title: The soluble form of LR11 protein is a regulator of hypoxia-induced, urokinase-type plasminogen activator receptor (uPAR)-mediated adhesion of immature hematological cells.
abstract: A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit(+) Lin(-) cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit(+) Lin(-) cells of lr11(-/-) mice was reduced by hypoxia much more than of lr11(+/+) animals. sLR11 induced the adhesion of U937 and c-Kit(+) Lin(-) cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1α, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1α-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1α binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche.
authors.affiliation: Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishii
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakaseko
authors.forename: Meizi
authors.initials: M
authors.lastname: Jiang
authors.forename: Naomi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Schneider
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bujo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D003035:Cobalt / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology*; D020298:U937 Cells
chemical_list: D000906:Antibodies; D016587:Antimutagenic Agents; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse; D003035:Cobalt; D019009:Proto-Oncogene Proteins c-kit; C018021:cobaltous chloride