Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34+ and CD38- phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34+ and CD34- cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34+ , CD34- and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34+ AML cells compared to CD34- AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.

COVID-19 infection: an overview on cytokine storm and related interventions.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a significant threat to global health. This virus affects the respiratory tract and usually leads to pneumonia in most patients and acute respiratory distress syndrome (ARDS) in 15% of cases. ARDS is one of the leading causes of death in patients with COVID-19 and is mainly triggered by elevated levels of pro-inflammatory cytokines, referred to as cytokine storm. Interleukins, such as interleukin-6 (1L-6), interleukin-1 (IL-1), interleukin-17 (IL-17), and tumor necrosis factor-alpha (TNF-α) play a very significant role in lung damage in ARDS patients through the impairments of the respiratory epithelium. Cytokine storm is defined as acute overproduction and uncontrolled release of pro-inflammatory markers, both locally and systemically. The eradication of COVID-19 is currently practically impossible, and there is no specific treatment for critically ill patients with COVID-19; however, suppressing the inflammatory response may be a possible strategy. In light of this, we review the efficacy of specific inhibitors of IL6, IL1, IL-17, and TNF-α for treating COVID-19-related infections to manage COVID-19 and improve the survival rate for patients suffering from severe conditions.

Effect of aberrant DNA methylation on cancer stem cell properties.

DNA methylation, as an epigenetic mechanism, occurs by adding a methyl group of cytosines in position 5 by DNA methyltransferases and has essential roles in cellular function, especially in the transcriptional regulation of embryonic and adult stem cells. Hypomethylation and hypermethylation cause either the expression or inhibition of genes, and there is a tight balance between regulating the activation or repression of genes in normal cellular activity. Abnormal methylation is well-known hallmark of cancer development and progression and can switch normal stem cells into cancer stem cells. Cancer Stem Cells (CSCs) are minor populations of tumor cells that exhibit unique properties such as self-regeneration, resistance to chemotherapy, and high ability of metastasis. The purpose of this paper is to show how aberrant DNA methylation accumulation affects self-renewal, differentiation, multidrug-resistant, and metastasis processes in cancer stem cells.

Bone marrow CD34 positive cells may be suitable for collection after death.

Hematopoietic stem cells (HSCs) which are characterized with CD34+ phenotype, have a pivotal role in blood cell regeneration. They are located in lowest hypoxic areas in the bone marrow niches. This microenvironment protects them from DNA damage and excessive proliferation, whereas the oxygenated area driving cells out of quiescent state into proliferation. Given the resistance of HSCs to hypoxia, it is reasonable to imagine that they can survive for some time in the absence of oxygen. Here, we evaluated CD34, Bax, Bcl-2, Bcl-xl, and p53 genes expression after death. Moreover, we established the ex-vivo development of HSCs using SCF, FLT3, IL-2, and IL-15 cytokines in culture system. Our finding indicated that although the most of the dead person's mononuclear cells were alive and adequately expressed the CD34 on their surfaces at the first day of isolation, the viability and CD34+/Ki-67 expression declined significantly after culture process. Taken together, our finding indicated that the viability and CD34+ expression was acceptable on day 0 and could be used as a novel method for therapeutic purposes.

Telomerase-based therapies in haematological malignancies.

Telomeres are specialized genetic structures present at the end of all eukaryotic linear chromosomes. They progressively get shortened after each cell division due to end replication problems. Telomere shortening (TS) and chromosomal instability cause apoptosis and massive cell death. Following oncogene activation and inactivation of tumour suppressor genes, cells acquire mechanisms such as telomerase expression and alternative lengthening of telomeres to maintain telomere length (TL) and prevent initiation of cellular senescence or apoptosis. Significant TS, telomerase activation and alteration in expression of telomere-associated proteins are frequent features of different haematological malignancies that reflect on the progression, response to therapy and recurrence of these diseases. Telomerase is a ribonucleoprotein enzyme that has a pivotal role in maintaining the TL. However, telomerase activity in most somatic cells is insufficient to prevent TS. In 85-90% of tumour cells, the critically short telomeric length is maintained by telomerase activation. Thus, overexpression of telomerase in most tumour cells is a potential target for cancer therapy. In this review, alteration of telomeres, telomerase and telomere-associated proteins in different haematological malignancies and related telomerase-based therapies are discussed.

