Journal Article

The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Fit3＋ lymphocyte-primed multipotent precursors

Jing Xiao Haibo Zhou Ning Wu Li Wu

2016

Overview

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 CD 172a-CD8a＋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 Fit3＋ 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 Fit3, Gfi-1, Ikaros, Bc111a, 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.

• Subject: Wnt信号通路 / 分化抑制 / 前体细胞 / 引物 / 树突状细胞 / 淋巴细胞 / 负调控 / 非经典