Article

Apoptotic Cells Activate the "Phoenix Rising" Pathway to Promote Wound Healing and Tissue Regeneration

Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Science Signaling (Impact Factor: 6.28). 02/2010; 3(110):ra13. DOI: 10.1126/scisignal.2000634
Source: PubMed

ABSTRACT

The ability to regenerate damaged tissues is a common characteristic of multicellular organisms. We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E(2), a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "phoenix rising" pathway.

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    • "A major challenge for exploring signaling heterogeneity in epithelial tissues with cytometry-based methods is the requirement of single-cell suspensions. Previous attempts to probe epithelial signaling involved stimulation experiments on single epithelial cells that were already dissociated and outside of their native contexts (Lin et al, 2010). To study single-cell signaling in the in situ epithelial context, we first tested whether a single-cell disaggregation procedure used routinely for flow sorting epithelial cells (Magness et al, 2013) (which we referred to as " the conventional method " ) preserves native signaling in single-cell suspensions. "
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    ABSTRACT: Understanding heterogeneous cellular behaviors in a complex tissue requires the evaluation of signaling networks at single-cell resolution. However, probing signaling in epithelial tissues using cytometry-based single-cell analysis has been confounded by the necessity of single-cell dissociation, where disrupting cell-to-cell connections inherently perturbs native cell signaling states. Here, we demonstrate a novel strategy (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue - DISSECT) that preserves native signaling for Cytometry Time-of-Flight (CyTOF) and fluorescent flow cytometry applications. A 21-plex CyTOF analysis encompassing core signaling and cell-identity markers was performed on the small intestinal epithelium after systemic tumor necrosis factor-alpha (TNF-α) stimulation. Unsupervised and supervised analyses robustly selected signaling features that identify a unique subset of epithelial cells that are sensitized to TNF-α-induced apoptosis in the seemingly homogeneous enterocyte population. Specifically, p-ERK and apoptosis are divergently regulated in neighboring enterocytes within the epithelium, suggesting a mechanism of contact-dependent survival. Our novel single-cell approach can broadly be applied, using both CyTOF and multi-parameter flow cytometry, for investigating normal and diseased cell states in a wide range of epithelial tissues. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Oct 2015 · Molecular Systems Biology
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    • "E 2 (PGE 2 ) production and release from apoptotic cells, which caused the activation of the Wnt/β-catenin pathway in neighboring nonapoptotic cells (Castellone et al., 2005; Zhao et al., 2006; Goessling et al., 2009) (Figure 2). It has been shown that this mechanism also plays a role in wound healing in mammalian cells by increasing the proliferation of keratinocyte progenitor cells by caspase-3 and -7 (Li et al., 2010). It has also been shown that some molecules released by pancreatic beta cells during caspase-dependent apoptotic death induced proliferation and differentiation of the neighboring cells (Bonner et al., 2010). "

    Full-text · Article · Oct 2015
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    • "Therefore, we sought to study the role of dying cell stimulation of living tumor cell growth in pancreatic cancer. In particular , we previously observed that when a small number of living tumor cells were seeded onto a much larger number of irradiated, dying tumor cells, the dying cells stimulated the growth of living tumor cells (Huang et al., 2011; Li et al., 2010). We discovered the " Phoenix Rising " pathway of dying cell stimulation of living tumor cell growth, which involves the release of paracrine signals resulting in proliferation of the living tumor cells. "
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    ABSTRACT: Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed using a pan PKC inhibitor GF109203x and a specific PKCδ inhibitor, rottlerin. Additionally, we found significantly increased phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK1/2) in the irradiated Panc1 cells. Mechanistically, PKCδ cleavage was attenuated in both DN_C3 and DN_C7 transduced Panc1 cells, and both Akt and p38 MAPK phosphorylation were attenuated in DN_PKCδ transduced Panc1 cells following radiation. Thus, this report suggests a novel finding that cellular signaling caspase 3/7-PKCδ-Akt/p38 MAPK is crucial to the repopulation in Panc1 cells after radiotherapy.
    Full-text · Article · Jan 2015 · Molecular Oncology
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