title: Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells.
abstract: Here, we show that the Wnt5a-haploinsufficient niche regenerates dysfunctional HSCs, which do not successfully engraft in secondary recipients. RNA sequencing of the regenerated donor Lin-SCA-1+KIT+(LSK) cells shows dysregulated expression of ZEB1-associated genes involved in the small GTPase-dependent actin polymerization pathway. Misexpression of DOCK2, WAVE2, and activation of CDC42 results in apolar F-actin localization, leading to defects in adhesion, migration and homing of HSCs regenerated in a Wnt5a-haploinsufficient microenvironment. Moreover, these cells show increased differentiation in vitro, with rapid loss of HSC-enriched LSK cells. Our study further shows that the Wnt5a-haploinsufficient environment similarly affects BCR-ABLp185leukemia-initiating cells, which fail to generate leukemia in 42% of the studied recipients, or to transfer leukemia to secondary hosts. Thus, we show that WNT5A in the bone marrow niche is required to regenerate HSCs and leukemic cells with functional ability to rearrange the actin cytoskeleton and engraft successfully.
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schreck
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Rouzanna
authors.identifier: 0000-0001-6652-9802
authors.initials: R
authors.lastname: Istvánffy
authors.affiliation: Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany.
authors.forename: Christoph
authors.identifier: 0000-0003-2208-4877
authors.initials: C
authors.lastname: Ziegenhain
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Sippenauer
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Ruf
authors.affiliation: Department of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Lynette
authors.initials: L
authors.lastname: Henkel
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilian-Universität, 81377 Munich, Germany.
authors.forename: Florian
authors.identifier: 0000-0001-6120-3723
authors.initials: F
authors.lastname: Gärtner
authors.affiliation: Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Vieth
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: M Carolina
authors.identifier: 0000-0002-5791-1310
authors.initials: MC
authors.lastname: Florian
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, TU Dresden, 01309 Dresden, Germany.
authors.forename: Nicole
authors.identifier: 0000-0002-5078-2333
authors.initials: N
authors.lastname: Mende
authors.affiliation: Biotechnology Center TU Dresden, 01307 Dresden, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Taubenberger
authors.affiliation: German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany.
authors.forename: Áine
authors.initials: Á
authors.lastname: Prendergast
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Pagel
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grziwok
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.|German Cancer Consortium, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Götze
authors.affiliation: Biotechnology Center TU Dresden, 01307 Dresden, Germany.
authors.forename: Jochen
authors.identifier: 0000-0002-1453-6119
authors.initials: J
authors.lastname: Guck
authors.affiliation: Molecular Targets Program, James Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Dean
authors.affiliation: Department of Internal Medicine I, Ludwig-Maximilian-Universität, 81377 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.affiliation: German Cancer Research Center (DKFZ) and Heidelberg Institute for Stem Cell Technology and Experimental Medicine, 69120 Heidelberg, Germany.
authors.forename: Marieke
authors.initials: M
authors.lastname: Essers
authors.affiliation: Regeneration in Hematopoiesis and Animal Models in Hematopoiesis, Institute for Immunology, TU Dresden, 01309 Dresden, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
authors.affiliation: Institute of Molecular Medicine, University of Ulm, 89081 Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.affiliation: Department of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Schiemann
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.|German Cancer Consortium, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Christian
authors.identifier: 0000-0003-0547-2886
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Anthropology and Human Genomics, Department of Biology II, Ludwig-Maximilian-Universität, 81377 Munich, Germany.
authors.forename: Wolfgang
authors.identifier: 0000-0002-4056-0550
authors.initials: W
authors.lastname: Enard
authors.affiliation: Third Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany robert.oostendorp@tum.de.
authors.forename: Robert A J
authors.identifier: 0000-0002-4947-0412
authors.initials: RA
authors.lastname: Oostendorp
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D057895:Haploinsufficiency / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007938:Leukemia / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration; D000071818:Wnt-5a Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D016044:Fusion Proteins, bcr-abl