Current Stem Cell Research & Therapy - Volume 16, Issue 7, 2021

In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of hematopoietic stem cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of the available strategies that may be used to protect HSCs from culture-induced stress conditions.

Imbalance between free radicals and antioxidants causes oxidative stress by the accumulation of reactive oxygen species (ROS) in the tissues and organs. Oxidative stress occurs in many damaged conditions, and the increase of ROS and reduction of antioxidants enhances inflammation, apoptosis, fibrosis and may worsen the pathology leading to organ failure. The potential therapies aim to increase antioxidants and decrease ROS. Mesenchymal stem cells (MSCs) isolated from the stroma of various tissues are multipotent cells and have beneficial effects on several diseases with their immunomodulation and regeneration capacities. MSCs trigger the proliferation of the cells with various secretory factors, reduce oxidative stress and decrease apoptosis, inflammation, fibrosis and thus, increase regeneration. However, survival, engraftment, and differentiation problems of transplanted MSCs restrict their protective and regenerative effects. Preconditioning of MSCs with several factors, such as cytokines, hypoxia, chemical agents, pharmacological drugs, physical factors and growth factors, enhances their repairing efficacy for injury and disease models. This review is mainly focused on insulin-like growth factor (IGF-1) and hepatocyte growth factor (HGF), and discusses the research on MSC priming/induction with IGF-1 and HGF stimulation either by supplementation or overexpression that can enhance the regenerative potential of MSCs on various oxidative stress conditions such as acute/chronic kidney diseases, lung injury, cancer, metabolic and cardiovascular diseases.

Cancer stem cells represent a rare subpopulation of cancer cells carrying self-renewal and differentiation features in multi-step tumorigenesis, tumor recurrence and metastasis. Proinflammatory stress is highly associated with cancer stemness via induction of cytokines, tumorpromoting immune cells and cancer stemness-related signaling pathways. This review summarizes the major pro-inflammatory factors affecting cancer stem cell characteristics and the critical immunotherapeutic strategies to eliminate cancer stem cells.

Umbilical cord and cord blood are acceptable as attractive sources of mesenchymal and hematopoietic stem cells, since their collection is non-invasive, painless, and does not evoke the ethical concerns. Microorganism-stem cell interaction plays an important role in stem cell self-renewal, differentiation, secretion profile and death. In the literature, few researchers are examining the relationship between pathogenic and commensal bacteria with umbilical cord-derived Mesenchymal Stem Cells (MSCs). These relationships vary depending on the bacterial load and the presence of the immune cell in the environment. Several bacterial pathogens act in the regenerative capacity of MSCs by changing their phenotype, development and viability due to several stress factors that are created by a microorganism such as hypoxia, oxidative stress, etc. On the other hand, the anti-inflammatory and antibacterial effects of MSCs were shown and these phenomena increased when the number of bacteria was high but decreased in the presence of low amounts of bacteria. The antibacterial effects of MSCs increased in the early period of infection, while their effects were decreased in the late period with high inflammatory response and bacterial load. In this review, we discussed the microbial stresses on human umbilical cord stem cells.

Telomeres are the protective end caps of eukaryotic chromosomes and they determine the proliferative lifespan of somatic cells, as the protectors of cell replication. Telomere length in leucocytes reflects telomere length in other somatic cells. Leucocyte telomere length can be a biomarker of human ageing. The risk of diseases associated with reduced cell proliferation and tissue degeneration, including aging or aging-associated diseases, such as dyskeratosis congenita, cardiovascular diseases, pulmonary fibrosis and aplastic anemia, is correlated with an increase in the shortening of telomeres. On the other hand, the risk of diseases that are associated with increased proliferative growth, including major cancers, is correlated with long telomeres. In most of the cancers, a telomere maintenance mechanism during DNA replication is essential. The reactivation of the functional ribonucleoprotein holoenzyme complex (telomerase) starts the cascade from normal and premalignant somatic cells to advanced malignant cells. Telomerase is overexpressed during the development of cancer and embryonic stem cells, through controlling genome integrity, cancer formation and stemness. Cancer cells have mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis, and halting cell division by critically short telomeres. Modulation of the human telomerase reverse transcriptase is the rate-limiting step for the production of functional telomerase and telomere maintenance. The human telomerase reverse transcriptase promoter promotes its gene expression only in tumor cells, but not in normal cells. Some cancers activate an alternative expansion of telomeres maintenance mechanism via DNA recombination to reduce the shortening of their telomeres. Not only heritability but also oxidative stress, inflammation, environmental factors, and therapeutic interventions have an effect on telomere shortening, explaining the variability in telomere length across individuals. There have been a large number of publications, which correlate human diseases with progressive telomere shortening. Telomere length of an individual at birth is also important to follow up telomere shortening, and it can be used as a biomarker for healthy aging. On the other hand, understanding of cellular stress factors, which affect stem cell behavior, will be useful in regeneration or treatment of cancer and age-associated diseases. In this review, we will understand the connection between stem cell and telomere biology, cancer, and aging-associated diseases. This connection may be useful for discovering novel drug targets and improve outcomes for patients having cancer and aging-associated diseases.