Stem cells-derived exosomes as cardiac regenerative agents.

Heart failure is a root cause of morbidity and mortality worldwide. Due to the limited regenerative capacity of the heart following myocardial injury, stem cell-based therapies have been considered a hopeful approach for improving cardiac regeneration. In recent years, different kinds of cell products have been investigated regarding their potential to treat patients with heart failure. Despite special attention to cell therapy and its products, therapeutic efficacy has been disappointing, and clinical application is not affordable. In the past few years, a subset of small extracellular vehicles (EVs), commonly known as "exosomes," was reported to grant regenerative and cardioprotective signals at a value similar to their donor cells. The conceptual advantage is that they may be ideally used without evoking a relevant recipient immune response or other adverse effects associated with viable cells. The evidence related to their beneficial effects in animal models of heart failure is rapidly growing. However, there is remarkable heterogeneity regarding source cells, isolation process, effective dosage, and delivery mode. This brief review will focus on the latest research and debates on regenerative potential and cardiac repair of exosomes from different sources, such as cardiac/non-cardiac stem, somatic cells, and progenitor cells. Overall, the current state of research on exosomes as an experimental therapy for heart diseases will be discussed.

Investigation the apoptotic effect of silver nanoparticles (Ag-NPs) on MDA-MB 231 breast cancer epithelial cells via signaling pathways.

Background: The discovery of novel cancer therapeutic strategies leads to the development of nanotechnology-based methods for cancer treatment. Silver nanoparticles (Ag-NPs) have garnered considerable interest owing to their size, shape, and capacity to modify chemical, optical, and photonic properties. This study aimed to investigate the impact of Ag-NPs on inducing of apoptosis in MDA-MB 231 cells by examining specific signaling pathways. Materials and methods: The cytotoxicity of Ag-NPs was determined using an MTT assay in MDA-MB 231 cells. The apoptotic effects were assessed using the Annexin-V/PI assay. Real-time PCR and western blotting were conducted to analyze the expression of apoptosis-related genes and proteins, respectively. Levels of ERK1/2 and cyclin D1 were measured using ELISA. Cell cycle assay was determined by flow cytometry. Cell migration was evaluated by scratch assay. Results: The results revealed that Ag-NPs triggered apoptosis and cell cycle arrest in MDA-MB 231 cells. The expression level of Bax (pro-apoptotic gene) was increased, while Bcl-2 (anti-apoptotic gene) expression was decreased. Increased apoptosis was correlated with increased levels of p53 and PTEN. Additionally, notable alterations were observed in protein expression related to the Janus kinase/Signal transducers (JAK/STAT) pathway, including p-AKT. Additionally, reduced expression of h-TERT was observed following exposure to Ag-NPs. ELISA results demonstrated a significant reduction in p-ERK/Total ERK and cyclin D1 levels in Ag-NPs-exposed MDA-MB 231 cells. Western blotting analysis also confirmed the reduction of p-ERK/Total ERK and cyclin D1. Decreased level of cyclin D is associated with suppression of cell cycle progression. The migratory ability of MDA-MB-231 cells was reduced upon treatment with Ag-NPs. Conclusions: Our findings revealed that Ag-NPs influenced the proliferation, apoptosis, cell cycle, and migration in MDA-MB 231 cells, possibly by modulating protein expression of the AKT/ERK/Cyclin D1 axis.

Targeting the stem cell niche micro-environment as therapeutic strategies in aging.

