N-Cadherin Expression Level Distinguishes Reserved versus Primed States of Hematopoietic Stem Cells

SummaryOsteoblasts expressing the homophilic adhesion molecule N-cadherin form a hematopoietic stem cell (HSC) niche. Therefore, we examined how N-cadherin expression in HSCs relates to their function. We found that bone marrow (BM) cells highly expressing N-cadherin (N-cadherinhi) are not stem cells, being largely devoid of a Lineage−Sca1+cKit+ population and unable to reconstitute hematopoietic lineages in irradiated recipient mice. Instead, long-term HSCs form distinct populations expressing N-cadherin at intermediate (N-cadherinint) or low (N-cadherinlo) levels. The minority N-cadherinlo population can robustly reconstitute the hematopoietic system, express genes that may prime them to mobilize, and predominate among HSCs mobilized from BM to spleen. The larger N-cadherinint population performs poorly in reconstitution assays when freshly isolated but improves in response to overnight in vitro culture. Their expression profile and lower cell-cycle entry rate suggest N-cadherinint cells are being held in reserve. Thus, differential N-cadherin expression reflects functional distinctions between two HSC subpopulations

Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

Cognition, emotion, and arithmetic in primary school: A cross-cultural investigation

The study investigated cross‐cultural differences in variability and average performance in arithmetic, mathematical reasoning, symbolic and non‐symbolic magnitude processing, intelligence, spatial ability, and mathematical anxiety in 890 6‐ to 9‐year‐old children from the United Kingdom, Russia, and China. Cross‐cultural differences explained 28% of the variance in arithmetic and 17.3% of the variance in mathematical reasoning, with Chinese children outperforming the other two groups. No cross‐cultural differences were observed for spatial ability and mathematical anxiety. In all samples, symbolic magnitude processing and mathematical reasoning were independently related to early arithmetic. Other factors, such as non‐symbolic magnitude processing, mental rotation, intelligence, and mathematical anxiety, produced differential patterns across the populations. The results are discussed in relation to potential influences of parental practice, school readiness, and linguistic factors on individual differences in early mathematics