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Review
. 2024 Jan;20(1):52-66.
doi: 10.1007/s12015-023-10610-5. Epub 2023 Oct 7.

WNT Signaling in Stem Cells: A Look into the Non-Canonical Pathway

Miguel Angel Sarabia-Sánchez  1 , Martha Robles-Flores  2
Affiliations
Review

WNT Signaling in Stem Cells: A Look into the Non-Canonical Pathway

Miguel Angel Sarabia-Sánchez et al. Stem Cell Rev Rep. 2024 Jan.

Abstract

Tissue homeostasis is crucial for multicellular organisms, wherein the loss of cells is compensated by generating new cells with the capacity for proliferation and differentiation. At the origin of these populations are the stem cells, which have the potential to give rise to cells with both capabilities, and persevere for a long time through the self-renewal and quiescence. Since the discovery of stem cells, an enormous effort has been focused on learning about their functions and the molecular regulation behind them. Wnt signaling is widely recognized as essential for normal and cancer stem cell. Moreover, β-catenin-dependent Wnt pathway, referred to as canonical, has gained attention, while β-catenin-independent Wnt pathways, known as non-canonical, have remained conspicuously less explored. However, recent evidence about non-canonical Wnt pathways in stem cells begins to lay the foundations of a conceivably vast field, and on which we aim to explain this in the present review. In this regard, we addressed the different aspects in which non-canonical Wnt pathways impact the properties of stem cells, both under normal conditions and also under disease, specifically in cancer.

Keywords: Cancer; Cancer stem cell; Non-canonical Wnt; Stemness.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Wnt signaling network. The canonical Wnt pathway is mediated by β-catenin-dependent transcription. Typical non-canonical signaling comprises Wnt/calcium and Wnt/PCP pathways, both of which cause activation of members of the GTPase family, with modulation of gene expression and cytoskeletal rearrangements. Wnt/calcium pathway activates effectors such as CaMKII, Calcineurin, and PKC through oscillations in intracellular calcium levels, in addition to upregulating NFAT. Meanwhile, Wnt/PCP pathway stimulates RAC and RhoA, as well as the transcriptional activity of JUN.
Fig. 2
Fig. 2
Regulation of self-renewal by Wnt ligands. Wnt3a and Wnt5a confer self-renewal capacity, where Wnt3a increases β-catenin activity, while Wnt5a stimulates JNK and PKC. Furthermore, PKC and JUN stimulate the migratory capacity of stem cells. Wnt5a and ROR2 mRNAs are downregulated by miR17-3p and miR-127-5P. However, these miRNAs are inhibited by circFOXP1. Wnt5a can elicit the expression of Hes-1, a component of the Notch pathway, to allow the self-renewal of HSC. In the case of MPC and LSC, the undifferentiated state is maintained by JUN, RhoA, and CaMKII.
Fig. 3
Fig. 3
Differentiation in response to Wnt. In specific stem cells, Wnt3a induces the expression of Wnt5a, in which Wnt5a mRNA can be targeted by miR-26a-5p. Wnt5a increases intracellular calcium levels and JNK activity to regulate downstream targets, including β-catenin. Possible direct interactions between effectors are indicated (dotted line). Positive regulation of differentiation is indicated (arrowhead line). Nevertheless, effectors described as activators and inhibitors of specific lineage are also indicated (round point line). Asymmetric division, as an initial step in differentiation, is dictated by Wnt5a through the function of the PAR complex. The role of other Wnt ligands, such as Wnt4, in osteogenic differentiation is shown
Fig. 4
Fig. 4
Communication of normal and cancer stem cells with the microenvironment. (A) Cellular components secrete Wnt3a and Wnt5a to upregulate β-catenin and JNK activities, respectively, allowing for self-renewal. Fibronectin, as an acellular component, depends on Wnt11/FZD7 complex to maintain stem cell proliferation. (B) Secreted Wnt3a and Wnt5a mediate paracrine communication between cancer and normal cells in the tumor, including MSC, fibroblasts, and macrophages. On the one hand, Wnt ligands transform non-malignant cells into protumoral components while stimulating migration and invasiveness in cancer cells, as well as CSC-associated capabilities, such as sphere formation
Fig. 5
Fig. 5
Relationship between the quiescent state and non-canonical Wnt pathways. Wnt5a maintains stem cells quiescence through two mechanisms. First, the upregulation of Cdc42 increases the expression of N-cadherin, which enables to keep the anchorage in the niche. Second, the reduction of intracellular Calcium-mediated by Fmi, which leads to restraining the activity of NFAT, a repressor of quiescence in HSC. Furthermore, low ROS levels are related to the quiescence state. For its part, Wnt4 activates the signaling module formed by RhoA/ROCK/YAP to augment the proliferation
Fig. 6
Fig. 6
Dual role of Wnt5a in senescence. Wnt5a restricts entry into senescence, in which the FZD5 receptor was identified. However, high levels of intracellular Wnt5a are found in senescent cells. Specifically, JAK/STAT and Calcium/CamKII/NFATc1 are signaling axes that act downstream of Wnt5a in these cells. Cdc42, besides to respond to Wnt5a, is linked to symmetric divisions according to its distribution in the daughter cells
Fig. 7
Fig. 7
Wnt signaling in CSC. Wnt3a and Wnt5a improve CSC-associated features, including chemoresistance, sphere formation, invasiveness, and tumorigenicity. Non-canonical Wnt pathways encompass increased intracellular calcium and GTPases activity. VANGL2 can act as an intermediary between Wnt5a/FZD and RhoA. FZD6 and FZD7 are reported to activate β-catenin-independent mechanisms and promote CSC functionality
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