title: The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3(+) lymphocyte-primed multipotent precursors.
abstract: The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a(-)CD8α(+)conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3(+) lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging.
authors.affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing 100084, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002645:Chickens; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011135:Polysaccharides, Bacterial / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017208:Rats, Wistar; D013583:Synovial Membrane / Q000166:cytology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018925:Chemokines; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D011135:Polysaccharides, Bacterial; C000604294:ebosin; C527539:FLT3 protein, rat; D051941:fms-Like Tyrosine Kinase 3; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases