Amniotic fluid-derived stem cells in regenerative medicine research

The stem cells isolated from amniotic fluid present an exciting possible contribution to the field of regenerative medicine and amniotic fluid-derived stem (AFS) cells have significant potential for research and therapeutic applications. AFS cells are multipotent, showing the ability to differentiate into cell types from all three embryonic germ layers. They express both embryonic and adult stem cell markers, expand extensively without feeder cells, double in 36 h, and are not tumorigenic. The AFS cells can be maintained for over 250 population doublings and preserve their telomere length and a normal karyotype. They differentiate easily into specific cell lineages and do not require human embryo tissue for their isolation, thus avoiding the current controversies associated with the use of human embryonic stem (ES) cells. The discovery of the AFS cells has been recent, and a great deal of work remains to be performed on the characterization and use of these cells. This review describes the various differentiated lineages that AFS cells can form and the future of these promising new stem cells in regenerative medicine research.     

Mesenchymal stem cells for cardiac regenerative therapy

Until recently, the concept of treating the injured or failing heart by generating new functional myocardium was considered physiologically impossible. Major scientific strides in the past few years have challenged the concept that the heart is a post-mitotic organ, leading to the hypothesis that cardiac regeneration could be therapeutically achieved. Bone marrow-derived adult stem cells were among the first cell populations that were used to test this hypothesis. Animal studies and early clinical experience support the concept that therapeutically delivered mesenchymal stem cells (MSCs) safely improve heart function after an acute myocardial infarction (MI). MSCs produce a variety of cardio-protective signalling molecules, and have the ability to differentiate into both myocyte and vascular lineages. Additionally, MSCs are attractive as a cellular vehicle for gene delivery, cell transplantation or for tissue engineering because they offer several practical advantages. They can be obtained in relatively large numbers through standard clinical procedures, and they are easily expanded in culture. The multi-lineage potential of MSC, in combination with their immunoprivileged status, make MSCs a promising source for cell therapy in cardiac diseases. Here we provide an overview of biological characteristics of MSCs, experimental animal studies and early clinical trials with MSCs. In addition, we discuss the routes of cell delivery, cell tracking experiments and current knowledge of the mechanistic underpinnings of their action.     

Combining polymeric devices and stem cells for the treatment of neurological disorders: a promising therapeutic approach

Cell therapy will probably become a major therapeutic strategy for neuronal disorders in the coming years. Nevertheless, due to poor survival of grafted cells and limited differentiation and integration in the host tissue, certain ameliorations must be envisaged. To address these difficulties, several strategies have been developed and among them, two methods seem particularly promising : in situ controlled drug delivery and implantation of cells adhered on biomaterial-based scaffolds. Indeed, the ability of drugs, such as growth factors, to regulate neuronal survival and/or plasticity infers the use of these molecules to treat neurodegeneration associated with human diseases. Moreover, the synthesis of cell scaffolds which mimic the extra-cellular matrix can help guide morphogenesis and tissue repair. Furthermore, cells can be cultivated on these matrices that may eventually make graft therapy a more practical approach for the treatment of neurological diseases. Nevertheless, for those two encouraging approaches multiple parameters have to be considered, such as the drug targeting strategy, but also the physical and morphological characteristics of the scaffold and the type of cells to be conveyed. This review thus focuses on those two promising strategies and also on their possible association to improve stem cell therapy of neurodegenerative disorders. Indeed, tissue replacement by grafting cells within or adhered onto drug delivering biomaterial-based devices, has recently been reported and seems to be very promising.     

MUC1 is a promising therapeutic target for prostate cancer therapy

Prostate cancer (CaP) is one of the most common malignancies in men, and the incidence of CaP is increasing. Because of the limitations of current therapeutic approaches, many patients die of secondary disease (metastases). Mucins are used as diagnostic markers as well as therapeutic targets due to their aberrant and unique expression pattern during cancer progression. There is a growing interest in mucins as treatment targets in human malignancies, including CaP. So far, 21 mucin genes have been identified. Of these, MUC1 has been investigated most extensively. In neoplastic tissues, MUC1 is underglycosylated compared with that in normal tissues. The reduced glycosylation permits the immune system to access the peptide core of the tumor-associated underglycosylated MUC1 antigen (uMUC1) and reveal epitopes that are masked in the normal cell. This feature makes it possible to design an antibody that discriminates between normal and adenocarcinoma cells and target tumor-associated MUC1 with toxins or radionuclides, or use a vaccine targeting tumor-associated MUC1 antigen. The results from our recent study have shown that over-expression of MUC1 plays a very important role in CaP progression and MUC1 is an ideal target for targeted therapy to control micrometastases and hormone refractory disease. This review will cover our current understanding of the structure and functions of MUC1, summarize its expression on human CaP tissues and focus on the MUC1-based immunotherapy for control of metastatic CaP.     

Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells

There is growing evidence to suggest that reservoirs of stem cells may reside in several types of adult tissue. These cells may retain the potential to transdifferentiate from one phenotype to another, presenting exciting possibilities for cellular therapies. Recent discoveries in the area of neural differentiation are particularly exciting given the limited capacity of neural tissue for intrinsic repair and regeneration. Adult adipose tissue is a rich source of mesenchymal stem cells, providing an abundant and accessible source of adult stem cells. These cells have been termed adipose derived stem cells (ASC). The characterization of these ASCs has defined a population similar to marrow-derived and skeletal muscle-derived stem cells. The success seen in differentiating ASC into various mesenchymal lineages has generated interest in using ASC for neuronal differentiation. Initial in vitro studies characterized the morphology and protein expression of ASC after exposure to neural induction agents. Additional in vitro data suggests the possibility that ASCs are capable of neuronal activity. Progress in the in vitro characterization of ASCs has led to in vivo modeling to determine the survival, migration, and engraftment of transplanted ASCs. While work to define the mechanisms behind the transdifferentiation of ASCs continues, their application to neurological diseases and injuries should also progress. The subject of this review is the capacity of adipose derived stem cells (ASC) for neural transdifferentiation and their application to the treatment of various neurologic disorders.     

Th17 cells: a promising therapeutic target for Parkinson’s disease?

Introduction: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder caused by the progressive loss of neurons in the midbrain and other brain regions. Only symptomatic treatment is currently available. Mounting evidence suggests that T cells are a key contributor to PD pathogenesis and neurodegeneration by a mechanism that requires further elucidation.

Areas covered: We discuss the evidence of imbalanced activation of effector T cell populations in PD and summarize the data of Th17 involvement and Th17-regulated mechanisms in PD pathology. Moreover, possible Th17-related molecular targets as possible neuroprotective immunomodulatory therapeutic targets for PD are examined.

Expert Opinion: Existing data show that Th17 cells, their effector molecules, and signaling pathways are potentially effective therapeutic targets for neuroprotective immunomodulation in PD treatment. However, specificity of action within Th17-mediated signaling pathways for PD requires careful consideration.     

Very small embryonic-like stem cells for regenerative medicine: WO2010039241

Background: The application is in the field of stem cells and regenerative medicine.

Objective: It aims at identifying and characterising a population of pluripotent stem cells present in adult tissues.

Methods: Cells were isolated and purified using Fluorescence-Activated Cell Sorting and Direct ImageStream analysis from various adult and umbilical cord tissues of rodents and humans. Cells were propagated in the presence of trophic factors and feeder cell layers of C2C12 cells. Cells were characterised by electron microscopy and immunocytology.

Results: A population of cells that do not express a panleukocytic antigen CD45 and are negative for other markers of haematopoietic lineages were isolated and purified. The isolated cells elicit morphological features of embryonic stem cells (ESCs). They express markers of pluripotent stem cells, such as Nanog, Oct-4 and SSEA-1. On culturing on feeder cell layers, the isolated and purified cells generate embryoid body-like sphere.

Conclusion: The identified and characterised cells elicit features of pluripotent stem cells and similarities with ESCs. They are termed very small embryonic-like stem cells (VSELs). The application claims the use of VSELs for cellular therapy and regenerative medicine.     

Embryonic stem cell lines for regenerative therapy and pharmaceutical research

The establishment of human embryonic stem (ES) cell lines has brought great potential and expectations for regenerative medicine and pharmaceutical research, because many types of human cells could be produced by their unlimited growth and differentiation in culture. Primate and human ES cell lines have been established from blastocysts of monkey and surplus human blastocysts from fertility clinics. They showed several differences compared to mouse ES cells, including a tendency to produce the trophectoderm lineage and a different expression pattern of surface antigens. This may reflect species-specific differences, or these primate ES cells could represent earlier stages of development than mouse ES cells. Also, they show no response to the LIF and gp130 signals, which are widely used to repress spontaneous differentiation of mouse ES cell colonies. We have established several ES cell lines from blastocysts of the cynomolgus monkey. They can be maintained in culture as stem cell colonies, and they produce several differentiated cell types in culture. When such ES cells were transplanted into SCID mice, they produced teratomas containing many differentiated tissues.     

IL-13: a promising therapeutic target for bronchial asthma

The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma, based on mainly analyses of mouse models. In addition to such analyses, the high expression of IL-13 in lesions and genetic association of several genes coding IL-13 signaling molecules with bronchial asthma have raised the possibility that IL-13 plays a pivotal role in the onset or exacerbation of human bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we describe how IL-13 is involved in the pathogenesis of bronchial asthma and then how therapeutic agents to block IL-13 signals are developed for bronchial asthma.     

Mesenchymal stem cells: a new trend for cell therapy

Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.     

