Ali Akbar Movassaghpour

Background Mesenchymal stem cell (MSC)-derived exosomes revealed therapeutic ability, particularly in cancer treatment, by transferring bioactive molecules like miRNAs. Hypoxia, a common tumor condition, influences both tumor progression and MSC behavior. This review explores how hypoxic conditions affect MSC-derived exosomes and their impact on cancer-related pathways and genes. Method The current systematic review study was conducted by searching four different databases, including PubMed, Scopus, Embase, and Web of Science, using keywords such as mesenchymal stem cells, exosomes, hypoxia, cancer, and related terms. All original pre-clinical studies that focused on the role and effect of hypoxia in MSC-derived extracellular vesicles in different cancers were included. Data were collected qualitatively. Result Overall, 264 articles were identified from searching in databases, and eight of them met the eligibility criteria and were included in the current study. Among the articles, four focused on lung cancer, two on breast cancer, one on hepatocellular carcinoma, and one on Multiple Myeloma. The results indicated that MSC-derived exosomes have an enhanced effect on cell viability, migration, proliferation, and invasion of cancerous cells both in vitro and in vivo settings, and also cause a reduction in apoptosis in these cells. Besides, hypo MSC-exosomes can change the expression of some miRNAs in cancer cells, which affect different signaling pathways. Conclusion In general, the current study suggests that hypoxia-preconditioning of MSC-derived exosomes can influence specific genes, miRNAs, and signaling pathways in cancer cells, leading to increased proliferation, migration, and invasion, as well as decreased apoptosis. Besides, the biological effects of hypoxia-modulated exosomes seem to be significantly context-dependent. Although they may exacerbate malignancy in cancer microenvironments, analogous pathways can also facilitate tissue repair and regeneration in non-cancerous situations. Graphical Abstract

Autophagy, a process of cellular degradation and recycling, plays a biphasic role in leukemia; it acts either as a protective process that promotes the cancer cell to survive, or as a pathway that triggers cell death depending on certain conditions. MicroRNAs (miRNAs) regulate many important genes of autophagy, and these involve autophagy’s role in leukemia progression, drug resistance and therapy response. In this review, we will lay out the framework of how autophagy and miRNAs interact in that context and concentrate upon studies representative of how certain miRNAs such as miR-21, miR-155, or miR-29, regulate autophagy signaling pathways. We will also reflect on the potential of targeting the autophagy-miRNA axis to overcome drug resistance and enhance the outcome with treatment of leukemia. Although the utilization of miRNA-therapy and inhibitors have shown preclinical viability in leukemia, issues of delivery, specificity and toxicity create many obstacles. A greater comprehension of the molecular mechanisms underlying miRNA-mediated regulation of autophagy could lead to effective and novel therapeutic strategies for leukemia. This review highlights a clinical rationale to employ miRNAs and target autophagy modulation as a possible strategy to combat drug resistance leukemia.

Background: Acute myeloid leukemia (AML), a malignancy Often resistant to common chemotherapy regimens (Cytarabine (Ara-c) + Daunorubicin (DNR)), is accompanied by frequent relapses. Many factors are involved in causing chemoresistance. Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1-alpha (HIF-1α) are two of the most well-known genes, reported to be overexpressed in AML and promote resistance against chemotherapy according to several studies. The main chemotherapy agent used for AML treatment is Ara-c. We hypothesized that simultaneous targeting of HO-1 and HIF-1α could sensitize AML cells to Ara-c. Method: In this study, we used our recently developed, Trans-Activator of Transcription (TAT) - Chitosan-Carboxymethyl Dextran (CCMD) - Poly Ethylene Glycol (PEG) - Nanoparticles (NPs), to deliver Ara-c along with siRNA molecules against the HO-1 and HIF-1α genes to AML primary cells (ex vivo) and cell lines including THP-1, KG-1, and HL-60 (in vitro). Subsequently, the effect of the single or combinational treatment on the growth, proliferation, apoptosis, and Reactive Oxygen Species (ROS) formation was evaluated. Results: The designed NPs had a high potential in transfecting cells with siRNAs and drug. The results demonstrated that treatment of cells with Ara-c elevated the generation of ROS in the cells while decreasing the proliferation potential. Following the silencing of HO-1, the rate of apoptosis and ROS generation in response to Ara-c increased significantly. While proliferation and growth inhibition were considerably evident in HIF-1α-siRNA-transfected-AML cells compared to cells treated with free Ara-c. We found that the co-inhibition of genes could further sensitize AML cells to Ara-c treatment. Conclusions: As far as we are aware, this study is the first to simultaneously inhibit the HO-1 and HIF-1α genes in AML using NPs. It can be concluded that HO-1 causes chemoresistance by protecting cells from ROS damage. Whereas, HIF-1α mostly exerts prolific and direct anti-apoptotic effects. These findings imply that simultaneous inhibition of HO-1 and HIF-1α can overcome Ara-c resistance and help improve the prognosis of AML patients.