The Hippo pathway, with its core components and the downstream transcriptional coactivators, controls the self-renewable capacity and stemness features of stem cells and serves as a stress response pathway by regulating proliferation, differentiation and apoptosis. The Hippo pathway interaction with other signaling pathways plays an important role in response to various stress stimuli arising from energy metabolism, hypoxia, reactive oxygen species, and mechanical forces. Depending on the energy levels, the Hippo pathway is regulated by AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), which in turn determines stem cell proliferation (cell survival and growth) and differentiation. Oxidative stress-driven by ROS production also affects the Hippo pathway with transcriptional changes through MST/YAP/FoxO pathway and leads to the activation of pro-apoptotic genes and eventually cell death. HIF1alpha/YAP signaling is critical for the long-term maintenance of mesenchymal stem cells (MSCs) under hypoxia. In this review, we present an overview of stem cell response to stress, including mechanical, hypoxia, metabolic and oxidative stress through the modulation of the Hippo pathway. The biological effects such as autophagy, apoptosis and senescence were discussed in the context of the Hippo pathway in stem cells.

Osteoarthritis (OA), characterized by the degeneration and destruction of articular cartilage, is one of the most significant public health issues around the world. In the course of OA, inflammatory response is an important factor leading to cartilage destruction and exacerbation of symptoms. The low immunogenicity, multi-directional differentiation and high portability properties make bone marrow mesenchymal stem cells (BMSCs) ideal seed cells for OA. Here, we review recent literature relating to the application of BMSCs for OA cell therapy and consider the following aspects: migration and homing of BMSCs, immunomodulatory and anti-inflammatory effects of BMSCs, anti-fibrotic effects of BMSCs, the application of biological scaffolds in cartilage regeneration by BMSCs and chondrogenic differentiation of BMSCs. Injecting BMSCs into joints with an inflammatory environment may increase the risk of osteoproliferation and ectopic calcification in patients. Further evidence and studies are needed to ensure the improvement and maintenance of the intra-articular environment for cartilage repair and regeneration.

Transmembrane integrin receptors represent a major component of cell-extracellular matrix (ECM) communications that mediate cellular biological activities, including proliferation and differentiation. Stem cells, especially mesenchymal stem cells (MSC), have rapidly emerged as promising therapies for various diseases. Dynamic links exist between extracellular and intracellular environments that profoundly influence the cellular activities via integrin receptors, such as cell morphology transformation and differentiation. Interpreting the roles of integrin receptors in the regulation of MSC differentiation may potentially lead to an amplified therapeutic effect. In this review, we summarize, for the first time, the potential mechanisms by which integrins promote MSC multilineage differentiation, including integrin downstream signaling cascades and the interactions between integrin and ion channels, the cytoskeleton, and nuclear mechanoresponses. Furthermore, we focus on the current state and future prospects of the application of integrins to promote cell differentiation.

