title: Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells.
abstract: Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin β1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Justyna
authors.identifier: 0000-0002-9398-4947
authors.initials: J
authors.lastname: Rak
authors.affiliation: Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom; and.
authors.forename: Katie
authors.initials: K
authors.lastname: Foster
authors.affiliation: Division of Immunology and.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Potrzebowska
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Mehrnaz Safaee
authors.identifier: 0000-0001-8429-7566
authors.initials: MS
authors.lastname: Talkhoncheh
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Miharada
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Karolina
authors.identifier: 0000-0002-2149-4084
authors.initials: K
authors.lastname: Komorowska
authors.affiliation: Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Torngren
authors.affiliation: Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Anders
authors.identifier: 0000-0002-1358-0695
authors.initials: A
authors.lastname: Kvist
authors.affiliation: Division of Oncology and Pathology, Lund University, Lund, Sweden.
authors.forename: Åke
authors.identifier: 0000-0002-5793-132X
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Immunology and.
authors.forename: Lena
authors.identifier: 0000-0001-6927-979X
authors.initials: L
authors.lastname: Svensson
authors.affiliation: Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Larsson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D005353:Fibronectins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D008815:Mice, Inbred Strains; D034622:RNA Interference
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; C065289:ICAM2 protein, human; D016023:Integrins; C100723:cytohesin-1; D018799:Intercellular Adhesion Molecule-1