For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection

The surveillance of the structural fidelity of the proteome is of utmost importance to all cells. The endoplasmic reticulum (ER) is the organelle responsible for proper folding and delivery of proteins to the secretory pathway. It contains a sophisticated protein proofreading and elimination mechanism. Failure of this machinery leads to disease and, finally, to cell death. Elimination of misfolded proteins requires retrograde transport across the ER membrane and depends on the central cytoplasmic proteolytic machinery involved in cellular regulation: the ubiquitin-proteasome system. The basics of this process as well as recent advances in the field are reviewed.     

Exercise tolls the bell for key mediators of low-grade inflammation in dysmetabolic conditions

Metabolic conditions share a common low-grade inflammatory milieu, which represents a key-factor for their ignition and maintenance. Exercise is instrumental for warranting systemic cardio-metabolic balance, owing to its regulatory effect on inflammation. This review explores the effect of physical activity in the modulation of sub-inflammatory framework characterizing dysmetabolic conditions. Regular exercise suppresses plasma levels of TNFα, IL-1β, FFAs and MCP-1, in dysmetabolic subjects. In addition, a single session of training increases the anti-inflammatory IL-10, IL-1 receptor antagonist (IL-1ra), and muscle-derived IL-6, mitigating low-grade inflammation. Resting IL-6 levels are decreased in trained-dysmetabolic subjects, compared to sedentary. On the other hand, the acute release of muscle-IL-6, after exercise, seems to exert a regulatory effect on the metabolic and inflammatory balance. In fact, muscle-released IL-6 is presumably implicated in fat loss and boosts plasma levels of IL-10 and IL-1ra. The improvement of adipose tissue functionality, following regular exercise, is also critical for the mitigation of sub-inflammation. This effect is likely mediated by muscle-released IL-15 and IL-6 and partly relies on the brown-shifting of white adipocytes, induced by exercise. In obese-dysmetabolic subjects, moderate training is shown to restore gut-microbiota health, and this mitigates the translocation of bacterial-LPS into bloodstream. Finally, regular exercise can lower plasma advanced glycated endproducts. The articulated physiology of circulating mediators and the modulating effect of the pathophysiological background, render the comprehension of the exercise-regulatory effect on sub-inflammation a key issue, in dysmetabolism.     

Imaging stem cell implant for cellular-based therapies

Stem cell-based cellular therapy represents a promising outlook for regenerative medicine. Imaging techniques provide a means for noninvasive, repeated, and quantitative tracking of stem cell implant or transplant. From initial deposition to the survival, migration and differentiation of the transplant/implanted stem cells, imaging allows monitoring of the infused cells in the same live object over time. The current review briefly summarizes and compares existing imaging methods for cell labeling and imaging in animal models. Several studies performed by our group using different imaging techniques are described, with further discussion on the issues with these current imaging approaches and potential directions for future development in stem cell imaging.     

Convergence of normal stem cell and cancer stem cell developmental stage: Implication for differential therapies

Increased evidence shows that normal stem cells may contribute to cancer development and progression by acting as cancer-initiating cells through their interactions with abnormal environmental elements.We postulate that normal stem cells and cancer stem cells (CSC) possess similar mechanisms of self-renewal and differentiation.CSC can be the key to the elaboration of anti-cancer-based therapy.In this article,we focus on a controversial new theme relating to CSC.Tumorigenesis may have a critical stage characterized as a "therapeutic window",which can be identified by asso-ciation of molecular,biochemical and biological events.Identifying such a stage can allow the production of more effective therapies (e.g.manipulated stem cells) to treat several cancers.More importantly,confirming the existence of a similar therapeutic window during the conversion of normal stem cells to malignant CSC may lead to targeted therapy specifically against CSC.This conversion information may be derived from investigating the biological behaviour of both normal stem cells and cancerous stem cells.Currently,there is little knowledge about the cellular and molecular mechanisms that govern the initiation and maintenance of CSC.Studies on co-evolution and interdependence of cancer with normal tissues may lead to a useful treatment paradigm of cancer.The crosstalk between normal stem cells and cancer formation may converge developmental stages of different types of stem cells (e.g.normal stem cells,CSC and embryonic stem cells).The differential studies of the convergence may result in novel therapies for treating cancers.     

Large animal models for cardiac stem cell therapies

Cardiovascular disease is the leading cause of death in developed countries and is one of the leading causes of disease burden in developing countries. Therapies have markedly increased survival in several categories of patients, nonetheless mortality still remains high. For this reason high hopes are associated with recent developments in stem cell biology and regenerative medicine that promise to replace damaged or lost cardiac muscle with healthy tissue, and thus to dramatically improve the quality of life and survival in patients with various cardiomyopathies.Much of our insight into the molecular and cellular basis of cardiovascular biology comes from small animal models, particularly mice. However, significant differences exist with regard to several cardiac characteristics when mice are compared with humans. For this reason, large animal models like dog, sheep and pig have a well established role in cardiac research. A distinct characteristic of cardiac stem cells is that they can either be endogenous or derive from outside the heart itself; they can originate as the natural course of their differentiation programme (e.g., embryonic stem cells) or can be the result of specific inductive conditions (e.g., mesenchymal stem cells). In this review we will summarize the current knowledge on the kind of heart-related stem cells currently available in large animal species and their relevance to human studies as pre-clinical models.     