Mesenchymal stem cells (MSCs) have shown promising therapeutic effects in a wide variety of medical conditions, including neurodegenerative disorders and cardiovascular diseases. Although preliminary research has emphasized the ability of MSCs to engraft at sites of injury, several studies have revealed that MSCs mediate their effects through the release of various paracrine factors and through their antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. The clinical implications of MSCs application are limited due to their low survival rate in conditions of inflammation, oxidative stress, and nutrient restriction in damaged areas. Furthermore, the function of isolated MSCs is usually affected by the patient’s health. Therefore, it is necessary to develop new methods to enhance the therapeutic efficacy of MSCs under pathophysiological conditions. This review provides an overview of the general properties of MSCs, their therapeutic potential in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease, as well as cardiovascular diseases such as myocardial infarction, diabetic cardiomyopathy, and dilated cardiomyopathy, and their related mechanisms. In addition, this review also discusses potential problems and side effects, as well as current and future directions for improvement of MSCs therapy and their implications and applications.

Background: Cancer stem cells (CSCs) are a small subpopulation of cells within tumors and play significant roles in tumorigenesis, metastasis, resistance to treatment, and relapse. They are defined by self-renewal and multi-lineage differentiation, and aggressiveness. Epigenetic modifications, including DNA methylation and acetylation, histone modifications, and non-coding. RNAs (ncRNAs), are partly responsible for CSC potentials and are involved in the modification of key components of crucial pathways such as Notch and Wnt signaling in breast cancer. Objective: In this review, we present an overview of the pathways and epigenetic events that lead to the transformation of mammary gland stem cells to breast CSCs (BCSCs). Based on the data presented here, important pathways such as TGF-β/SMAD2 and Wnt/β-catenin and epigenetic modifications, including histone modifications, DNA methylations, and microRNAs, play important roles in BCSC formation and maintenance. Conclusion: Epigenetic events can alter the expression of genes and functional RNAs, resulting in tumor initiation and progression. Thus, a better understanding of epigenetic modifications involved in BCSC maintenance signaling pathways may help to eliminate or suppress BCSCs and overcome cancer by generating more effective and efficient therapeutic agents.

Liver disease (hepatic disease) adversely affects the normal function of the liver and causes liver problems. Drug-induced liver injury (DILI) can be predicted by primary human hepatocytes. However, the sources of hepatocytes for large-scale drug toxicity screening are limited. To solve this problem, pluripotent stem cells (PSCs), mesenchymal stem cells (MSCs), and hepatic stem cells (HSCs) have emerged as attractive cell sources for cell-based therapies. Human PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the ability to undergo self-renewal and differentiate into lineages of ectoderm, mesoderm, and endoderm. Human PSC can be used for the generation of hepatocytes to facilitate the development of novel drugs for the treatment of severe liver diseases. The therapeutic potential of PSC-derived hepatocytes for liver failure have been identified to enhance the development of chemically defined and xenogenic- free 3D culture methods. To date, several hepatic differentiation strategies and various extracellular matrix (ECM) components have been employed to produce hepatocytes or hepatic-like cells (HLCs) in vitro. In this review, we focused on the potential of Matrigel, collagen type 1, Ro- Gel, and laminin as ECM on the differentiation and function of hESC- and hiPSC-derived hepatocytes. The hepatic differentiation of human ESCs and iPSCs would offer an ideal tool for cell therapy and liver diseases.

Atherosclerosis is a multifactorial and complex disease involving the arterial intima of the circulatory system. The main risk factors of atherosclerosis are diabetes mellitus, hypertension, hyperlipidemic states, smoking, mental stress, unhealthy diet, and a lack of physical activity. Recent studies have shown that dyslipidemia, inflammation and immune cells are involved in all stages of the development of atherosclerosis. Mesenchymal stem cells are a heterogeneous subset of multipotent cells that can be isolated from nearly all human organs and tissues, and they possess both regenerative and immunomodulatory properties. Recent studies have shown that mesenchymal stem cells are able to provide immunosuppressive, regenerative, and atheroprotective effects by reducing dyslipidemia, inflammation and inhibiting endothelial cell dysfunction and plaque formation during the development of atherosclerosis in animal models. Based on these beneficial effects, mesenchymal stem cells are considered a promising alternative therapeutic approach for the effective treatment of atherosclerosis. In this review, we summarize the current findings on potential applications of mesenchymal stem cells for preventing and regressing atherosclerosis as well as discuss strategies for improving the efficacy of mesenchymal stem cell-based therapy.