Volume 19, Nº 1 (2024)

Medicine

Preface

Yoo J.
Current Stem Cell Research & Therapy. 2024;19(1):vii-vii
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Meet the Editorial Board Member

Deng W.
Current Stem Cell Research & Therapy. 2024;19(1):1-1
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Functional Roles of Mesenchymal Stem Cell-derived Exosomes in Ischemic Stroke Treatment

Farzaneh M., Khoshnam S.

Resumo

Stroke is a life-threatening disease and one of the leading causes of death and physical disability worldwide. Currently, no drugs on the market promote neural recovery after stroke insult, and spontaneous remodeling processes are limited to induce recovery in the ischemic regions. Therefore, promoting a cell-based therapy has been needed to elevate the endogenous recovery process. Mesenchymal stem cells (MSCs) have been regarded as candidate cell sources for therapeutic purposes of ischemic stroke, and their therapeutic effects are mediated by exosomes. The microRNA cargo in these extracellular vesicles is mostly responsible for the positive effects. When it comes to the therapeutic viewpoint, MSCsderived exosomes could be a promising therapeutic strategy against ischemic stroke. The aim of this review is to discuss the current knowledge around the potential of MSCs-derived exosomes in the treatment of ischemic stroke.

Current Stem Cell Research & Therapy. 2024;19(1):2-14
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Age-Related Alterations in Mesenchymal Stem Cell Function: Understanding Mechanisms and Seeking Opportunities to Bypass the Cellular Aging

Rasouli M., Naeimzadeh Y., Hashemi N., Hosseinzadeh S.

Resumo

Undoubtedly, mesenchymal stem cells (MSCs) are the most common cell therapy candidates in clinical research and therapy. They not only exert considerable therapeutic effects to alleviate inflammation and promote regeneration, but also show low-immunogenicity properties, which ensure their safety following allogeneic transplantation. Thanks to the necessity of providing a sufficient number of MSCs to achieve clinically efficient outcomes, prolonged in vitro cultivation is indisputable. However, either following long-term in vitro expansion or aging in elderly individuals, MSCs face cellular senescence. Senescent MSCs undergo an impairment in their function and therapeutic capacities and secrete degenerative factors which negatively affect young MSCs. To this end, designing novel investigations to further elucidate cellular senescence and to pave the way toward finding new strategies to reverse senescence is highly demanded. In this review, we will concisely discuss current progress on the detailed mechanisms of MSC senescence and various inflicted changes following aging in MSC. We will also shed light on the examined strategies underlying monitoring and reversing senescence in MSCs to bypass the comprised therapeutic efficacy of the senescent MSCs.

Current Stem Cell Research & Therapy. 2024;19(1):15-32
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Hypoxia and Hypoxia Mimetic Agents As Potential Priming Approaches to Empower Mesenchymal Stem Cells

Yasan G., Gunel-Ozcan A.

Resumo

Mesenchymal stem cells (MSC) exhibit self-renewal capacity and multilineage differentiation potential, making them attractive for research and clinical application. The properties of MSC can vary depending on specific micro-environmental factors. MSC resides in specific niches with low oxygen concentrations, where oxygen functions as a metabolic substrate and a signaling molecule. Conventional physical incubators or chemically hypoxia mimetic agents are applied in cultures to mimic the original low oxygen tension settings where MSC originated.

:This review aims to focus on the current knowledge of the effects of various physical hypoxic conditions and widely used hypoxia-mimetic agents-PHD inhibitors on mesenchymal stem cells at a cellular and molecular level, including proliferation, stemness, differentiation, viability, apoptosis, senescence, migration, immunomodulation behaviors, as well as epigenetic changes.

Current Stem Cell Research & Therapy. 2024;19(1):33-54
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Mesenchymal Stem Cells Therapy for COVID-19: From Basic Research to Clinical Trial

Tao Y., Chen E.

Resumo

The novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a serious challenge for human health. In severe cases, patients suffer from acute respiratory distress syndrome even organ failure, usually owing to the dysregulated immune response and widespread inflammation. Considering that there is no known cure for COVID-19 despite the increased morbidity and mortality rate of COVID-19, modalities targeting immunity and inflammation may be promising therapeutics against COVID-19. Mesenchymal stem cells (MSCs) possessing immunomodulatory, anti-inflammatory, anti-apoptotic, and antiviral properties, can be of potential benefit to a subset of severe and critically ill patients with COVID-19. In the present study, we described the underlying mechanisms of MSCs therapy and provided a thorough research study on the recent clinical trials of MSCs for SARS-CoV-2 infection.

Current Stem Cell Research & Therapy. 2024;19(1):55-62
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Neurogenesis, A Potential Target for Intermittent Hypoxia Leading to Cognitive Decline

Liu Y., Tan J., Miao Y., Zhang Q.