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy

Currently the main treatment of acute myeloid leukemia (AML) is chemotherapy combining hematopoietic stem cell transplantation. However, the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice. Thus, there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects. Here, we revealed that umbilical cord-derived mesenchymal stem cells (UC-MSC) efficiently induced AML cell differentiation by shuttling the neutrophil elastase (NE)-packaged extracellular vesicles (EVs) into AML cells. Interestingly, the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor (VDR) activation in UC-MSC. Chemical activation of VDR by using its agonist 1α,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model. Based on these discoveries, to evade the risk of hypercalcemia, we synthetized and identified sw-22, a novel non-steroidal VDR agonist, which exerted a synergistic pro-differentiation function with UC-MSC on mitigating the progress of AML. Collectively, our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.     

Embryonic stem cells: a perfect marriage between gene regulation and regenerative medicine

The mechanism of mammalian gene regulation is highly complex, involving multiple layers of feedback control loops and dynamic chromatin remodeling. The current approach used to dissect the genetic circuitry of mammalian gene regulation utilizes somatic cells and protein fusion as a means to modulate protein interactions. This approach has several limitations that include (i) genome inaccessibility, (ii) high background interferences and, (iii) limited cellular phenotypes. Previously, the two broad fields of research "control of gene expression" and "stem cell biology" had been pursued separately by cell biologists; this review outlines evidence suggesting that integration of these two fields would provide a comprehensive platform for interdisciplinary research seeking to address mechanistic questions concerning gene regulation-that could have enormous implication for the development of therapeutic applications.     

The apelinergic system: a promising therapeutic target

Importance of the field: Apelin is a bioactive peptide known as the ligand of the G-protein-coupled receptor APJ. In recent years, there has been a growing body of evidence regarding the importance of apelin and APJ in the pathophysiology of cardiovascular, metabolic and gastrointestinal diseases, brain signalling, HIV infection and tumor angiogenesis. Therefore, the apelinergic system is involved in the pathogenesis of several diseases that represent a major burden to our society.

Areas covered in this review: The goal of this paper is to give an up-to-date review of existing information on apelin/APJ since the discovery of apelin in 1998, with particular focus on their involvement in the regulation of human body systems and potential therapeutic applications.

What the reader will gain: An overview of the most important physiological functions of the apelinergic system and the diseases that may benefit in the future from its modulation as a therapeutic target.

Take home message: Today, the established biological effects of apelin involve major cardiovascular actions, neoangiogenesis, immunologic modulation and insulinemia control as well as body fluid and glucose homeostasis. However, the physiological and pathophysiological role of endogenous apelin is still unsettled and a better and profound knowledge of this system in humans is necessary for the development of novel apelinergic-based therapeutic targets.     

Non-genetic engineering of cells for drug delivery and cell-based therapy

Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non-genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions.     

Targeting FtsZ for antibacterial therapy: a promising avenue

The widespread problem of bacterial resistance towards existing drugs and the paucity of effective drugs for the treatment of bacterial infections have prompted the scientific community to think about novel strategies for discovering new classes of antibacterial drugs. Target-based screening of inhibitory molecules has emerged as an important alternative for the development of potent antibacterials. FtsZ is a prokaryotic cytoskeleton protein, which plays an important role in bacterial cell division. It forms a highly dynamic Z-ring at the centre of the cell and recruits other accessory proteins, which are involved in bacterial cytokinesis. Here, we discuss the assembly dynamics of FtsZ and the key features that place it among the novel antibacterial drug targets. The recent progress in finding the inhibitors of functional properties of FtsZ and its interactions with other proteins, which has been enabled by advanced screening methods and structure-based design, are presented herein. Although there are significant challenges in the development of this new class of antibacterial drugs, nonetheless the therapeutic potential of FtsZ as a drug target is motivating researchers to find lead molecules with enhanced efficacy and reduced toxicity.     

Soluble epoxide hydrolase: a promising therapeutic target for cardiovascular diseases

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP450) products of arachidonic acid and EETs are endogenous lipid mediators synthesized by the vascular endothelium which perform important biological functions, including vasodilation, anti-inflammation, antimigratory, and cellular signaling regulations. However, EETs are rapidly degraded by soluble epoxide hydrolase (sEH) to the corresponding diols: dihydroxyeicosatrienoic acids (DHETs), which have little active in causing vasorelaxation. A number of studies have supported that the inhibition of sEH (sEHIs) had cardiovascular protective effects in hypertension, cardiac hypertrophy, atherosclerosis, ischemia-reperfusion injury, and ischemic stroke. Moreover, sEHIs could slow the progression of inflammation, protect end-organ damage and prevent ischemic events, also, attenuate endothelial dysfunction, suggesting that the pharmacological blockade of sEH might provide a broad and novel avenue for the treatment of many cardiovascular diseases.