title: Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver.
abstract: Hematopoietic stem cells (HSCs) are maintained in specialized niches in adult bone marrow. However, niche and HSC maintenance mechanism in fetal liver (FL) still remains unclear. Here, we investigated the niche and the molecular mechanism of HSC maintenance in mouse FL using HSCs expressing endothelial protein C receptor (EPCR). The antiapoptotic effect of activated protein C (APC) on EPCR(+) HSCs and the expression of protease-activated receptor 1 (Par-1) mRNA in these cells suggested the involvement of the cytoprotective APC/EPCR/Par-1 pathway in HSC maintenance. Immunohistochemistry revealed that EPCR(+) cells were localized adjacent to, or integrated in, the Lyve-1(+) sinusoidal network, where APC and extracellular matrix (ECM) are abundant, suggesting that HSCs in FL were maintained in the APC- and ECM-rich perisinusoidal niche. EPCR(+) HSCs were in a relatively slow cycling state, consistent with their high expression levels of p57 and p18. Furthermore, the long-term reconstitution activity of EPCR(+) HSCs decreased significantly after short culture but not when cocultured with feeder layer of FL-derived Lyve-1(+) cells, which suggests that the maintenance of the self-renewal activity of FL HSCs largely depended on the interaction with the perisinusoidal niche. In conclusion, EPCR(+) HSCs resided in the perisinusoidal niche in mouse FL.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan. hiroko-ko@umin.ac.jp
authors.forename: Hiroko
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Fumio
authors.initials: F
authors.lastname: Arai
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
authors.forename: Maria
authors.initials: M
authors.lastname: Dahl
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D000074283:Endothelial Protein C Receptor; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011956:Receptors, Cell Surface; D055153:Stem Cell Niche / Q000166:cytology* / Q000378:metabolism / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface; D019009:Proto-Oncogene Proteins c-kit