Resumo

As a sleep breathing disorder, characterized by intermittent hypoxia (IH) and Obstructive sleep apnea (OSA), is believed to decrease the cognitive function of patients. Many factors are thought to be responsible for cognitive decline in OSA patients. Neurogenesis, a process by which neural stem cells (NSCs) differentiate into new neurons in the brain, is a major determinant affecting cognitive function. However, there is no clear relationship between IH or OSA and neurogenesis. In recent years, increasing numbers of studies on IH and neurogenesis are documented. Therefore, this review summarizes the effects of IH on neurogenesis; then discusses the influencing factors that may cause these effects and the potential signaling pathways that may exist. Finally, based on this impact, we discuss potential methods and future directions for improving cognition.

Current Stem Cell Research & Therapy. 2024;19(1):63-70
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Anti-inflammatory Effects of Umbilical Cord Mesenchymal Stem Cell and Autologous Conditioned Serum on Oligodendrocyte, Astrocyte, and Microglial Specific Gene in Cuprizone Animal Model

Alavi O., Alizadeh A., Dehghani F., Alipour H., Tanideh N.

Resumo

Background:Inflammation, myelin loss, astrocytosis, and microgliosis are pathological signs of the autoimmune and demyelinating disease known as multiple sclerosis (MS). Axonal and neuronal degenerations have basic molecular pathways. The remyelination process can be influenced by the secretome of mesenchymal stem cells due to their capacity for immunomodulation, differentiation, and neuroprotection. Microglial cells are divided into two subgroups: M1 and M2 phenotypes. A crucial component of the microglial function is the colony stimulating factor 1 receptor (CSF1R). We aimed to evaluate the immunomodulating effects of secretome and conditioned serum on the microglial phenotypes and improvement of demyelination in a cuprizone model of MS.

Methods:The study used 48 male C57BL/6 mice, which were randomly distributed into 6 subgroups (n = 8), i.e., control, cuprizone, MSC (confluency 40% and 80%) secretome group, and blood derived conditioned serum (autologous and humanized). The animals were fed with 0.2% cuprizone diet for 12 weeks. Supplements were injected into the lateral tail vein using a 27-gauge needle every 3 days 500 µl per injection.

Results:At 14 days after transplantation, animals from each group were sacrificed and analyzed by Real time PCR. The results showed that the administration of MSC secretome can efficiently reduce expression of pro-inflammatory cytokines (IL-1, IL6 and TNF-α) in the corpus callosum; also, conditioned serum downregulated IL-1. Moreover, the oligodendrocyte-specific gene was upregulated by secretome and conditioned serum treatment. Also, the expression of microglial- specific gene was reduced after treatment.

Conclusions:These findings demonstrated that the secretome isolated from MSCs used as a therapy decreased and increased the M1 and M2 levels, respectively, to control neuroinflammation in CPZ mice. In conclusion, the current study showed the viability of devising a method to prepare suitable MSCs and secreted factor to cure neurodegenerative diseases, as well as the capability of regulating MSC secretome patterns by manipulating the cell density.

Current Stem Cell Research & Therapy. 2024;19(1):71-82
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Evaluation of BMP-2 as a Differentiating and Radiosensitizing Agent for Colorectal Cancer Stem Cells

Mahmoudi R., Afshar S., Amini R., Jalali A., Saidijam M., Najafi R.

Resumo

Background:Despite effective clinical responses, a large proportion of patients undergo resistance to radiotherapy. The low response rate to current treatments in different stages of colorectal cancer depends on the prominent role of stem cells in cancer.

Objective:In the present study, the role of BMP-2 as an ionizing radiation-sensitive factor in colorectal cancer cells was investigated.

Methods:A sphere formation assay was used for the enrichment of HCT-116 cancer stem cells (CSCs). The effects of combination therapy (BMP-2+ radiation) on DNA damage response (DDR), proliferation, and apoptosis were evaluated in HCT-116 and CSCs. Gene expressions of CSCs and epithelialmesenchymal transition (EMT) markers were also evaluated.

Results:We found that the sphere formation assay showed a significant increase in the percentage of CSCs. Moreover, expression of CSCs markers, EMT-related genes, and DNA repair proteins significantly decreased in HCT-116 cells compared to the CSCs group after radiation. In addition, BMP-2 promoted the radiosensitivity of HCT-116 cells by decreasing the survival rate of the treated cells at 2, 4, and 6 Gy compared to the control group in HCT-116 cells.

Conclusion:Our findings indicated that BMP-2 could affect numerous signaling pathways involved in radioresistance. Therefore, BMP-2 can be considered an appealing therapeutic target for the treatment of radioresistant human colorectal cancer.

Current Stem Cell Research & Therapy. 2024;19(1):83-93
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Electrospun Propolis-coated PLGA Scaffold Enhances the Osteoinduction of Mesenchymal Stem Cells

Askari M., Jadid Tavaf M., Ghorbani M., Yazdanian M., Moghaddam M.

Resumo

Background:Major injuries that are caused by trauma and cancer can not be repaired through bone remodeling. The goal of bone regeneration by tissue engineering approaches is to fabricate bone implants in order to restore bone structure and functions. The use of stem cells and polymer scaffolds provides the conditions for tissue regeneration based on tissue engineering.

