Endothelial cell-derived Apelin inhibits tumor growth by altering immune cell localization

The Apelin/APJ signalling pathway, involved in multiple physiological and pathological processes, has been attracting increasing interest recently. In our previous study, Apelin overexpression in colon26 tumor cells suppressed tumor growth by inducing vascular maturation. Here, we found that MC38 and LLC tumor growth were greater in the absence of Apelin than in wild-type (WT) mice, suggesting that Apelin acts as a tumor suppressor. Consistent with this, treating WT mice with [Pyr1]Apelin-13 inhibited tumor growth. In MC38 tumors, only endothelial cells (ECs) strongly express APJ, a cognate receptor for Apelin, indicating that EC-derived Apelin might regulate tumor formation in an autocrine manner. Comparing with WT mice, larger numbers of vessels with narrower diameters were observed in tumors of Apelin knockout mice and lack of Apelin enhanced tumor hypoxia. Investigating immune cells in the tumor revealed that [Pyr1]Apelin-13 infusion induced the accumulation of CD8+ and CD4+ T cells in central areas. Moreover, RNA-sequencing analysis showed that Apelin induces chemokine CCL8 expression in ECs. Thus, enhancing anti-tumor immunity might be one of the mechanisms by which Apelin is involved in tumor growth. Our result indicated that increased CCL8 expression might induce CD8 + T cells infiltration into tumor and tumor inhibition.

αβ/γδ T cell lineage outcome is regulated by intrathymic cell localization and environmental signals

αβ and γδ T cells are two distinct sublineages that develop in the vertebrate thymus. Thus far, their differentiation from a common progenitor is mostly understood to be regulated by intrinsic mechanisms. However, the proportion of αβ/γδ T cells varies in different vertebrate taxa. How this process is regulated in species that tend to produce a high frequency of γδ T cells is unstudied. Using an in vivo teleost model, the medaka, we report that progenitors first enter a thymic niche where their development into γδ T cells is favored. Translocation from this niche, mediated by chemokine receptor Ccr9b, is a prerequisite for their differentiation into αβ T cells. On the other hand, the thymic niche also generates opposing gradients of the cytokine interleukin-7 and chemokine Ccl25a, and, together, they influence the lineage outcome. We propose a previously unknown mechanism that determines the proportion of αβ/γδ lineages within species.

Scleraxis-lineage cell depletion improves tendon healing and disrupts adult tendon homeostasis

Despite the requirement for Scleraxis-lineage (ScxLin) cells during tendon development, the function of ScxLin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we inducibly depleted ScxLin cells (ScxLinDTR) prior to tendon injury and repair surgery and hypothesized that ScxLinDTR mice would exhibit functionally deficient healing compared to wild-type littermates. Surprisingly, depletion of ScxLin cells resulted in increased biomechanical properties without impairments in gliding function at 28 days post-repair, indicative of regeneration. RNA sequencing of day 28 post-repair tendons highlighted differences in matrix-related genes, cell motility, cytoskeletal organization, and metabolism. We also utilized ScxLinDTR mice to define the effects on post-natal tendon growth and adult tendon homeostasis and discovered that adult ScxLin cell depletion resulted in altered tendon collagen fibril diameter, density, and dispersion. Collectively, these findings enhance our fundamental understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.

Dihydro-Si-Rhodamine for Live-Cell Localization Microscopy

Fluorophores with photo-modulatory fluorescence properties are valuable for cutting-edge localization microscopy. The existing probes are either photo-activatable, or photo-switchable, but not both. We report a probe (DH-SiR), a leuco-dye obtained...

Adult blood stem cell localization reflects the abundance of reported bone marrow niche cell types and their combinations

The exact localization of hematopoietic stem cells (HSCs) in their native bone marrow (BM) microenvironment remains controversial, because multiple cell types have been reported to physically associate with HSCs. In this study, we comprehensively quantified HSC localization with up to 4 simultaneous (9 total) BM components in 152 full-bone sections from different bone types and 3 HSC reporter lines. We found adult femoral α-catulin-GFP+ or Mds1GFP/+Flt3Cre HSCs proximal to sinusoids, Cxcl12 stroma, megakaryocytes, and different combinations of those populations, but not proximal to bone, adipocyte, periarteriolar, or Schwann cells. Despite microanatomical differences in femurs and sterna, their adult α-catulin-GFP+ HSCs had similar distributions. Importantly, their microenvironmental localizations were not different from those of random dots, reflecting the relative abundance of imaged BM populations rather than active enrichment. Despite their functional heterogeneity, dormant label-retaining (LR) and non-LR hematopoietic stem and progenitor cells both had indistinguishable localization from α-catulin-GFP+ HSCs. In contrast, cycling juvenile BM HSCs preferentially located close to Cxcl12 stroma and farther from sinusoids/megakaryocytes. We expect our study to help resolve existing confusion regarding the exact localization of different HSC types, their physical association with described BM populations, and their tissue-wide combinations.