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

Hematology: Preserving a stable home for stem cells 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

Regulation of mesenchymal stromal cells through fine tuning of canonical Wnt signaling

AbstractMesenchymal stromal cells (MSCs) have been extensively utilized for various cell therapeutic trials, but the signals regulating their stromal function remain largely unclear. Here, we show that canonical Wnt signals distinctively regulate MSCs in a biphasic manner depending on signal intensity, i.e., MSCs exhibit proliferation and progenitor self-renewal under low Wnt/β-catenin signaling, whereas they exhibit enhanced osteogenic differentiation with priming to osteoblast-like lineages under high Wnt/β-catenin signaling. Moreover, low or high levels of β-catenin in MSCs distinctly regulated the hematopoietic support of MSCs to promote proliferation or the undifferentiated state of hematopoietic progenitors, respectively. A gene expression study demonstrated that different intracellular levels of β-catenin in MSCs induce distinct transcriptomic changes in subsets of genes belonging to different gene function categories. Different β-catenin levels also induced differences in intracellular levels of the β-catenin co-factors, Tcf-1 and Lef-1. Moreover, nano-scale mass spectrometry of proteins that co-precipitated with β-catenin revealed distinctive spectra of proteins selectively interacting with β-catenin at specific expression levels. Together, these results show that Wnt/β-catenin signals can coax distinct transcription milieu to induce different transcription profiles in MSCs depending on the signal intensity and that fine-tuning of the canonical Wnt signaling intensity can regulate the phase-specific functionality of MSCs