Purpose Neutropenic fever remains a major complication in acute leukemia. Decolonization is assumed as a promising intervention for eradicating causative agents of infection. Methods In this randomized clinical trial, 96 patients with acute leukemia were assigned randomly to mupirocin nasal drop 2% (n = 32), chlorhexidine mouthwash 0.2% (n = 33), and control group (n = 31). In control group, patients did not receive any medication for decolonization. All patients received treatment for 5 days (2 days prior to chemotherapy until 3 days after chemotherapy). Pharynx and nasal swabs were taken prior to the intervention and at the end of decolonization period in all groups. Antibiotic susceptibility testing was performed by the disc diffusion method in order to identify bacterial isolates. Results Bacterial recovery of both nasal and pharynx swabs was observed after global decolonization with mupirocin nasal drop. Decolonization with mupirocin significantly eradicated Coagulase-negative staphylococci (CONS) in both nasal and pharynx swabs (p-value = 0.000). Moreover, mupirocin decreased Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) species. Chlorhexidine mouthwash significantly eradicated CONS in pharynx swabs (p-value = 0.000). In addition, both decolonization strategies decreased both antibiotic use and frequency of fever in leukemic patients. Conclusion Global decolonization with mupirocin nasal drop not only eradicates both nasal and pharynx microorganisms, but also reduces antibiotic requirement and frequency of fever in patients with acute leukemia. The protocol of the present study was approved on December 2016 (registry number: IRCT20160310026998N6).

Background: Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed. Main body: According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways. Conclusion: HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia.

Background: Mesenchymal stem cells (MSCs) are undifferentiated cells with the ability of multi-potency, pluripotency, and self-renewal. MSCs show great promise in cancer therapy due to their unique features. MSC secrete various cytokines with multifunctional properties, although their roles are unclear. Methods: We have investigated the influence of secreted cytokines from MSCs on KG-1 cells as a cell model of acute myeloid leukemia (AML). For this purpose, following the culture and characterization of MSCs, a trans-well system was used for co-culturing MSCs and KG-1. To determine apoptosis induction Ki/Caspase-3 assay was conducted for cultured KG-1 alone and in co-culture with MSCs (10:1) on day 7. In the following step, the protein was isolated from both groups (control and experimental) and western blotting was done for investigating the BAX and BCL-2 proteins expression. Results: It was found that MSCs significantly enhanced caspase-3 activity in KG-1 cells (P<0.05). Besides, A significant increase in protein expression of BAX was detected, while BCL-2 displayed a dramatic reduction (P<0.01). Conclusion: As a concluding remark, MSCs have a contributory role in the apoptosis of KG-1 cells that is mediated by Caspase-3, BAX, and BCL2 expression.

Objective: Animal environments for the growth of stem cells cause the transmission of some diseases and immune problems for the recipient. Accordingly, replacing these environments with healthy environments, at least with human resources, is essential. One of the media that can be used as an alternative to animal serums is Wharton acellular jelly (AWJ). Therefore, in this study, we intend to replace FBS with Wharton jelly and investigate its effect on the expression of megakaryocyte-related genes and markers in stem cells. Materials and Methods: In this study, cord blood-derived CD34 positive HSCs were cultured and expanded in the presence of cytokines including SCF, TPO, and FLT3-L. Then, the culture of expanded CD34 positive HSCs was performed in two groups: 1) IMDM culture medium containing 10% FBS and 100 ng / ml thrombopoietin cytokine 2) IMDM culture medium containing 10% AWJ, 100 ng / ml thrombopoietin cytokine. Finally, CD41 expressing cells were analyzed with the flow cytometry method. The genes related to megakaryocyte lineage including FLI1 and GATA2 were also evaluated using the RT-PCR technique. Results: The expression of CD41, a specific marker of megakaryocyte lineage in culture medium containing Wharton acellular jelly was increased compared to the FBS group. Additionally, the expression of GATA2 and FLI1 genes was significantly increased related to the control group. Conclusion: This study provided evidence of differentiation of CD34 positive hematopoietic stem cells from umbilical cord blood to megakaryocytes in a culture medium containing AWJ.

