Renal stem cells: fact or science fiction?

The kidney is widely regarded as an organ without regenerative abilities. However, in recent years this dogma has been challenged on the basis of observations of kidney recovery following acute injury, and the identification of renal populations that demonstrate stem cell characteristics in various species. It is currently speculated that the human kidney can regenerate in some contexts, but the mechanisms of renal regeneration remain poorly understood. Numerous controversies surround the potency, behaviour and origins of the cell types that are proposed to perform kidney regeneration. The present review explores the current understanding of renal stem cells and kidney regeneration events, and examines the future challenges in using these insights to create new clinical treatments for kidney disease

Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack

The acquisition of mesenchymal features by carcinoma cells is now recognized as a driver of metastasis and tumor resistance to a range of anticancer therapeutics, including chemotherapy, radiation, and certain small-molecule targeted therapies. With the recent successful implementation of immunotherapies for the treatment of various types of cancer, there is growing interest in understanding whether an immunological approach could be effective at eradicating carcinoma cells bearing mesenchymal features. Recent studies, however, demonstrated that carcinoma cells that have acquired mesenchymal features may also exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8+ T cells, innate natural killer (NK), and lymphokine-activated killer (LAK) cells. Here, we investigated the mechanism involved in the immune resistance of carcinoma cells that express very high levels of the transcription factor brachyury, a molecule previously shown to drive the acquisition of mesenchymal features by carcinoma cells. Our results demonstrate that very high levels of brachyury expression drive the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, p21), an event that results in decreased tumor susceptibility to immune-mediated lysis. We show here that reconstitution of p21 expression markedly increases the lysis of brachyury-high tumor cells mediated by antigen-specific CD8+ T cells, NK, and LAK cells, TNF-related apoptosis-inducing ligand, and chemotherapy. Several reports have now demonstrated a role for p21 loss in cancer as an inducer of the epithelial–mesenchymal transition. The results from the present study situate p21 as a central player in many of the aspects of the phenomenon of brachyury-mediated mesenchymalization of carcinomas, including resistance to chemotherapy and immune-mediated cytotoxicity. We also demonstrate here that the defects in tumor cell death described in association with very high levels of brachyury could be alleviated via the use of a WEE1 inhibitor. Several vaccine platforms targeting brachyury have been developed and are undergoing clinical evaluation. These studies provide further rationale for the use of WEE1 inhibition in combination with brachyury-based immunotherapeutic approaches

Atlas of Cellular Dynamics during Zebrafish Adult Kidney Regeneration

The zebrafish is a useful animal model to study the signaling pathways that orchestrate kidney regeneration, as its renal nephrons are simple, yet they maintain the biological complexity inherent to that of higher vertebrate organisms including mammals. Recent studies have suggested that administration of the aminoglycoside antibiotic gentamicin in zebrafish mimics human acute kidney injury (AKI) through the induction of nephron damage, but the timing and details of critical phenotypic events associated with the regeneration process, particularly in existing nephrons, have not been characterized. Here, we mapped the temporal progression of cellular and molecular changes that occur during renal epithelial regeneration of the proximal tubule in the adult zebrafish using a platform of histological and expression analysis techniques. This work establishes the timing of renal cell death after gentamicin injury, identifies proliferative compartments within the kidney, and documents gene expression changes associated with the regenerative response of proliferating cells. These data provide an important descriptive atlas that documents the series of events that ensue after damage in the zebrafish kidney, thus availing a valuable resource for the scientific community that can facilitate the implementation of zebrafish research to delineate the mechanisms that control renal regeneration

Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity

BackgroundDespite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.MethodsTwo soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.ResultsWe demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.ConclusionsThis study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic