The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma.

Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.

Roles of Mesenchymal Stem Cells in Breast Cancer Therapy: Engineered Stem Cells and Exosomal Cell-Free Based Therapy.

Breast cancer has a high prevalence among women, with a high mortality rate. The number of people who suffer from breast cancer disease is increasing, whereas metastatic cancers are mostly incurable, and existing therapies have unfavorable side effects. For an extended duration, scientists have dedicated their efforts to exploring the potential of mesenchymal stem cells (MSCs) for the treatment of metastatic cancers, including breast cancer. MSCs could be genetically engineered to boost their anticancer potency. Furthermore, MSCs can transport oncolytic viruses, suicide genes, and anticancer medicines to tumors. Extracellular vesicles (EVs) are MSC products that have attracted scientist's attention as a cell-free treatment. This study narratively reviews the current state of knowledge on engineered MSCs and their EVs as promising treatments for breast cancer.

Recent Approaches to Enhance Osteogenesis of Dental Pulp Stem Cells on Electrospun Scaffolds.

Critical-sized bone defects are a challenging issue during bone regeneration. Bone tissue engineering is aimed to repair such defects using biomimicking scaffolds and stem cells. Electrospinning allows the fabrication of biocompatible, biodegradable, and strengthened scaffolds for bone regeneration. Natural and synthetic polymers, alone or in combination, have been employed to fabricate scaffolds with appropriate properties for the osteogenic differentiation of stem cells. Dental pulps are rich in stem cells, and dental pulp stem cells (DPSCs) have a high capacity for proliferation, differentiation, immunomodulation, and trophic factor expression. Researchers have tried to enhance osteogenesis through scaffold modification approaches, including incorporation or coating with mineral, inorganic materials, and herbal extract components. Among them, the incorporation of nanofibers with hyaluronic acid (HA) has been widely used to promote osteogenesis. In this review, the electrospun scaffolds and their modifications used in combination with DPSCs for bone regeneration are discussed.

Revisiting Recent Tissue Engineering Technologies in Alveolar Cleft Reconstruction.

Tissue engineering and regenerative medicine have received significant attention in treating degenerative disorders and presented unique opportunities for researchers. The latest research on tissue engineering and regenerative medicine to reconstruct the alveolar cleft has been reviewed in this study. Three approaches have been used to reconstruct alveolar cleft: Studies that used only stem cells or biomaterials and studies that reconstructed alveolar defects by tissue engineering using a combination of stem cells and biomaterials. Stem cells, biomaterials, and tissue-engineered constructs have shown promising results in the reconstruction of alveolar defects. However, some contrary issues, including stem cell durability and scaffold stability, were also observed. It seems that more prospective and comprehensive studies should be conducted to fully clarify the exact dimensions of the stem cells and tissue engineering reconstruction method in the therapy of alveolar cleft.

The therapeutic effects of mesenchymal stem cells and their secretome on oral squamous cell carcinoma.

Oral cancers are prevalent in the human population, particularly in unindustrialized countries. In 90 % of oral cancers, the tumors arise from squamous cells, which is called oral squamous cell carcinoma (OSCC). Despite new treatment strategies, the morbidity and mortality rates are still high. Current treatment options including surgery, chemotherapy, and radiotherapy are not effective in the treatment of the tumor. Cell therapy with mesenchymal stem cells (MSCs) is considered one of the leading strategies in cancer treatment. However, the field of MSC therapy in OSCC is immature and ongoing studies are being conducted in experimental and pre-clinical studies. Here, we reviewed these studies to figure out whether the use of MSCs could be worthwhile in OSCC therapy or not. Both native and engineered MSCs as well as their secretome have been used in the treatment of OSCC. It seems that genetically modified MSCs or their secretome could inhibit the tumorigenesis of OSCC. However, further pre-clinical studies are required to come to a conclusion.

The functional role of circular RNAs in the pathogenesis of retinoblastoma: a new potential biomarker and therapeutic target?