Hematopoietic stem cells (HSCs) transplantation is considered a suitable treatment for malignant or nonmalignant hematological diseases. This study aims to investigate the HSCs homing factors in bone marrow (BM) donors of acute lymphoblastic leukemia (ALL) patients following granulocyte colony‐stimulating factor (G‐CSF) injection, as well as the G‐CSF effects on BM transplantation quality in these patients. To mobilize HSCs into peripheral blood, G‐CSF was used for ALL patient's BM donors. For HSCs counting, CD34+ cells were evaluated in analogous and autologous donors using flow cytometry. The expression of stem cell homing factors in CD34+ cells and peripheral blood mononuclear cells (PBMCs) were investigated using a real‐time polymerase chain reaction. Finally, hematological factors after BM transplantation in ALL patients were assessed. According to our results, after G‐CSF injection, the level of CD34+ HSCs was statistically increased. Besides, autologous donors showed a higher level of CD34+ cells compared to analogous donors before and after G‐CSF injection. Additionally, a higher number of CD34+ HSCs was achieved in the autologous samples following G‐CSF injection. Furthermore, after G‐CSF injection, the expression of matrix metalloproteinase (MMP)‐2, MMP‐9 was increased; while, stromal cell‐derived factor 1, intercellular adhesion molecule‐1, and vascular cell adhesion molecule‐1 expression were decreased. Moreover, the expression of C‐X‐C chemokine receptor type 4, lymphocyte function‐associated antigen 1, and very late antigen‐4 in CD34+ cells and PBMCs were decreased. BM transplantation on Day 90 also caused an increased level of white blood cells, red blood cells, and platelets as compared to the first day; however, no statistical differences were observed in hemoglobin level. In conclusion, G‐CSF by altering the expression of HSCs homing factors in ALL donors improves BM transplantation quality in ALL patients.

Many studies have been performed about regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) and their application in different treatment approaches. The present study aimed to investigate the immunomodulatory effect of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) on the gene expression profile of cytokines in stimulated T-lymphocytes. For this purpose, MSCs were isolated from umbilical cord blood samples and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. The nature of MSCs was identified by flow cytometry analysis and differentiation to the adipocyte and osteocyte lineage. Moreover, to investigate the immunomodulatory effects of MSCs on T cells, a co-culture system was designed and expression levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) genes were measured; using the real-time polymerase chain reaction (RT-PCR) technique. Our results demonstrated the ability of MSCs to differentiate into adipocyte and osteocyte lineages. Further investigation also displayed that although UCB-MSCs could significantly reduce the expression of pro-inflammatory cytokines like IL-2, IL-6, IFN-γ, and TNF-α in activated T-lymphocytes, they noticeably potentiated the expression levels of IL-4, IL-10, IL-13, and TGF-β in the co-culture setting. In conclusion, UCB-MSCs have immunomodulatory effects on activated T-lymphocytes in favor of anti-inflammatory responses.

Purpose: Acute myeloid leukemia (AML) is known to be an invasive and highly lethal hematological malignancy in adults and children. Resistance to the present treatments, including radiotherapy and chemotherapy with their side effects and telomere length shortening are the main cause of the mortality in AML patients. Telomeres sequence which are located at the end of eukaryotic chromosome play pivotal role in genomic stability. Recent studies have shown that apoptosis process is blocked in AML patient by the excessive telomerase activity in cancerous blasts. Therefore, the find of effective ways to prevent disease progression has been considered by the researchers. Natural killer (NK) cells as granular effector cells play a critical role in elimination of abnormal and tumor cells. Given that the cytotoxic function of NK cells is disrupted in the AML patients, we investigated the effect of telomerase inhibitors on NK cell differentiation. Methods: To evaluate telomerase inhibition on NK cell differentiation, the expression of CD105, CD56, CD57, and KIRs was evaluated in CD34+ derived NK cells after incubation of them with BIBR1532. Results: The results showed that the expression of CD105, CD56, CD57, and KIRs receptors reduces after telomerase inhibition. According to these findings, BIBR1532 affected the final differentiation of NK cells. Conclusion: The results revealed that telomerase inhibitor drugs suppress cancer cell progression in a NK cells-independent process.