While it has long been speculated that mammalian stem cells undergo asymmetric and symmetric division, whether this actually occurs has not been clearly demonstrated. We have used a transgenic Notch ...reporter mouse, in which the GFP status of a cell acts as a sensor for the differentiated state, to image how mammalian hematopoietic stem cells divide and respond to signals during growth, differentiation, and oncogenic transformation. We show that mammalian hematopoietic stem cells have the ability to undergo both symmetric and asymmetric divisions and that the balance between these divisions is not hardwired in precursors but, instead, responsive to extrinsic and intrinsic cues. In addition, we show that oncoproteins can also influence a cell's choice between symmetric and asymmetric division. Cumulatively, this work not only establishes a novel system in which division of early hematopoietic precursor cells can not only be tracked in real time, but also indicates that the distribution of symmetric and asymmetric division can be modulated in response to the microenvironment and subverted by oncogenes.
The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth ...factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.
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► Pleiotrophin (PTN) regulates hematopoietic stem cell self-renewal in vivo ► Deletion of protein tyrosine phosphatase receptor zeta amplifies the hematopoietic stem cell pool ► PTN is expressed and secreted by bone marrow endothelial cells ► PTN regulates hematopoietic progenitor cell homing and retention
Much remains unknown regarding how the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate. Chute and colleagues demonstrate that BM endothelial cells secrete pleiotrophin (PTN), a heparin-binding growth factor, in the HSC niche. Mice lacking PTN contained decreased BM HSCs and a severe defect in hematopoietic regenerative capacity. Antibody blockade of PTN inhibited HSC homing to the niche and promoted HSC mobilization to the blood. Thus, PTN is a secreted component of the vascular niche that regulates HSC retention and self-renewal.
Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map ...the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
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•Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening•Expression and direct utilization of cytokine and immune signals in PDAC stem cells•Nuclear hormone receptor RORγ regulates mouse and human pancreatic cancer•Pharmacologic blockade of RORγ reduces tumor burden and improves survival
Pancreatic cancer stem cells co-opt immuno-regulatory pathways, a vulnerability that could be exploited therapeutically by agents currently in trials for autoimmune diseases.
β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with ...various mitogenic and developmental signals, the genetic role of β-arrestins in driving oncogenesis is not known. Here we have investigated the role of β-arrestin in hematologic malignancies and have found that although both β-arrestin1 and -2 are expressed in the hematopoietic system, loss of β-arrestin2 preferentially leads to a severe impairment in the establishment and propagation of the chronic and blast crisis phases of chronic myelogenous leukemia (CML). These defects are linked to a reduced frequency, as well as defective self-renewal capacity of the cancer stem-cell population, in mouse models and in human CML patient samples. At a molecular level, the loss of β-arrestin2 leads to a significant inhibition of β-catenin stabilization, and ectopic activation of Wnt signaling reverses the defects observed in the β-arrestin2 mutant cells. These data cumulatively show that β-arrestin2 is essential for CML disease propagation and indicate that β-arrestins and the Wnt/β-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance.
There is an increasing drive to provide improved levels of trust within an Internet-of-Things (IoTs) environments, but the devices and sensors used tend to be limited in their capabilities for ...dealing with traditional cryptography methods. Resource constraints and security are often the two major concerns of IIoT (Industrial IoT applications and big data generation at the present time. The strict security measures are often not significantly resource-managed and therefore, negotiation normally takes place between these. Following this, various light-weight versions of generic security primitives have been developed for IIoT and other resource-constrained sustainability. In this paper, we address the authentication concerns for resource-constrained environments by designing an efficient authentication protocol. Our authentication scheme is based on LiSP (light-weight Signcryption Protocol); however, some further customization has been performed on it to make it more suitable for IIoT-like resource-constrained environments. We use Keccack as the hash function in the process and Elli for light-weight public-key cryptography. We name our authentication scheme: Extended light-weight Signcryption Protocol with Keccack (LiSP-XK). The paper outlines a comparative analysis on our new design of authentication against a range of state-of-the-art schemes. We find the suitability of LiSP-XK for IIoT like environments due to its lesser complexity and less energy consumption. Moreover, the signcryption process is also beneficial in enhancing security. Overall the paper shows that LiSP-XK is overall 35% better in efficiency as compared to the other signcryption approaches.
The energy conservative extension of the Internet of Things (IoT), green IoT, is a revolutionary approach in connecting people, processes, and things in an energy-efficient way. The existing research ...works in the domain of green IoT forbid the use of decentralized management (e.g., blockchain) of data due to its intrinsic disadvantages of block mining, transaction incentives, and less throughput. However, the advantages of blockchains urge the development of new decentralized strategies utilizing the architecture of green IoT. The infancy stage of the conjunction between green IoT and blockchains, and the need of decentralization in energy management in green IoT motivate us for the present research. In this article, we address the problems of decentralization, energy conservation, and privacy simultaneously. We introduce the first blockchain-based privacy-preserving framework for green IoT. We name this framework “Blockchain-based energy-efficient and privacy-preserving data management scheme for GREEN-iot (BENIGREEN)” for smart cities. BENIGREEN uses weight metrics for energy-efficient cluster heads (CHs) selection. The use of weight metrics is a novel contribution in the field of green IoT. Furthermore, we integrate a decentralized blockchain framework with an authentication scheme for secure transmission among base station (BS) and sensor nodes by employing registration, certification, and revocation phases. Consequently, BS allocates the collected information from CHs to decentralized blockchain and cloud storage. The BS eliminates all malicious nodes from the network by employing a certificate revocation process. We execute thorough experiments in terms of the operation time, throughput, average energy consumption, and computational latency. The comparative analysis with the state-of-the-art schemes show that BENIGREEN is efficient for IoT paradigm.
Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways ...that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. β-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking β-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, β-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on β-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.
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