Adult stem cells (ASCs) reside throughout the body and support various tissue. Owing to their self-renewal capacity and differentiation potential, ASCs have the potential to be used in regenerative medicine. Their survival, quiescence, and activation are influenced by specific signals within their microenvironment or niche. In better words, the stem cell function is significantly influenced by various extrinsic signals derived from the niche. The stem cell niche is a complex and dynamic network surrounding stem cells that plays a crucial role in maintaining stemness. Studies on stem cell niche have suggested that aged niche contributes to the decline in stem cell function. Notably, functional loss of stem cells is highly associated with aging and age-related disorders. The stem cell niche is comprised of complex interactions between multiple cell types. Over the years, essential aspects of the stem cell niche have been revealed, including cell-cell contact, extracellular matrix interaction, soluble signaling factors, and biochemical and biophysical signals. Any alteration in the stem cell niche causes cell damage and affects the regenerative properties of the stem cells. A pristine stem cell niche might be essential for the proper functioning of stem cells and the maintenance of tissue homeostasis. In this regard, niche-targeted interventions may alleviate problems associated with aging in stem cell behavior. The purpose of this perspective is to discuss recent findings in the field of stem cell aging, heterogeneity of stem cell niches, and impact of age-related changes on stem cell behavior. We further focused on how the niche affects stem cells in homeostasis, aging, and the progression of malignant diseases. Finally, we detail the therapeutic strategies for tissue repair, with a particular emphasis on aging.

The effects of encapsulation on NK cell differentiation potency of C-kit+ hematopoietic stem cells via identifying cytokine profiles.

Natural killer cells (NK cells) can kill cancerous cells without prior sensitization. This feature makes them appealing candidates for cellular therapy. Due to the degradation rate and controlled release of these matrices, hydrogels hold great promise in cell differentiation. The study aims to investigate the effect of encapsulated alginate-gelatin on the differentiation potential of C-kit+ cells toward NK cells which are mediated by cytokines detection. Under both encapsulated and unencapsulated conditions, C-kit+ cells can differentiate into NK cells. In the following, real-time PCR and western blotting were done to investigate the mRNA and protein expression, respectively. Determine cytokine profiles from the collected culture medium conducted a Cytokine antibody array. The differentiated cells were then co-cultured with Molt-4 cells to examine the expression levels of INF-γ, TNF-α, and IL-10 using real-time-PCR. There was a substantial change in protein expression of the Notch pathway. Also, the encapsulation increased the mRNA expression of INF-γ and TNF-α in Molt-4 cells. Based on these findings, the encapsulation effects on the differentiation of C-kit+ cells toward NK cells could be related to the secreted cytokines such as interleukin-10 and INF-γ and the Notch protein expression.

Granulocyte differentiation of rat bone marrow resident C-kit+ hematopoietic stem cells induced by mesenchymal stem cells could be considered as new option in cell-based therapy.

Mesenchymal stem cells (MSCs) are effective in hematopoietic engraftment and tissue repair in stem cell transplantation. In addition, these cells control the process of hematopoiesis by secreting growth factors and cytokines. The aim of the present study is to investigate the effect of rat bone marrow (BM)-derived MSCs on the granulocyte differentiation of rat BM-resident C-kit+ hematopoietic stem cells (HSCs). The mononuclear cells were collected from rat BM using density gradient centrifugation and MSCs and C-kit+ HSCs were isolated. Then, cells were divided into two groups and differentiated into granulocytes; C-kit+ HSCs alone (control group) and co-cultured C-kit+ HSCs with MSCs (experimental group). Subsequently, the granulocyte-differentiated cells were collected and subjected to real-time PCR and Western blotting for the assessment of their telomere length (TL) and protein expressions, respectively. Afterwards, culture medium was collected to measure cytokine levels. CD34, CD16, CD11b, and CD18 granulocyte markers expression levels were significantly increased in the experimental group compared to the control group. A significant change was also observed in the protein expression of Wnt and ß-catenin. In addition, MSCs caused an increase in the TL of granulocyte-differentiated cells. MSCs could affect the granulocyte differentiation of C-kit+ HSCs via increasing TL and Wnt/ß-catenin protein expression.

