Niche WNT5A regulates the actin cytoskeleton during regeneration of hematopoietic stem cells

被引：41

作者：

Schreck, Christina ^{[1
]}

Istvanffy, Rouzanna ^{[1
]}

Ziegenhain, Christoph ^{[3
]}

Sippenauer, Theresa ^{[1
]}

Ruf, Franziska ^{[1
]}

Henkel, Lynette ^{[2
]}

Gaertner, Florian ^{[4
]}

Vieth, Beate ^{[3
]}

Florian, M. Carolina ^{[5
]}

Mende, Nicole ^{[6
]}

Taubenberger, Anna ^{[7
]}

Prendergast, Aine ^{[8
,9
]}

Wagner, Alina ^{[1
]}

Pagel, Charlotta ^{[1
]}

Grziwok, Sandra ^{[1
]}

Goetze, Katharina S. ^{[1
,10
]}

Guck, Jochen ^{[7
]}

Dean, Douglas C. ^{[11
]}

Massberg, Steffen ^{[4
]}

Essers, Marieke ^{[8
,9
]}

Waskow, Claudia ^{[6
]}

Geiger, Hartmut ^{[5
]}

Schiemann, Mathias ^{[2
]}

Peschel, Christian ^{[1
,10
]}

Enard, Wolfgang ^{[3
]}

Oostendorp, Robert A. J. ^{[1
]}

机构：

[1] Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 3, D-81675 Munich, Germany

[2] Tech Univ Munich, Dept Med Microbiol Immunol & Hyg, D-81675 Munich, Germany

[3] Ludwig Maximilians Univ Munchen, Dept Biol 2, Anthropol & Human Genom, D-81377 Munich, Germany

[4] Ludwig Maximilians Univ Munchen, Dept Internal Med 1, D-81377 Munich, Germany

[5] Univ Ulm, Inst Mol Med, D-89081 Ulm, Germany

[6] Tech Univ Dresden, Inst Immunol, Regenerat Hematopoiesis & Anim Models Hematopoies, D-01309 Dresden, Germany

[7] Tech Univ Dresden, Biotechnol Ctr, D-01307 Dresden, Germany

[8] German Canc Res Ctr, D-69120 Heidelberg, Germany

[9] Heidelberg Inst Stem Cell Technol & Expt Med, D-69120 Heidelberg, Germany

[10] DKFZ, German Canc Consortium, D-69120 Heidelberg, Germany

[11] Univ Louisville, Hlth Sci Ctr, James Brown Canc Ctr, Mol Targets Program, Louisville, KY 40202 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 01期

关键词：

P21-ACTIVATED KINASE; PROLIFERATION; REPOPULATION; MIGRATION; BCR/ABL; IMPAIRS; POLYMERIZATION; MAINTENANCE; SIGNALS; PATHWAY;

D O I：

10.1084/jem.20151414

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-ABLp(185) 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.

引用

页码：165 / 181

页数：17

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