Retinoblastoma (RB) is a common cancer in infants and children. It is a curable disease; however, a delayed diagnosis or treatment makes the treatment difficult. Genetic mutations have a central role in the pathogenesis of RB. Genetic materials such as RNAs (coding and non-coding RNAs) are also involved in the progression of the tumor. Circular RNA (circRNA) is the most recently identified RNA and is involved in regulating gene expression mainly through "microRNA sponges". The dysregulation of circRNAs has been observed in several diseases and tumors. Also, various studies have shown that circRNAs expression is changed in RB tissues. Due to their role in the pathogenesis of the disease, circRNAs might be helpful as a diagnostic or prognostic biomarker in patients with RB. In addition, circRNAs could be a suitable therapeutic target to treat RB in a targeted therapy approach.

Hypoxia-circular RNA crosstalk to promote breast cancer.

The expression of hypoxia-inducible factors (HIFs), particularly HIF-1, plays a major role in the adaptation of solid tumors to hypoxic conditions. The activation of the HIF pathway results in an expression of genes involved in the promotion of cell growth, proliferation, vascularization, metastasis, and therapeutic resistance. Circular RNA (CircRNA) is considered as a major regulator of gene expression. CircRNAs could regulate the HIF-1 pathway in cancer cells. In addition, they might be regulated by the HIF-1 pathway to promote cancer progression. Therefore, the crosstalk between hypoxia and circRNA might be involved in the pathogenesis of cancers, including breast cancer. In this review, we discussed the function of HIF-related circRNAs in the progression, angiogenesis, metabolic reprogramming, and stemness maintenance of breast cancer. In addition, the correlation between HIF-related circRNAs and clinical features of breast cancer is reviewed.

Recent advancements to engineer mesenchymal stem cells and their extracellular vesicles for targeting and destroying tumors.

Mesenchymal stem cells (MSCs) have the ability to migrate into tumor sites and release growth factors to modulate the tumor microenvironment. MSC therapy have shown a dual role in cancers, promoting or inhibiting. However, MSCs could be used as a carrier of anticancer agents for targeted tumor therapy. Recent technical improvements also allow engineering MSCs to improve tumor-targeting properties, protect anticancer agents, and decrease the cytotoxicity of drugs. While some of MSC functions are mediated through their secretome, MSCs-derived extracellular vesicles (EVs) are also proposed as a possible viechle for cancer therapy. EVs allow efficient loading of anticancer agents and have an intrinsic ability to target tumor cells, making them suitable for targeted therapy of tumors. In addition, the specificity and selectivity of EVs to the tumor sites could be enhanced by surface modification. In this review, we addressed the current approaches used for engineering MSCs and EVs to effectively target tumor sites and deliver anticancer agents.

The role of hypoxia-inducible factors in breast cancer stem cell specification.

Breast tumor is heterogeneous cancer with high morbidity and mortality rates, particularly in developing countries. Despite new efforts to reduce the breast cancer implications, the number of newly diagnosed cases is increasing worldwide. It is believed that cancer stem cells (CSCs) are responsible for the implication of cancers including breast cancer. Although CSCs compose a small population in tumor bulks, they play a crucial role in tumor initiation, progression, metastasis, and chemotherapeutic resistance. These events are mediated by the hypoxia-inducible factor (HIF) pathway which regulates the transcription of genes involved in CSC maintenance and tumorigenesis. In this review, we discussed the mechanisms by which hypoxia- or chemotherapy-induced HIFs promote breast CSC specification.

PI3K/AKT/mTOR signaling pathway modulation by circular RNAs in breast cancer progression.

The PI3K/Akt/mTOR signaling pathway is responsible for many cellular behaviors, including survival, growth, and proliferation. A newly identified RNA, circular RNA (circRNA), plays a crucial role in the regulation of gene expression. The upregulation of the PI3K/Akt pathway through dysregulated circRNAs promotes breast tumor initiation, growth, and progression. The dysregulation of PI3K/Akt-regulating circRNAs seems to be directly correlated with breast cancer clinical features, including overall survival, tumor size, cancer stage, and lymph node metastasis. In addition, targeting these circRNAs may be a promising option in cancer-targeted therapy. Understanding the molecular pathogenesis of the circRNA-PI3K/AKT axis may give the insight to develop new therapeutic and diagnostic approaches for breast cancer therapy. Here we reviewed the expression and functions of PI3K/AKT-regulating circRNAs, and their correlation with breast cancer clinical features. In addition, the potential of PI3K/AKT-regulating circRNAs as diagnostic/prognostic biomarkers or therapeutic targets was discussed.