Adipose Tissue-Mesenchymal Stem Cells Caused to Change the Methylation Status of hTERT Gene Promoter CpG Islands of Molt-4 Leukemia Cells as Cell-based Therapy.

BACKGROUND: DNA methylation was considered as prognostic information in some hematological malignancies. Previous studies have reported the in vitro and in vivo biology role of mesenchymal stem cells (MSCs) on leukemic cells. The aim of this study was to investigate the effect of MSCs on the promoter methylation status of hTERT as a catalytic subunit of telomerase enzyme. METHODS: In the experimental study, the Molt-4 leukemic cells were co-cultured with MSCs for 7 days. At the end of the co-culture period, the Molt-4 cells were collected, DNA and protein were extracted. Then methylation specific-PCR and western blotting were done for evaluating the hTERT gene promoter methylation status and cyclin D1 and hTERT protein expression, respectively. In the following, the flow cytometry was done for cell cycle distribution assay. RESULTS: It was found that MSCs resulted in a significant decrease in the cyclin D1 and hTERT protein expression levels. Also, MSCs caused changes in the methylation status of the CpG islands in the hTERT gene promoter region. The following results showed that MSCs caused a significant increase in the number of cells at G0/G1 phase and arrest the G0/G1 phase as well as decrease in the cell proliferation of Molt-4 cells. CONCLUSION: It is concluded that co-culture of MSCs with Molt-4 cells could be involved in changing the methylation status of hTERT gene promoter, cell cycle and hTERT protein expression; it could be potentially beneficial for further investigations regarding the cell transplantation and cell-based therapy.

Investigation of L-carnitine effects on CD44+ cancer stem cells from MDA-MB-231 breast cancer cell line as anti-cancer therapy.

Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells, capable of metastasis, recurrence, and drug resistance in breast cancer patients. Therefore, targeting BCSCs appears to be a promising strategy for the treatment and prevention of breast cancer metastasis. Mounting evidence supports the fact that carnitine, a potent antioxidant, modulates various mechanisms by enhancing cellular respiration, inducing apoptosis, and reducing proliferation and inflammatory responses in tumor cells. The objective of this study was to investigate the impact of L-carnitine (LC) on the rate of proliferation and induction of apoptosis in CD44+ CSCs. To achieve this, the CD44+ cells were enriched using the Magnetic-activated cell sorting (MACS) isolation method, followed by treatment with LC at various concentrations. Flow cytometry analysis was used to determine cell apoptosis and proliferation, and western blotting was performed to detect the expression levels of proteins. Treatment with LC resulted in a significant decrease in the levels of p-JAK2, p-STAT3, Leptin receptor, and components of the leptin pathway. Moreover, CD44+ CSCs-treated cells with LC exhibited a reduction in the proliferation rate, accompanied by an increase in the percentage of apoptotic cells. Hence, it was concluded that LC could potentially influence the proliferation and apoptosis of CD44+ CSC by modulating the expression levels of specific protein.

Magnetic nanoparticle-based hyperthermia: A prospect in cancer stem cell tracking and therapy.

Tumor heterogeneity is a major problem in cancer treatment. Cancer stem cells (CSCs) are a subpopulation of tumor masses that produce proliferating and quiescent cells. Under stress-related conditions, quiescent cells are capable of repopulating tumor masses. Consequently, many attempts have been made to identify, isolate, and eradicate CSCs from various tumors. Research has found that quiescent CSCs are less susceptible to conventional therapy than bulk cancer cells. This could be due to reduced cell cycling and increased DNA repair capacity of these cells. Indeed, disease progression is temporarily suppressed by eliminating fast-proliferating tumor cells and sparing quiescent CSCs lead to cancer relapse. Among all the available therapeutic modalities for cancer treatment, hyperthermia uses moderate heat to kill tumor cells. Nanoparticle-based platforms have the potential to deposit heat locally and selectively with the simultaneous activation of nanoparticles as heat transducers. Over the past few decades, magnetic nanoparticles (MNPs) have been widely investigated in the biomedical field. Magnetic hyperthermia therapy (MHT) is a promising therapeutic approach in which MNPs are delivered directly through targeting (systemic) or by direct injection into a tumor under exposure to an alternating magnetic field (AMF). Heat is generated by the MNPs subjected to AMF at a frequency of 100 kHz. Despite the widespread use of MHT alone or in combination therapies, its effectiveness in targeting CSCs remains unclear. This review discusses various types of MHT and their related mechanisms in cancer therapy, particularly concerning the eradication of CSCs.

