Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche |
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Authors: | Ryohichi Sugimura Xi C He Aparna Venkatraman Fumio Arai Andrew Box Craig Semerad Jeffrey S Haug Lai Peng Xiao-Bo Zhong Toshio Suda Linheng Li |
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Institution: | 1 Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA 2 Centre for Stem Cell Research, Christian Medical College, Vellore 632002, India 3 Department of Cell Differentiation, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan 4 Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA 5 Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA |
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Abstract: | Wnt signaling is involved in self-renewal and maintenance of hematopoietic stem cells (HSCs); however, the particular role of noncanonical Wnt signaling in regulating HSCs in vivo is largely unknown. Here, we show Flamingo (Fmi) and Frizzled (Fz) 8, members of noncanonical Wnt signaling, both express in and functionally maintain quiescent long-term HSCs. Fmi regulates Fz8 distribution at the interface between HSCs and N-cadherin(+) osteoblasts (N-cad(+)OBs that enrich osteoprogenitors) in the niche. We further found that N-cad(+)OBs predominantly express noncanonical Wnt ligands and inhibitors of canonical Wnt signaling under homeostasis. Under stress, noncanonical Wnt signaling is attenuated and canonical Wnt signaling is enhanced in activation of HSCs. Mechanistically, noncanonical Wnt signaling mediated by Fz8 suppresses the Ca(2+)-NFAT- IFNγ pathway, directly or indirectly through the CDC42-CK1α complex and also antagonizes canonical Wnt signaling in HSCs. Taken together, our findings demonstrate that noncanonical Wnt signaling maintains quiescent long-term HSCs through Fmi and Fz8 interaction in the niche. |
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