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Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. Mutations that activate canonical Wnt/β-catenin signaling also initiate and maintain several cancer states, including colorectal cancer and leukemia, and hence Wnt inhibitors are currently being explored as therapeutic options. In this review, we summarize previous studies and update recent findings on canonical Wnt signaling and its components, as well as their roles in somatic stem cell homeostasis and maintenance of cancer-initiating cells.

Background Deciphering molecular mechanisms underlying the division of hematopoietic stem cells (HSCs) and malignant precursors would improve our understanding of the basis of stem cell-fate decisions and oncogenic transformation. Methods Using a novel reporter of hematopoietic precursor, Evi1-GFP, we tracked the division of hematopoietic precursors in culture in real time. Results First, we confirmed that Evi1-GFP is a faithful reporter of HSC activity and identified three dividing patterns of HSCs: symmetric renewal, symmetric differentiation, and asymmetric division. Moreover, we found that the cytokine and growth factor combination (STIF) promotes symmetric renewal, whereas OP9 stromal cells balance symmetric renewal and differentiation of HSCs ex vivo. Interestingly, we found that Tet2 knockout HSCs underwent more symmetric differentiation in culture compared with the wild-type control. Intriguingly, OP9 stromal cells reverse the phenotype of Tet2 knockout HSCs ex vivo. Furthermore, we demonstrated that Tet2 –/– ; Flt3 ITD acute myeloid leukemia (AML) precursors primarily underwent symmetric renewal divisions in culture. Mechanistically, we demonstrated that inhibiting DNA methylation can reverse the aberrant division phenotypes of Tet2 –/– and Tet2 –/– ; FLT3 ITD precursors, suggesting that abnormal DNA methylation plays an important role in controlling (pre-)leukemic precursor fate decision ex vivo. Conclusions Our study exploited a new system to explore the molecular mechanisms of the regulation of benign and malignant hematopoietic precursor division ex vivo. The knowledge learned from these studies will provide new insights into the molecular mechanisms of HSC fate decision and leukemogenesis.

The secretory protein Dickkopf-1 (DKK-1) is a known Wnt antagonist and has been shown to suppress tumorigenesis in some cancer cells; however, it is also upregulated in many types of cancer and associated with poor prognosis. Wnt-independent mechanisms by which DKK-1 promotes cancer cell proliferation are not well understood. In this issue of the JCI, Kimura and colleagues demonstrate that DKK-1 interacts with cytoskeleton-associated protein 4 (CKAP4) to promote activation of AKT. They show that both DKK-1 and CKAP4 are frequently upregulated in pancreatic and lung cancers. Importantly, targeting this interaction with an anti-CKAP4 antibody prevented tumor formation in murine xenograft models. These results identify a previously unrecognized DKK-1-mediated pathway and suggest CKAP4 as a potential therapeutic target for certain cancers.

Platelets upon activation change their shape, aggregate and secrete alpha and dense granule contents among which ADP acts as a feedback activator. Different Protein Kinase C (PKC) isoforms have specific non-redundant roles in mediating platelet responses including secretion and thrombus formation. Protein Kinase Ç delta (PKCδ), a novel class of PKC isoform requiring diacyl glycerol but not calcium for its activation, has been shown to play an important role in several pathological processes. The aims of our current study are 1) to identify possible PKCδ specific substrates in platelets, 2) evaluate a novel PKCδ selective inhibitor and 3) to investigate the role of PKCδ in ADP-induced platelet activation. We show that Protein kinase D2 (PKD2) is the major isoform of PKD that is expressed in human as well as murine platelets and is a specific substrate for PKCδ in platelets. CGX1037 was identified and characterized as a selective small molecule inhibitor of PKCδ in platelets. Furthermore, by using PKCδ knock out murine platelets, we showed that PKCδ plays a functional role in mediating ADP-induced thromboxane generation and classical PKC isoforms /β regulate tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through a tyrosine kinase, Lyn and a tyrosine phosphatase, Shp1 suggesting an important role of PKCδ to agonistinduced platelet activation.

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ~5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the BCL11A+58 enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.Competing Interest StatementSAP is a consultant for bluebirdbio and Agios Pharmaceutics. SAP and PSK have independent sponsored research agreements with Blueprint Medicines.Footnotes* https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE248311

The growth of the industrial sector has resulted in a higher use of Aluminium Metal Matrix Composites (AMMCs). These composites are well-known for their exceptional mechanical and tribological qualities, attracting worldwide attention, especially in the automotive, architectural, and aerospace industries. Advanced Metal Matrix Composites (AMMCs) exhibit increased specific strength, improved strength-to-weight ratio at increasing temperatures, and better wear resistance when compared to the basic matrix without any additional components. SiC and B4C particle reinforcements are used to enhance the metallurgical and mechanical characteristics of the base matrix. Authors have used several production methods such as Powder Metallurgy for solid-state procedures and Stir Casting, Compo-casting, Squeeze Casting, and in-situ casting for liquid-state processes to create AMMCs. Stir casting is the most cost-effective and easy process for producing AMMC. This article provides an in-depth explanation of the procedure for producing Aluminium Matrix Metal Composites (AMMCs) utilising AL-7175 as the matrix material, together with B4C and SiC as reinforcements, with the stir casting technique.