Τετάρτη, 1 Μαΐου 2019

Stem Cells

Effect of Radiation Exposures on Fetal Hematopoietic Cells

Abstract

Purpose of this Review

It has generally been thought that fetuses are highly sensitive to radiation-induced cancer. Epidemiologic case-control studies indicated that X-ray exposures given to pregnant women (on the order of 1 cGy) could have increased the risk of developing childhood leukemia and solid cancers in the offspring. The authors wished to re-consider this observation.

Recent Findings

Atomic bomb survivors who were exposed in utero were found to show almost no increase in the frequency of translocations in their blood lymphocytes when the survivors were examined at around 40 years of age. Subsequent animal studies revealed that tissue stem cells in embryos/fetuses may or may not retain radiation-induced chromosome damage depending on the developmental stage at the time of irradiation.

Summary

Our data are compatible with the model that radiation effects can be recorded only when an exposure occurs after the stem cells have settled in their appropriate niche, and that a small fraction of fetal hematopoietic stem cells began making long-term contributions to the lymphoid cell pool in both mice and humans. It remains to be established whether or not the increased risk of childhood leukemia and other childhood cancers was caused by fetal X-ray exposures of about 1 cGy.



Leukemia's Clonal Evolution in Development, Progression, and Relapse

Abstract

Purpose of Review

Advances in high-throughput methods have enabled the molecular characterization of leukemias and have improved our understanding of their clonal evolution from leukemogenesis in hematopoietic stem/progenitor cells to overt diagnosable disease.

Recent Findings

It has now been revealed that during leukemia's development and progression, genetic alterations accumulate according to the principles of Darwinian evolution. Drug resistance often emerges from changes in evolutionary trajectories of disease through selection of subpopulations that have greater fitness under therapy. In this manuscript, we will review recent data on prevalence of highly branched evolutionary patterns in myeloid and lymphoid leukemias and discuss how different treatment strategies differentially shape leukemia's clonal architecture.

Summary

Increasing evidence on clinical impact of small pre-malignant clones prior to diagnosis and small resistant clones during treatment strongly suggests that highly sensitive experimental and mathematical models are necessary for accurate dissection of hematopoietic populations and robust identification of predictive markers for disease transformation and relapse.



Low-Dose Radiation Prevents Chemotherapy-Induced Cardiotoxicity

Abstract

Purpose of Review

In this review, we will address the cardioprotective effect of low-dose radiation (LDR) on chemotherapeutic agents.

Recent Findings

Cancer has become the most important cause of death in the world, and the morbidity and mortality are gradually increased. The application of anti-tumor drugs is an important therapeutic tool for cancer therapy at present, while its potential cardiotoxicity cannot be ignored. How to prevent and reduce the occurrence of cardiotoxicities needs further exploration.

Summary

LDR induces an adaptive or hormetic response in cells and tissues, showing a tolerance to subsequently high dose of radiation- or chemical-induced damage in vitro and in vivo. LDR may exert its cardioprotective effects through different mechanisms, such as stimulating the proliferation of normal cells during anti-tumor therapy, enhancing anti-tumor immunity, stimulating antioxidative functions in normal tissues, activating DNA damage repair system, and improving metabolic function in normal tissues. Therefore, there may be a potential to apply LDR as an adjunct to myocardial protection for anti-tumor therapy.



Mathematical Models of Stem Cell Differentiation and Dedifferentiation

Abstract

Purpose of Review

To maintain and repair adult tissues, a balance must be maintained between stem cell proliferation and generation of differentiated offspring. This review explores recent mathematical and computational models that address stem cell fate decisions in adult tissues in the context of normal tissue regulation and cancer development.

Recent Findings

Quantitative models suggest that upregulation of stem cell self-renewal has a crucial impact on the dynamics of differentiated cells and plays an important role in cancer progression. Assuming cancer stem cells are the primary cause of drug resistance, models have estimated how different treatments may influence the prognosis of the disease. Recent evidence of phenotype switching and plasticity in cancer cell populations complicates the cancer stem cell hypothesis of unidirectional differentiation.

Summary

Mathematical models of stem cell dynamics can make counterintuitive predictions about cancer initiation, metastasis, and treatment response. By challenging current paradigms, they can shape future research in stem cell biology.



Translating HSC Niche Biology for Clinical Applications

Abstract

Purpose of Review

Over the final 3 decades of the twentieth century, the advent and evolution of hematopoietic stem cell transplantation (HSCT) to cure refractory malignancies and severe non-malignant diseases created a need to better understand basic scientific mechanisms underlying the maintenance and migration of hematopoietic stem cells (HSC). Over the past 20 years, researchers have discovered complex overlapping bone marrow (BM) HSC niches that utilize a number of signaling pathways to tightly regulate HSC physiology. Here, we review recent efforts to define critical mediators of HSC niche function in health and disease, and how these discoveries are now enabling the development of the next generation of cellular therapies for cancer and severe non-malignant diseases.

Recent Findings

A number of cellular interactions and molecular pathways critical for HSC mobilization, donor HSC engraftment after HSCT, and HSC/progenitor cell recovery following chemotherapy have recently been identified. Additional studies have defined mechanisms by which cancer and bone marrow failure states disrupt the normal function of these pathways. Translational investigators are now leveraging these discoveries to develop preclinical and clinical strategies to target the niche for regenerative and cancer therapy.

