title: BIGH3 modulates adhesion and migration of hematopoietic stem and progenitor cells.
abstract: Cell adhesion and migration are important determinants of homing and development of hematopoietic stem and progenitor cells (HSPCs) in bone marrow (BM) niches. The extracellular matrix protein transforming growth factor-β (TGF-β) inducible gene H3 (BIGH3) is involved in adhesion and migration, although the effect of BIGH3 is highly cell type-dependent. BIGH3 is abundantly expressed by mesenchymal stromal cells, while its expression in HSPCs is relatively low unless induced by certain BM stressors. Here, we set out to determine how BIGH3 modulates HSPC adhesion and migration. We show that primary HSPCs adhere to BIGH3-coated substrates, which is, in part, integrin-dependent. Overexpression of BIGH3 in HSPCs and HL60 cells reduced the adhesion to the substrate fibronectin in adhesion assays, which was even more profound in electrical cell-substrate impedance sensing (ECIS) assays. Accordingly, the CXCL12 induced migration over fibronectin-coated surface was reduced in BIGH3-expressing HSPCs. The integrin expression profile of HSPCs was not altered upon BIGH3 expression. Although expression of BIGH3 did not alter actin polymerization in response to CXCL12, it inhibited the PMA-induced activation of the small GTPase RAC1 as well as the phosphorylation and activation of extracellular-regulated kinases (ERKs). Reduced activation of ERK and RAC1 may be responsible for the inhibition of cell adhesion and migration by BIGH3 in HSPCs. Induced BIGH3 expression upon BM stress may contribute to the regulation of BM homeostasis.
authors.affiliation: Department of Hematopoiesis; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Sofieke E
authors.initials: SE
authors.lastname: Klamer
authors.affiliation: Department of Hematopoiesis; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Carlijn G M
authors.initials: CG
authors.lastname: Kuijk
authors.affiliation: Department of Molecular Cell Biology; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.affiliation: Department of Experimental Immunohematology; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands; Department of Hematology; Academic Medical Centre; Amsterdam, the Netherlands.
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.affiliation: Department of Hematopoiesis; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Department of Hematopoiesis; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Paula B
authors.initials: PB
authors.lastname: van Hennik
authors.affiliation: Department of Hematopoiesis; Sanquin Research and Landsteiner Laboratory; Academic Medical Centre; University of Amsterdam; Amsterdam, the Netherlands.
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000378:metabolism; D017097:Electric Impedance; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D054377:Chemokine CXCL12; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein
keywords: BIGH3; ECIS; ECM; ERK; HSPC; RAC1; adhesion; hematopoiesis; integrins; migration