Enabling stem cell therapies for tissue repair: Current and future challenges

Stem cells embody the tremendous potential of the human body to develop, grow, and repair throughout life. Understanding the biologic mechanisms that underlie stem cell-mediated tissue regeneration is key to harnessing this potential. Recent advances in molecular biology, genetic engineering, and material science have broadened our understanding of stem cells and helped bring them closer to widespread clinical application. Specifically, innovative approaches to optimize how stem cells are identified, isolated, grown, and utilized will help translate these advances into effective clinical therapies. Although there is growing interest in stem cells worldwide, this enthusiasm must be tempered by the fact that these treatments remain for the most part clinically unproven. Future challenges include refining the therapeutic manipulation of stem cells, validating these technologies in randomized clinical trials, and regulating the global expansion of regenerative stem cell therapies.     

Prospects for pluripotent stem cell therapies: into the clinic and back to the bench

Pluripotent stem cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, both hold great promise for the understanding and treatment of disease. They can be used for drug testing, as in vitro models for human disease progression, and for transplantation therapies. Research in this area has been influenced by the ever-changing political landscape, particularly in the United States. In this review, we discuss the prospects for clinical application using pluripotent cells, focusing on an evaluation of iPS cell potential, the continuing concern of tumor formation, and a summary of in vitro differentiation protocols and animal models used. We also describe the current clinical trials underway in the United States, as well as the ups and downs of funding for ES cell work.     

Towards stem cell replacement therapies for Parkinson’s disease

Current therapeutic approaches for Parkinson’s disease (PD) provide symptomatic relief but none of them change the course of disease. There is therefore a clear need for regenerative and cell replacement therapies (CRT). However, CRT faces several important challenges. First, the main symptoms of PD result from the loss of midbrain dopamine (DA) neurons, but other cell types are also affected. Second, transplantation of human ventral midbrain tissue from aborted fetuses has lead to proof of principle that CRT may work, however, it has also pointed out to important patient-, surgery- and cell preparation-related variables, which need to be improved. Third, while some patients have developed dyskinesias and, with time, Lewy bodies in the grafted cells, other patients have experienced remarkable improvement and have been able to stop their medication. Is there a case for PD CRT today? What is the possible contribution of stem cells to CRT? In this review, I will discuss what we learned from clinical trials using fetal tissue grafts, recent progress in the development of human stem cell-derived-DA neurons for CRT, and some of the issues that need to be solved in order to develop stem cells as tools for PD CRT.     

The remyelination Philosopher's Stone: stem and progenitor cell therapies for multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease that leads to oligodendrocyte loss and subsequent demyelination of the adult central nervous system (CNS). The pathology is characterized by transient phases of recovery during which remyelination can occur as a result of resident oligodendroglial precursor and stem/progenitor cell activation. However, myelin repair efficiency remains low urging the development of new therapeutical approaches that promote remyelination activities. Current MS treatments target primarily the immune system in order to reduce the relapse rate and the formation of inflammatory lesions, whereas no therapies exist in order to regenerate damaged myelin sheaths. During the last few years, several transplantation studies have been conducted with adult neural stem/progenitor cells and glial precursor cells to evaluate their potential to generate mature oligodendrocytes that can remyelinate axons. In parallel, modulation of the endogenous progenitor niche by neural and mesenchymal stem cell transplantation with the aim of promoting CNS progenitor differentiation and myelination has been studied. Here, we summarize these findings and discuss the properties and consequences of the various molecular and cell-mediated remyelination approaches. Moreover, we address age-associated intrinsic cellular changes that might influence the regenerative outcome. We also evaluate the extent to which these experimental treatments might increase the regeneration capacity of the demyelinated human CNS and hence be turned into future therapies.     

Low temperature cell pausing: an alternative short-term preservation method for use in cell therapies including stem cell applications

Encouraging advances in cell therapies have produced a requirement for an effective short-term cell preservation method, enabling time for quality assurance testing and transport to their clinical destination. Low temperature pausing of cells offers many advantages over cryopreservation, including the ability to store cells at scale, reduced cost and a simplified procedure with increased reliability. This review will focus on the importance of developing a short-term cell preservation platform as well highlighting the major successes of cell pausing and the key challenges which need addressing, to enable application of the process to therapeutically relevant cells.     

Embryonic stem cells and cell replacement therapies in the nervous system

Embryonic stem (ES) cells are pluripotential cells derived from the pre-implantation embryo. They can proliferate indefinitely in vitro while retaining pluripotency. ES cells can also be made to differentiate into a large variety of cell types in vitro. This has paved the way to research aimed at using ES-derived cells for cell replacement therapies. Hence, mouse ES cells can efficiently differentiate into neural precursors which can further generate functional neurons, astrocytes, and oligodendrocytes. Methods have also been developed to coax mouse ES-derived neural stem cells to differentiate into either dopaminergic neurons or motoneurons. Mouse ES-derived neural stem cells, or their fully differentiated progeny, have been shown to survive, integrate, and to some extent, function following transplantation within appropriate rodent host tissue. Research on human ES cells is still in its infancy. Considerable work has to be done: (1) to master growth and genetic manipulation of human ES cells; (2) to master their differentiation into specific cell types; and (3) to demonstrate that they can provide long term therapeutical benefits upon grafting into damaged tissues in humans. From the ethical point of view, the establishment of appropriate primate model will be an obligatory prerequisite to clinical trials based on ES cells derivatives grafting.