Niche WNT5A Regulates the Actin Cytoskeleton During Regeneration of Hematopoietic Stem Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2016 Dec 22

PMID 27998927

Citations 31

Authors

Christina Schreck

Rouzanna Istvanffy

Christoph Ziegenhain

Theresa Sippenauer

Franziska Ruf

Lynette Henkel

Florian Gartner

Beate Vieth

M Carolina Florian

Nicole Mende

Anna Taubenberger

Aine Prendergast

Alina Wagner

Charlotta Pagel

Sandra Grziwok

Katharina S Gotze

Jochen Guck

Douglas C Dean

Steffen Massberg

Marieke Essers

Claudia Waskow

Hartmut Geiger

Mathias Schiemann

Christian Peschel

Wolfgang Enard

Robert A J Oostendorp

Affiliations

Soon will be listed here.

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-ABL leukemia-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.

Citing Articles

Cellular crosstalk in the bone marrow niche.

Huang Z, Iqbal Z, Zhao Z, Liu J, Alabsi A, Shabbir M J Transl Med. 2024; 22(1):1096.

PMID: 39627858 PMC: 11613879. DOI: 10.1186/s12967-024-05900-6.

The role of the haematopoietic stem cell niche in development and ageing.

Cain T, Derecka M, McKinney-Freeman S Nat Rev Mol Cell Biol. 2024; 26(1):32-50.

PMID: 39256623 DOI: 10.1038/s41580-024-00770-8.

Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.

Landspersky T, Stein M, Sacma M, Geuder J, Braitsch K, Riviere J Blood Adv. 2024; 8(20):5400-5414.

PMID: 39159429 PMC: 11526086. DOI: 10.1182/bloodadvances.2024012879.

Extra-hematopoietic immunomodulatory role of the guanine-exchange factor DOCK2.

Scharler C, Poupardin R, Ebner-Peking P, Wolf M, Schreck C, Brachtl G Commun Biol. 2022; 5(1):1246.

PMID: 36380073 PMC: 9666545. DOI: 10.1038/s42003-022-04078-1.

Frizzled-6 promotes hematopoietic stem/progenitor cell mobilization and survival during LPS-induced emergency myelopoiesis.

Nguyen T, Abidin B, Heinonen K Stem Cell Reports. 2022; 17(10):2303-2317.

PMID: 36084638 PMC: 9561701. DOI: 10.1016/j.stemcr.2022.08.004.

References

Schreck C, Bock F, Grziwok S, Oostendorp R, Istvanffy R . Regulation of hematopoiesis by activators and inhibitors of Wnt signaling from the niche. Ann N Y Acad Sci. 2014; 1310:32-43. DOI: 10.1111/nyas.12384. View

Sengupta A, Arnett J, Dunn S, Williams D, Cancelas J . Rac2 GTPase deficiency depletes BCR-ABL+ leukemic stem cells and progenitors in vivo. Blood. 2010; 116(1):81-4. PMC: 2904584. DOI: 10.1182/blood-2009-10-247437. View

Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G . Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011; 208(13):2691-703. PMC: 3244040. DOI: 10.1084/jem.20111490. View

Nemeth M, Topol L, Anderson S, Yang Y, Bodine D . Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci U S A. 2007; 104(39):15436-41. PMC: 1986571. DOI: 10.1073/pnas.0704747104. View

Yang L, Wang L, Geiger H, Cancelas J, Mo J, Zheng Y . Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc Natl Acad Sci U S A. 2007; 104(12):5091-6. PMC: 1829299. DOI: 10.1073/pnas.0610819104. View

Florian M, Dorr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M . Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 2012; 10(5):520-30. PMC: 3348626. DOI: 10.1016/j.stem.2012.04.007. View

Luis T, Naber B, Roozen P, Brugman M, de Haas E, Ghazvini M . Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion. Cell Stem Cell. 2011; 9(4):345-56. DOI: 10.1016/j.stem.2011.07.017. View

Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R . Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014; 14(5):673-88. PMC: 4070311. DOI: 10.1016/j.stem.2014.03.002. View

Ruf F, Schreck C, Wagner A, Grziwok S, Pagel C, Romero S . Loss of Sfrp2 in the Niche Amplifies Stress-Induced Cellular Responses, and Impairs the In Vivo Regeneration of the Hematopoietic Stem Cell Pool. Stem Cells. 2016; 34(9):2381-92. DOI: 10.1002/stem.2416. View

10.

Florian M, Nattamai K, Dorr K, Marka G, Uberle B, Vas V . A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature. 2013; 503(7476):392-6. PMC: 4078992. DOI: 10.1038/nature12631. View

11.

Reddy P, Radu M, Xu K, Wood J, Harris C, Chernoff J . p21-activated kinase 2 regulates HSPC cytoskeleton, migration, and homing via CDC42 activation and interaction with β-Pix. Blood. 2016; 127(16):1967-75. PMC: 4841040. DOI: 10.1182/blood-2016-01-693572. View

12.

Istvanffy R, Vilne B, Schreck C, Ruf F, Pagel C, Grziwok S . Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro. Stem Cell Reports. 2015; 5(5):702-715. PMC: 4649380. DOI: 10.1016/j.stemcr.2015.09.018. View

13.

Rauner M, Stein N, Winzer M, Goettsch C, Zwerina J, Schett G . WNT5A is induced by inflammatory mediators in bone marrow stromal cells and regulates cytokine and chemokine production. J Bone Miner Res. 2011; 27(3):575-85. DOI: 10.1002/jbmr.1488. View

14.

Kajiwara M, Nonoyama S, Eguchi M, Morio T, Imai K, Okawa H . WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro. Br J Haematol. 1999; 107(2):254-62. DOI: 10.1046/j.1365-2141.1999.01694.x. View

15.

Murdoch B, Chadwick K, Martin M, Shojaei F, Shah K, Gallacher L . Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci U S A. 2003; 100(6):3422-7. PMC: 152308. DOI: 10.1073/pnas.0130233100. View

16.

Renstrom J, Istvanffy R, Gauthier K, Shimono A, Mages J, Jardon-Alvarez A . Secreted frizzled-related protein 1 extrinsically regulates cycling activity and maintenance of hematopoietic stem cells. Cell Stem Cell. 2009; 5(2):157-67. DOI: 10.1016/j.stem.2009.05.020. View

17.

Li S, Ilaria Jr R, Million R, Daley G, Van Etten R . The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med. 1999; 189(9):1399-412. PMC: 2193055. DOI: 10.1084/jem.189.9.1399. View

18.

Rau A, Gallopin M, Celeux G, Jaffrezic F . Data-based filtering for replicated high-throughput transcriptome sequencing experiments. Bioinformatics. 2013; 29(17):2146-52. PMC: 3740625. DOI: 10.1093/bioinformatics/btt350. View

19.

Zhao C, Blum J, Chen A, Kwon H, Jung S, Cook J . Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007; 12(6):528-41. PMC: 2262869. DOI: 10.1016/j.ccr.2007.11.003. View

20.

Yamaguchi T, Bradley A, McMahon A, Jones S . A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999; 126(6):1211-23. DOI: 10.1242/dev.126.6.1211. View