Circular RNAs in neuroblastoma: Pathogenesis, potential biomarker, and therapeutic target.

Neuroblastoma (NB) is a common cancer in childhood responsible for 15 % of fatalities by pediatric cancers. Epigenetic factors play an important role in the pathogenesis of NB. Recently, it has been demonstrated that circular RNAs (circRNAs, ciRNAs), a newly identified class of non-coding RNAs, are also dysregulated in NB. CircRNAs mediate their functions by regulating gene expression mainly through microRNA (miRNA) sponging. The dysregulation (abnormal upregulation or downregulation) of circRNAs is involved in tumorigenesis of a variety of tumors including NB. It seems that the expression of some circRNAs is correlated with NB prognosis and clinical features. CircRNAs might be favorable as a diagnostic/prognostic biomarker and therapeutic target. However, due to the lack of studies, it is difficult to make a conclusion regarding the clinical benefits of circRNAs. In this review, we discussed the circRNAs that experimentally have been proved to be dysregulated in NB tissues and cancer cells.

The therapeutic effect of exosomes from mesenchymal stem cells on colorectal cancer: Toward cell-free therapy.

Colorectal cancer (CRC) is known for its high mortality rate and affects more men than women. The treatment requires invasive surgical interventions, however, the progression of CRC metastasis is difficult to control in most cases. Mesenchymal stem cells (MSCs) with their outstanding characteristics have been widely used in the treatment of degenerative diseases as well as cancers. They affect the tumor microenvironment through either cell-cell interactions or communications with their secretome. While stem cells may represent a dual role in tumor proliferation and progression, exosomes have attracted much attention as a cell-free therapy in CRC treatment. Exosomes derived from native or genetically modified MSCs, as well as exosomal microRNAs (miRNAs), have been evaluated on CRC progression. Moreover, MSC-derived exosomes have been used as a carrier to deliver anticancer agents in colorectal cancer. In this review, we overview and discuss the current knowledge in both stem cell-based and cell-free exosome therapy of CRC.

PI3K/Akt/mTOR signaling pathway in cancer stem cells.

Cancer stem cells (CSCs) as a small subpopulation in tumor bulk are believed to initiate tumor formation and are responsible for the resistance to cancer therapy. The proliferation and differentiation of CSCs result in heterogeneity in a tumor which increases the chance of tumor survival and invasion. Many signaling pathways are abnormally activated or repressed in CSCs. Understanding these pathways and the metabolisms in CSCs may help targeted therapy in drug-resistant tumors. The PI3K/Akt/mTOR pathway is one of the major signaling pathways in CSCs involved in the maintenance of stemness, proliferation, differentiation, epithelial to mesenchymal transition (EMT), migration, and autophagy. Thus, suppressing the PI3K/Akt/mTOR pathway with inhibitors might be a promising strategy for targeted cancer therapy. Although the pathway is well-recognized and reviewed in tumor bulks, the functions in CSCs have not been well focused. Here, we reviewed the PI3K/Akt/mTOR signaling pathway and its functions in CSCs and addressed the potential therapeutic applications in drug-resistant tumors.

The expression of salivary microRNAs in oral lichen planus: Searching for a prognostic biomarker.