Summary

Ongoing research to define fundamental aspects of HSC niche biology will lead to further refinements and precision approaches to improve the safety and efficacy of clinical cell therapy.



Role of the Extracellular Matrix in Stem Cell Maintenance

Abstract

Purpose of Review

Stem cells reside in specialized anatomical locations called niches where supportive stromal cells and the extracellular matrix (ECM) regulate their self-renewal and differentiation. This review explores the critical roles of the ECM in stem cell maintenance in tissue homeostasis, aging, and disease.

Recent Findings

It is well established that ECM proteins and their biomechanical properties control stem cell fate. In addition to specific molecular interactions, the ECM composition determines the topology and stiffness of the substrate, which also regulate stem cell behavior. Changes in the ECM during aging and disease can impair cell-ECM interactions and ultimately contribute to aging and disease pathogenesis.

Summary

A deeper understanding of the mechanisms by which the ECM regulates stem cell behavior in health, as well as during aging and in disease states, will facilitate the development of therapeutic strategies. These therapies should focus on recovering normal matrix synthesis and deposition aiming at promoting endogenous repair.



Deciphering the Dynamics of Epithelial-Mesenchymal Transition and Cancer Stem Cells in Tumor Progression

Abstract

Purpose of Review

The epithelial-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two fundamental aspects contributing to tumor growth, acquisition of resistance to therapy, formation of metastases, and tumor relapse. Recent experimental data identifying the circuits regulating EMT and CSCs has driven the development of computational models capturing the dynamics of these circuits, and consequently various aspects of tumor progression.

Recent Findings

We review the contribution made by these models in (a) recapitulating experimentally observed behavior, (b) making experimentally testable predictions, and (c) driving emerging notions in the field, including the emphasis on the aggressive potential of hybrid epithelial-mesenchymal (E/M) phenotype(s). We discuss dynamical and statistical models at intracellular and population level relating to dynamics of EMT and CSCs, and those focusing on interconnections between these two processes.

Summary

These models highlight the insights gained via mathematical modeling approaches and emphasizes that the connections between hybrid E/M phenotype(s) and stemness can be explained by analyzing underlying regulatory circuits. Such experimentally curated models have the potential of serving as platforms for better therapeutic design strategies.



Recasting the Cancer Stem Cell Hypothesis: Unification Using a Continuum Model of Microenvironmental Forces

Abstract

Purpose of review

Here, we identify shortcomings of standard compartment-based mathematical models of cancer stem-cells, and propose a continuous formalism which includes the tumor microenvironment.

Recent findings

Stem-cell models of tumor growth have provided explanations for various phenomena in oncology including, metastasis, drug- and radio-resistance, and functional heterogeneity in the face of genetic homogeneity. While some of the newer models allow for plasticity, or de-differentiation, there is no consensus on the mechanisms driving this. Recent experimental evidence suggests that tumor microenvironment factors like hypoxia, acidosis, and nutrient deprivation have causative roles.

Summary

To settle the dissonance between the mounting experimental evidence surrounding the effects of the microenvironment on tumor stemness, we propose a continuous mathematical model where we model microenvironmental perturbations like forces, which then shape the distribution of stemness within the tumor. We propose methods by which to systematically measure and characterize these forces, and show results of a simple experiment which support our claims.



Non-apoptotic Roles of Caspases in Stem Cell Biology, Carcinogenesis, and Radiotherapy

Abstract

Purpose of Review

To summarize recent findings on novel roles of caspases in stem cell biology, tumor repopulation, and tissue regeneration. Contrary to the long-held notion that apoptotic caspases are exclusively executioners of programmed cell death, an abundance of evidence is emerging that activation of caspases does not inevitably lead to cell death.

Recent Findings

It is now known that sublethal activation of caspases occurs in development, stem cell differentiation, epigenetic reprogramming, and a whole host of other key biological processes. Important for cancer biology, recent studies show that activation of caspases in tumors facilitates carcinogenesis, metastasis, and tumor relapse after cancer treatment. We have found that apoptotic cells secrete prostaglandins to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues and stem cells in multiple organisms, but it also poses problems in emerging tumor resistance to chemotherapy and radiotherapy.

Summary

Novel findings on caspases are contrary to established paradigms and might explain why cancer therapies aimed at activating apoptotic caspases have not been very successful in the clinic. In this brief review, we summarize some novel findings regarding caspases with the hope of stimulating more interest in this nascent but increasingly important research area. Better understanding of the diverse roles of caspases may one day help us establish novel approaches for treating cancer.



Mini Review: Application of Human Mesenchymal Stem Cells in Gene and Stem Cells Therapy Era

Abstract

Purpose of Review

Mesenchymal stem cells (MSCs) have abilities of self-renewal and multi-lineage differentiation. MSCs can evade immune rejection following allogeneic transplantation setting due to their downregulation of HLA Class II antigen. Therefore, we review the current understanding of using MSCs or MSC-conditioned media as treatment for various diseases.

Recent Findings

(1) MSCs regulate the balance of Th17/Treg cells in autoimmune disease models, which is associated with complex interactions among different pro- or anti-inflammation cytokines. (2) With the nature of MSCs migrating to multiple tissues under various homing signals, we also found MSCs are widely used as cell vehicles for gene or chemokine delivery.

Summary

MSCs or MSC-conditioned media therapies have been explored with advanced techniques. However, it still requires further investigations on (1) how MSCs respond to various microenvironments and (2) how to isolate, purify and expand enough MSCs ex vivo.




Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

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