L-Carnitine Reduced Cellular Aging of Bone Marrow Resident C-Kit+ Hematopoietic Progenitor Cells Through Telomere Dependent Pathways.

BACKGROUND: Increased oxygen species levels can induce mitochondrial DNA damage and chromosomal aberrations and cause defective stem cell differentiation, leading finally to senescence of stem cells. In recent years, several studies have reported that antioxidants can improve stem cell survival and subsequently affect the potency and differentiation of these cells. Finding factors, which reduce the senescence tendency of stem cells upon expansion, has great potential for cellular therapy in regenerative medicine. This study aimed to evaluate the effects of L-carnitine (LC) on the aging of C-kit+ hematopoietic progenitor cells (HPCs) via examining the expression of some signaling pathway components. METHODS: For this purpose, bone marrow resident C-kit+ HPCs were enriched by the magnetic-activated cell sorting (MACS) method and were characterized using flow cytometry as well as immunocytochemistry. Cells were treated with LC, and at the end of the treatment period, the cells were subjected to the realtime PCR technique along with a western blotting assay for measurement of the telomere length and assessment of protein expression, respectively. RESULTS: The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the TERT protein expression. In addition, a significant increase was observed in the protein expression of p38, p53, BCL2, and p16 as key components of the telomere-dependent pathway. CONCLUSION: It can be concluded that LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the C-kit+ HPCs via these signaling pathway components.

Bidirectional Relations Between Anxiety, Depression, and Cancer: A Review.

Epidemiological evidence continues to accumulate on the effect of stress and depression on cancer initiation and progression. Depression has been introduced as an independent predictor of increased cancer mortality. At the same time, early intervention for depression increases the survival rate. Even some evidence has given prognostic value for depression to predict cancer recurrence and mortality. This article presents current evidence on the correlations of molecular mechanisms of cancer and depression through; I. The evidence shows the role of pre-existing depression and anxiety in the development and progression of cancer. II. The Immune system performs a crucial role in stress, depression, and cancer. III. The role of stress and depression-induced inflammation. IV. The evidence has proposed that cancer may result in depression and the effect of depression on cancer outcomes. In conclusion, the importance of preventive interventions to monitor patients' mental health during cancer treatment is very significant and should not be underestimated. In other words, the initial interventions can improve depressive symptoms and increase cancer survival. On the other hand, by identifying key biomarkers of depression, physicians can identify cancer patients at risk for depression or those who may not respond to routine treatments. Revealing the molecular mechanism of the cancer microenvironment in the development of comorbidities promises innovative therapeutic options for cancer. Identifying these mechanisms opens a new avenue in identifying cancer patients at risk for depression and can also provide considerable potential in identifying depressive patients prone to cancer.

