Loss of Sfrp2 in the Niche Amplifies Stress-Induced Cellular Responses, and Impairs the In Vivo Regeneration of the Hematopoietic Stem Cell Pool.

Autor: Ruf F; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Schreck C; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Wagner A; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Grziwok S; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Pagel C; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Romero S; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Kieslinger M; Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria., Shimono A; RIKEN Center for Developmental Biology, Kobe 650-0047, Japan., Peschel C; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany.; German Cancer Consortium (DKTK) and the German Cancer Research Center (DKFZ), Heidelberg, Germany., Götze KS; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany.; German Cancer Consortium (DKTK) and the German Cancer Research Center (DKFZ), Heidelberg, Germany., Istvanffy R; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany., Oostendorp RA; 3rd Department of Internal Medicine, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany. robert.oostendorp@tum.de.
Jazyk: angličtina
Zdroj: Stem cells (Dayton, Ohio) [Stem Cells] 2016 Sep; Vol. 34 (9), pp. 2381-92. Date of Electronic Publication: 2016 Jun 30.
DOI: 10.1002/stem.2416
Abstrakt: Sfrp2 is overexpressed in stromal cells which maintain hematopoietic stem cells (HSCs) during in vitro culture. We here showed, that coculture of hematopoetic cells with stromal cells with reduced expression of Sfrp2 increases the number lineage-negative Kit(+) Sca-1(+) (LSK) and progenitor cells in vitro. The LSK cells from these cocultures showed activation of canonical Wnt signaling, higher levels of Ki-67, BrdU incorporation, and the number of γH2A.X positive foci. Total repopulating activity of these cultures was, however, diminished, indicating loss of HSC. To extend these in vitro data, we modelled stress in vivo, i.e., by aging, or 5-FU treatment in Sfrp2(-) (/) (-) mice, or replicative stress in regeneration of HSCs in Sfrp2(-) (/) (-) recipients. In all three in vivo stress situations, we noted an increase of LSK cells, characterized by increased levels of β-catenin and cyclin D1. In the transplantation experiments, the increase in LSK cells in primary recipients was subsequently associated with a progressive loss of HSCs in serial transplantations. Similar to the in vitro coculture stress, in vivo genotoxic stress in 5-FU-treated Sfrp2(-) (/) (-) mice increased cell cycle activity of LSK cells with higher levels of BrdU incorporation, increased expression of Ki-67, and canonical Wnt signaling. Importantly, as noted in vitro, increased cycling of LSKs in vivo was accompanied by a defective γH2A.X-dependent DNA damage response and depolarized localization of acetylated H4K16. Our experiments support the view that Sfrp2 expression in the niche is required to maintain the HSC pool by limiting stress-induced DNA damage and attenuating canonical Wnt-mediated HSC activation. Stem Cells 2016;34:2381-2392.
(© 2016 AlphaMed Press.)
Databáze: MEDLINE
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