Oral lichen planus (OLP) is a premalignant disease with unknown etiology. It has been demonstrated that inflammation and immune activation play a central role in the pathogenesis of OLP. Various cellular and molecular mechanisms are involved in the pathogenesis of OLP. Studies have shown that 2-7% of OLP patients develop oral squamous cell carcinoma (OSCC). As a result, determining the prognosis of the disease will be promising in preventing oral carcinoma. MicroRNAs are involved in the regulation of cytokine expression and cytokines have a central role in the pathogenesis of OLP. As a result, their evaluation in body fluids may be helpful in assessing the disease's status and progression, and facilitating the treatment process. In this regard, much attention has been paid to the saliva of OLP patients as the sampling is cost-effective and non-invasive. Here, we discuss the potential of miRNAs in predicting the disease severity and progression.

Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering.

ABSTRACT: Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.

The Role of MicroRNAs in the Induction of Pancreatic Differentiation.

Stem cell-based therapy is one of the therapeutic options with promising results in the treatment of diabetes. Stem cells from various sources are expanded and induced to generate the cells capable of secreting insulin. These insulin-producing cells [IPCs] could be used as an alternative to islets in the treatment of patients with diabetes. Soluble growth factors, small molecules, geneencoding transcription factors, and microRNAs [miRNAs] are commonly used for the induction of stem cell differentiation. MiRNAs are small non-coding RNAs with 21-23 nucleotides that are involved in the regulation of gene expression by targeting multiple mRNA targets. Studies have shown the dynamic expression of miRNAs during pancreatic development and stem cell differentiation. MiR- 7 and miR-375 are the most abundant miRNAs in pancreatic islet cells and play key roles in pancreatic development as well as islet cell functions. Some studies have tried to use these small RNAs for the induction of pancreatic differentiation. This review focuses on the miRNAs used in the induction of stem cells into IPCs and discusses their functions in pancreatic ß-cells.

Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance.

Cancer stem cells (CSCs) are rare sub-population in tumor mass with self-renewal and differentiation abilities; CSCs are considered as the main cells which are responsible for tumor metastasis, cancer recurrence, and chemo/radio-resistance. CSCs are believed to contain low mitochondria in quantity, high concentration of nuclear factor erythroid 2-related factor 2 (Nrf2), and low reactive oxygen species (ROS) levels. Mitochondria regulate certain cellular functions, including controlling of cellular energetics, calcium signaling, cell growth and cell differentiation, cell cycle regulation, and cell death. Also, mitochondria are the main sources of intrinsic ROS production. Dysfunction of CSCs mitochondria due to oxidative phosphorylation is reported in several pathological conditions, including metabolic disorders, age-related diseases, and various types of cancers. ROS levels play a significant role in cellular signal transduction and CSCs' identity and differentiation capability. Nrf2 is a master transcription factor that plays critical functions in maintaining cellular redox hemostasis by regulating several antioxidant and detoxification pathways. Recently, the critical function of Nrf2 in CSCs has been revealed by several studies. Nrf2 is an essential molecule in the maintenance of CSCs' stemness and self-renewal in response to different oxidative stresses such as chemotherapy-induced elevation of ROS. Nrf2 enables these cells to recover from chemotherapy damages, and promotes establishment of invasion and dissemination. In this study, we have summarized the role of Nrf2 and mitochondria function CSCs, which promote cancer development. The significant role of Nrf2 in the regulation of mitochondrial function and ROS levels suggests this molecule as a potential target to eradicate CSCs.

The potency of hsa-miR-9-1 overexpression in photoreceptor differentiation of conjunctiva mesenchymal stem cells on a 3D nanofibrous scaffold.

