No abstract

In recent years, there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here, we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of each subset, we reveal diverse cellular origins and differential response to signaling cues. Finally, we show that lymphatic vessels are required for cardiac regeneration in zebrafish as mutants lacking lymphatics display severely impaired regeneration capabilities. Overall, our results provide novel insight into the mechanisms underlying lymphatic formation during development and regeneration, opening new avenues for interventions targeting specific lymphatic populations.

No abstract

The function of mammalian cells is largely influenced by their tissue microenvironment. Advances in spatial transcriptomics open the way for studying these important determinants of cellular function by enabling a transcriptome-wide evaluation of gene expression in situ. A critical limitation of the current technologies, however, is that their resolution is limited to niches (spots) of sizes well beyond that of a single cell, thus providing measurements for cell aggregates which may mask critical interactions between neighboring cells of different types. While joint analysis with single-cell RNA-sequencing (scRNA-seq) can be leveraged to alleviate this problem, current analyses are limited to a discrete view of cell type proportion inside every spot. This limitation becomes critical in the common case where, even within a cell type, there is a continuum of cell states that cannot be clearly demarcated but reflects important differences in the way cells function and interact with their surroundings. To address this, we developed Deconvolution of Spatial Transcriptomics profiles using Variational Inference (DestVI), a probabilistic method for multi-resolution analysis for spatial transcriptomics that explicitly models continuous variation within cell types. Using simulations, we demonstrate that DestVI is capable of providing higher resolution compared to the existing methods and that it can estimate gene expression by every cell type inside every spot. We then introduce an automated pipeline that uses DestVI for analysis of single tissue slices and comparison between tissues. We apply this pipeline to study the immune crosstalk within lymph nodes to infection and explore the spatial organization of a mouse tumor model. In both cases, we demonstrate that DestVI can provide a high resolution and accurate spatial characterization of the cellular organization of these tissues, and that it is capable of identifying important cell-type-specific changes in gene expression -between different tissue regions or between conditions. DestVI is available as an open-source software package in the scvi-tools codebase (https://scvi-tools.org). 2.

The p53 tumor suppressor exerts a variety of cell-autonomous effects that are aimed to thwart tumor development. In addition, however, there is growing evidence for cell nonautonomous tumor suppressor effects of p53. In the present study, we investigated the impact of stromal p53 on tumor growth. Specifically, we found that ablation of p53 in fibroblasts enabled them to promote more efficiently the growth of tumors initiated by PC3 prostate cancer-derived cells. This stimulatory effect was dependent on the increased expression of the chemokine SDF-1 in the p53-deficient fibroblasts. Notably, fibroblasts harboring mutant p53 protein were more effective than p53-null fibroblasts in promoting tumor growth. The presence of either p53-null or p53-mutant fibroblasts led also to a markedly elevated rate of metastatic spread of the PC3 tumors. These findings implicate p53 in a cell nonautonomous tumor suppressor role within stromal fibroblasts, through suppressing the production of tumor stimulatory factors by these cells. Moreover, expression of mutant p53 by tumor stroma fibroblasts might exert a gain of function effect, further accelerating tumor development. Cancer Res; 70(23); 9650-8.Ó2010 AACR.