluxes of HSCs entering the fetal bloodstream, and that HSCs constitutively circulate at low levels during the gestational period from 12 to 17 days postconception. Newly forming hematopoietic tissues are seeded gradually by HSCs, suggesting initial seeding is occurring as hematopoietic niches in the spleen and bone marrow form and become capable of supporting HSC self-renewal. We demonstrate that fetal and adult HSCs exhibit specific differences in chemotactic behavior. While both migrate in response to SDF-1alpha, fetal HSCs also respond significantly to the cytokine SLF. In addition, the combination of SDF-1alpha and SLF results in substantially enhanced migration of fetal HSCs, leading to migration of nearly all fetal HSCs in this assay. This finding indicates the importance of the combined effects of SLF and SDF-1alpha in the migration of fetal HSCs, and is, to our knowledge, the first demonstration of a synergistic effect of two chemoattractive agents on HSCs.

PMID:
15024423
PMCID:
PMC368169
DOI:
10.1371/journal.pbio.0020075
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

JLC is currently employed by and has stock options in Cellerant Therapeutics, a company seeking to transplant human HSCs. As a former advisory board member of Amgen, ILW owns significant Amgen stock. He also cofounded and consulted for Systemix; cofounded Cellerant Therapeutics, a spin-off from Systemix Novartis to transplant human HSCs; and is a cofounder and a director of Stem Cells, Inc., which is involved in the isolation and study of human central nervous system stem cells, liver-repopulating cells, and pancreatic islet stem/progenitor cells.

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