MiRNAs are small non-coding RNAs that are ordinarily involved in modulating mRNAs and stem cell differentiation. 3D nanofibrous scaffolds have an important role in the differentiation of stem cells due to their similarity to the extracellular matrix (ECM). In the present study, we tried to introduce a new approach to guiding the differentiation of conjunctiva mesenchymal stem cells (CJMSCs) into photoreceptor-like cells by hsa-miR-9-1 delivery on both 2D and 3D substrates. First, the CJMSCs were transduced by a lentiviral vector carrying miR-9 (pCDH + hsa-miR-9-1) and then cell transduction efficacy verified by using fluorescent microscopy, flow cytometry, and qPCR analyses. Silk Fibroin-poly-L-lactic acid (SF-PLLA) scaffold was fabricated by the electrospinning technique while the scaffold characteristics including morphology, chemical properties, and biocompatibility were evaluated by SEM, FTIR, and MTT assays, respectively. Then, the miR-9-CJMSCs were seeded on both TCPS and the scaffold; photoreceptor gene and protein expressions were evaluated by RT-qPCR and immunostaining after 14 and 21 days of transduction. More than 80% of CJMSCs were transduced and miR-9 expression was significantly higher in miR-9-CJMSCs compared with empty vector (EV)-CJMSCs. SEM and FTIR confirmed the fabrication of the SF/PLLA hybrid structure. RT-qPCR and immunostaining analyses showed that the specific photoreceptor genes and proteins were expressed in miR-9 transduced CJMSCs. Mir-9 induced CJMSCs into photoreceptor-like cells in a time-dependent manneron on both TCPS and nanofibrous scaffold.We have proved that hsa-miR-9-1 has the potency to guide the photoreceptor differentiation of mesenchymal stem cells and promote retinal regeneration.

In vitro differentiation of conjunctiva mesenchymal stem cells into insulin producing cells on natural and synthetic electrospun scaffolds.

Polymers are used in tissue engineering as a scaffold. In this study the differentiation capability of conjunctiva mesenchymal stem cells (CJMSCs) on natural and synthetic nanofibrous electrospun scaffolds into insulin producing cells (IPCs) were studied. Natural Silk fibroin and synthetic PLLA polymers were used to fabricate electrospun scaffolds. These scaffolds are characterized by SEM and CJMSCs were differentiated into IPCs on these scaffolds. The differentiation efficiency was measured by analysis the expression of specific pancreatic markers by RT-qPCR and insulin release capacity via ELISA. Microscopy analysis showed the fabrication of uniform nanofibers and the formation of the islet-like clusters at the end of differentiation period. Significant differences in expression of Pdx-1 and glucagon were observed in PLLA scaffold compared to Silk scaffold (Fold: 1.625 and 1.434, respectively; P-value ≤ 0.0001 for both). Furthermore, insulin secretion at high glucose concentration was significantly higher in cells differentiated on PLLA scaffold than those cultured on Silk scaffold (P-value: 0.012). The scaffolds can enhance the differentiation of IPCs from CJMSCs. In this way, PLLA synthetic scaffold was more efficient than Silk natural scaffold. We conclude that the nanofibrous scaffolds reported herein could be used as a potential supportive matrix for islet tissue engineering.

Differentiation of microfluidic-encapsulated trabecular meshwork mesenchymal stem cells into insulin producing cells and their impact on diabetic rats.

Tissue and stem cell encapsulation andtransplantation were considered as promising tools in the treatment of patients with diabetes mellitus. The aim of this study was to evaluate the effect of microfluidic encapsulation on the differentiation of trabecular meshwork mesenchymal stem cells (TM-MSC), into insulin-producing cells (IPCs) both in vitro and in vivo. The presence of differentiated cells in microfibers (three dimensional [3D]) and tissue culture plates (TCPS; two dimensional [2D]) culture was evaluated by detecting mRNA and protein expression of pancreatic islet-specific markers as well as measuring insulin release of cells in response to glucose challenges. Finally, semi-differentiated cells in microfibers (3D) and 2D cultures were used to control the glucose level in diabetic rats. The results of this study showed that MSCs differentiated in alginate microfibers (fabricated by microfluidic device) express more Pdx-1 mRNA (1.938-fold, p-value: 0.0425) and Insulin mRNA (2.841-fold, p-value: 0.0001) compared with those cultured on TCPS. Furthermore, cell encapsulation in microfluidic derived microfibers decreased the level of blood glucose in diabetic rats. The approach used in this study showed the possibility of alginate microfibers as a matrix for differentiation of TM-MSCs (as a new source) into IPCs. In addition, it could minimize different steps in stem cell differentiation, handling, and encapsulation, which lead to loss of an unlimited number of cells.