Synergistic effect of chrysin and radiotherapy against triple-negative breast cancer (TNBC) cell lines.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, accounting for 20% of cases. Due to the lack of a molecular target, limited options are available for TNBC treatment. Radiation therapy (RT) is a treatment modality for the management of TNBC following surgery; however, it has a detrimental effect on surrounding healthy tissues/cells at a higher rate. METHODS: We examined the effect of RT in combination with chrysin as a possible radiosensitizing agent in an MDA-MB-231 cell line as a model of a TNBC. The growth inhibitory effects of chrysin were examined using an MTT assay. Flow cytometry was performed to evaluate apoptosis and expression of hypoxia-induced factor-1α (HIF-1α). The protein expression of p-STAT3/STAT3 and Cyclin D1 was examined using western blotting. Real-time PCR determined apoptotic-related genes (Bax, BCL2, p53). RESULTS: Treatment of MDA-MB-231 cells with chrysin in combination with RT caused synergistic antitumor effects, with an optimum combination index (CI) of 0.495. Our results indicated that chrysin synergistically potentiated RT-induced apoptosis in MDA-MB-231 compared with monotherapies (chrysin and/or RT alone). Expression of HIF-1α was decreased in the cells exposed to combinational therapy. The apoptotic effect of combinational therapy was correlated with increased Bax (pro-apoptotic gene) and p53 levels along with reduced expression of Bcl-2 (anti-apoptotic gene). Increased apoptosis was associated with reduced expression of Cyclin D1, p-STAT3. CONCLUSION: These findings highlight the potential effect of chrysin as a radiosensitizer, indicating the synergistic anti-cancer effect of chrysin and RT in TNBC. Further investigation is warranted in this regard.

Oxidative stress regulation and related metabolic pathways in epithelial-mesenchymal transition of breast cancer stem cells.

Epithelial-mesenchymal transition (EMT) is a cell remodeling process in which epithelial cells undergo a reversible phenotype switch via the loss of adhesion capacity and acquisition of mesenchymal characteristics. In other words, EMT activation can increase invasiveness and metastatic properties, and prevent the sensitivity of tumor cells to chemotherapeutics, as mesenchymal cells have a higher resistance to chemotherapy and immunotherapy. EMT is orchestrated by a complex and multifactorial network, often linked to episodic, transient, or partial events. A variety of factors have been implicated in EMT development. Based on this concept, multiple metabolic pathways and master transcription factors, such as Snail, Twist, and ZEB, can drive the EMT. Emerging evidence suggests that oxidative stress plays a significant role in EMT induction. One emerging theory is that reducing mitochondrial-derived reactive oxygen species production may contribute to EMT development. This review describes how metabolic pathways and transcription factors are linked to EMT induction and addresses the involvement of signaling pathways.

Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation.

Metabolic reprogramming is a common hallmark of cancer cells. Cancer cells exhibit metabolic flexibility to maintain high proliferation and survival rates. In other words, adaptation of cellular demand is essential for tumorigenesis, since a diverse supply of nutrients is required to accommodate tumor growth and progression. Diversity of carbon substrates fueling cancer cells indicate metabolic heterogeneity, even in tumors sharing the same clinical diagnosis. In addition to the alteration of glucose and amino acid metabolism in cancer cells, there is evidence that cancer cells can alter lipid metabolism. Some tumors rely on fatty acid oxidation (FAO) as the primary energy source; hence, cancer cells overexpress the enzymes involved in FAO. Carnitine is an essential cofactor in the lipid metabolic pathways. It is crucial in facilitating the transport of long-chain fatty acids into the mitochondria for ß-oxidation. This role and others played by carnitine, especially its antioxidant function in cellular processes, emphasize the fine regulation of carnitine traffic within tissues and subcellular compartments. The biological activity of carnitine is orchestrated by specific membrane transporters that mediate the transfer of carnitine and its derivatives across the cell membrane. The concerted function of carnitine transporters creates a collaborative network that is relevant to metabolic reprogramming in cancer cells. Here, the molecular mechanisms relevant to the role and expression of carnitine transporters are discussed, providing insights into cancer treatment.

Cellular and Molecular Mechanisms Involved in Hematopoietic Stem Cell Aging as a Clinical Prospect.

There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs. The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-ß) pathway, and wingless-related integration site (Wnt) pathway. To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.

Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor- Mesenchymal Stem Cell Interaction for Therapeutic Interventions.

Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.