Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics

Background: The role of tumor-associated B cells in human cancer is only starting to emerge. B cells typically undergo a series of developmental changes in phenotype and function, however, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance.Methods: In this study, we compared the number and distribution of six major B cell and antibody secreting cell subpopulations outside tertiary lymphoid structures in whole tumor sections of 154 human cutaneous melanoma samples (53 primary tumors without subsequent metastasis, 44 primary tumors with metastasis, 57 metastatic samples) obtained by seven color multiplex immunohistochemistry and automated tissue imaging and analysis.Results: In primary melanomas, we observed the highest numbers for plasmablast-like, memory-like, and activated B cell subtypes. These cells showed a patchy, predominant paratumoral distribution at the invasive tumor-stroma margin. Plasma cell-like cells were hardly detected, germinal center- and transitional/regulatory-like B cells not at all. Of the major clinicopathologic prognostic factors for primary melanomas, metastasis was associated with decreased memory-like B cell numbers and a higher age associated with higher plasmablast-like cell numbers. When we compared the composition of B cell subpopulations in primary melanomas and metastatic samples, we found a significantly higher proportion of plasma cell-like cells at distant metastatic sites and a higher proportion of memory-like B cells at locoregional than distant metastatic sites. Both cell types were detected mainly in the para- and intratumoral stroma.Conclusion: These data provide a first comprehensive and comparative spatiotemporal analysis of major B cell and antibody secreting cell subpopulations in human melanoma and describe metastasis-, tumor stage-, and age-associated dynamics, an important premise for B cell-related biomarker and therapy studies.

Efficiency of Stem Cell (SC) Differentiation into Insulin-Producing Cells for Treating Diabetes: a Systematic Review

Over the recent years, the use of stem cells has provided a new opportunity to treat various disorders including diabetes. Stem cells are unspecialized cells with a capacity for self-renewal and differentiation into more specialized cell types. Many factors contribute to the differentiation of SCs and thus play an important role in regulating the fate of stem cells. Accordingly, a wide range of protocols has been used to differentiate SCs to insulin-producing cells but the effectiveness of SC differentiation varies. The aim of this systematic review was to evaluate the results obtained from different studies on SC differentiation for higher efficacy to treat diabetes. This search was done in PubMed, Web of Science (WOS), and Scopus using keywords “insulin-producing cell (IPC),” “pancreatic B cell,” “insulin-secreting cell,” “stem cell,” “progenitor cells,” “mother cell,” and “colony-forming unit.” Among more than 3646 papers, 32 studies were considered eligible for more evaluations. The obtained results indicated that most of the studies were performed on the mesenchymal stem cells (MSCs) derived from different tissues as compared with other types of SCs. Different evaluations of in vitro studies as well as animal models supported their role in the recovery of diabetes. In the present review, we summarize and discuss recent advances in increasing the efficiency of SC differentiation using different materials, but despite the promising results of this systematic review, further studies are needed to assess the efficiency and safety of transplantation of these cells in diabetes recovery.

Effects of salinity level on the activity of chloride cell and mucus secreting cell in the gill of the female Shortfin molly, Poecilia mexicana Steindachner, 1863

Ovoviviparous poeciliid fishes have been relatively well studied in the unique reproductive strategy, but their osmoregulatory system largely remains unknown. In this study, we conducted a short-term (7 days) lab experiment to investigate the effect of different salinity levels from 0 (freshwater) to 50 ppt (mesosaline) on the number of chloride cells and mucus secreting cells of female Poecilia mexicana. The density of chloride cells and mucus secreting cell were also arranged along the epithelial lamellae in wild fish. More interestingly, the average density of chloride cells and the mucus secreting cell were mostly differed between these levels (P < 0.05). Integrative data from our study suggested that the potential function of the osmoregulatory mechanism/strategy was supported by chloride and mucus secreting cells of female P. mexicana gill.

A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition

The activated B-cell (ABC) to plasmablast transition encompasses the cusp of antibody-secreting cell (ASC) differentiation. We explore this transition with integrated analysis in human cells, focusing on changes that follow removal from CD40-mediated signals. Within hours of input signal loss, cell growth programs shift toward enhanced proliferation, accompanied by ER-stress response, and up-regulation of ASC features. Clustering of genomic occupancy for IRF4, BLIMP1, XBP1, and CTCF with histone marks identifies a dichotomy: XBP1 and IRF4 link to induced but not repressed gene modules in plasmablasts, whereas BLIMP1 links to modules of ABC genes that are repressed, but not to activated genes. Between ABC and plasmablast states, IRF4 shifts away from AP1/IRF composite elements while maintaining occupancy at IRF and ETS/IRF elements. This parallels the loss of BATF expression, which is identified as a potential BLIMP1 target. In plasmablasts, IRF4 acquires an association with CTCF, a feature maintained in plasma cell myeloma lines. Thus, shifting occupancy links IRF4 to both ABC and ASC gene expression, whereas BLIMP1 occupancy links to repression of the activation state.

Ykt6-dependent endosomal recycling is required for Wnt secretion in the Drosophila wing epithelium

ABSTRACTMorphogens are important signalling molecules for tissue development and their secretion requires tight regulation. In the wing imaginal disc of flies, the morphogen Wnt/Wingless is apically presented by the secreting cell and re-internalized before final long-range secretion. Why Wnt molecules undergo these trafficking steps and the nature of the regulatory control within the endosomal compartment remain unclear. Here, we have investigated how Wnts are sorted at the level of endosomes by the versatile v-SNARE Ykt6. Using in vivo genetics, proximity-dependent proteomics and in vitro biochemical analyses, we show that most Ykt6 is present in the cytosol, but can be recruited to de-acidified compartments and recycle Wnts to the plasma membrane via Rab4-positive recycling endosomes. Thus, we propose a molecular mechanism by which producing cells integrate and leverage endocytosis and recycling via Ykt6 to coordinate extracellular Wnt levels.