Ryk modulates the niche activity of mesenchymal stromal cells by fine-tuning canonical Wnt signaling

The importance of modulating the intensity of Wnt signaling has been highlighted in various biological models, but their mechanisms remain unclear. In this study, we found that Ryk—an atypical Wnt receptor with a pseudokinase domain—has a Wnt-modulating effect in bone marrow stromal cells to control hematopoiesis-supporting activities. We first found that Ryk is predominantly expressed in the mesenchymal stromal cells (MSCs) of the bone marrow (BM) compared with hematopoietic cells. Downregulation of Ryk in MSCs decreased their clonogenic activity and ability to support self-renewing expansion of primitive hematopoietic progenitors (HPCs) in response to canonical Wnt ligands. In contrast, under high concentrations of Wnt, Ryk exerted suppressive effects on the transactivation of target genes and HPC-supporting effects in MSCs, thus fine-tuning the signaling intensity of Wnt in BM stromal cells. This ability of Ryk to modulate the HPC-supporting niche activity of MSCs was abrogated by induction of deletion mutants of Ryk lacking the intracellular domain or extracellular domain, indicating that the pseudokinase-containing intracellular domain mediates the Wnt-modulating effects in response to extracellular Wnt ligands. These findings indicate that the ability of the BM microenvironment to respond to extracellular signals and support hematopoiesis may be fine-tuned by Ryk via modulation of Wnt signaling intensity to coordinate hematopoietic activity. Steady production of immune and blood cells depends on a signaling protein that helps maintain stable stem cell populations within the bone marrow. Hematopoietic stem cells (HSCs), which give rise to blood cells, reside within a supportive “niche” surrounded by mesenchymal stromal cells (MSCs), with extensive communication between the two populations. Researchers led by Il-Hoan Oh at The Catholic University of Korea, Seoul, have now identified a mechanism that MSCs employ to stabilize the niche environment through fine-tuning the signaling intensity of Wnt. Oh and colleagues focused on a signaling pathway that controls the undifferentiated state of HSCs, and showed that these signals are specifically modulated by an MSC protein known as Ryk. Without Ryk, MSCs can no longer promote HSC proliferation. However, when these signals are excessively strong, Ryk helps suppress proliferation to keep HSC numbers under control.