Objective:This study aimed to fabricate a combined matrix of poly(lactide-co-glycolide) (PLGA) and propolis extract, which is a mixture of pollen and beeswax collected by bees from certain plants and has long been used in traditional herbal medicine, to promote the osteogenic differentiation of human adipose- derived mesenchymal stem cells (AD-MSCs).

Methods:The scaffold was fabricated through electrospinning and was immersed in a propolis extract solution. Then, AD-MSCs were cultured and differentiated into the osteogenic lineage. The cell viability on the scaffold was evaluated by MTT assay. Osteogenic differentiation of the seeded stem cells was detected by evaluating calcium content, alkaline phosphatase (ALP) activity, and the expression of bonespecific genes.

Results:The viability of cells was not affected by propolis-coated and uncoated fabricated scaffolds, while higher calcium content, ALP activity, and expression of RUNX-2, type I collagen, osteocalcin, and osteonectin were observed in cells differentiated on propolis-coated PLGA scaffold on days 7, 14, and 21 of differentiation compared to PLGA scaffold.

Conclusion:The results of this study showed that the presence of propolis in the scaffold could lead to better cell attachment and strengthen the osteoinduction process in stem cells.

Current Stem Cell Research & Therapy. 2024;19(1):94-102
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Piezo1-ERK1/2-YAP Signaling Cascade Regulates the Proliferation of Urine-derived Stem Cells on Collagen Gels

Wang X., Li L., Sun B., Hou X., Song S., Shi C., Chen W.

Resumo

Background:Urine-derived stem cells (USCs) were considered to be an ideal source of stem cells for repairing urological diseases. However, the proliferative ability of USCs significantly decreased when cultured on plastic dishes, which limited their clinical application. It was found that collagen gels could promote the proliferation of USCs, but the underlying molecular mechanisms were unclear.

Objective:The study aims to investigate the role of the mechanically activated cation channel Piezo1 and the transcriptional coactivator YAP in the regulation of proliferation of USCs on collagen gels.

Methods:USCs were cultured on collagen gels (group COL), or plastic dishes (group NON). MTT assay, Scratch assay, EDU staining, and immunofluorescence (IF) of Ki67 were performed to evaluate the proliferation of USCs; IF of YAP was conducted to observe its nuclear localization; calcium imaging experiment was executed to evaluate the function of Piezo1; western blot was used to compare changes in protein expression of YAP, LATS1, ERK1/2, and p-ERK1/2. In addition, the regulatory effect of YAP on the proliferative capacity of USCs was confirmed by intervening YAP with its inhibitor verteporfin (VP); and the inhibitor or activator of Piezo1, GsMTx4 or Yoda1 was used to explore the effect of Piezo1 on the nuclear localization of YAP, the proliferation of USCs and the regeneration of injured bladder.

Results:The results showed that cell proliferation was significantly enhanced in USCs in the COL group with the nuclear accumulation of YAP compared with the NON group and VP attenuated these effects. The expression and function of Piezo1 were higher in the COL group compared with the NON group. Blockage of Piezo1 by GsMTx4 decreased nuclear localization of YAP, the proliferation of USCs, and caused the failure of bladder reconstruction. Activation of Piezo1 by Yoda1 increased the nuclear expression of YAP, and the proliferation of USCs, which further improved the regeneration of the injured bladder. Finally, the ERK1/2 rather than LATS1 was revealed to participate in the Piezo1/YAP signal cascades of USCs proliferation.

Conclusion:Taken together, Piezo1-ERK1/2-YAP signal cascades were involved in regulating the proliferation ability of USCs in collagen gels which would be beneficial for the regeneration of the bladder.

Current Stem Cell Research & Therapy. 2024;19(1):103-115
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Differential Expression of microRNAs and Target Genes Analysis in Olfactory Ensheathing Cell-derived Extracellular Vesicles Versus Olfactory Ensheathing Cells

Yang Y., Li J., Liu W., Guo D., Gao Z., Zhao Y., Zhao M., He X., Chang S.

Resumo

Introduction:Olfactory ensheathing cells (OECs) are important transplantable cells for the treatment of spinal cord injury. However, information on the mechanism of OEC-derived extracellular vesicles (EVs) in nerve repair is scarce.

Methods:We cultured OECs and extracted the OEC-derived EVs, which were identified using a transmission electron microscope, nanoparticle flow cytometry, and western blotting. High throughput RNA sequencing of OECs and OEC-EVs was performed, and the differentially expressed microRNAs (miRNAs) (DERs) were analyzed by bioinformatics. The target genes of DERs were identified using miRWalk, miRDB, miRTarBase, and TargetScan databases. Gene ontology and KEGG mapper tools were used to analyze the predicted target genes. Subsequently, the STRING database and Cytoscape software platform were used to analyze and construct miRNA target genes' protein-protein interaction (PPI) network.

Results:Overall, 206 miRNAs (105 upregulated and 101 downregulated) were differentially expressed in OEC-EVs (p < 0.05;⋅log2 (fold change)⋅>2). Six DERs (rno-miR-7a-5p, rno-miR-143-3p, rno-miR-182, rno-miR-214-3p, rno-miR-434-5p, rno-miR-543-3p) were significantly up-regulated , and a total of 974 miRNAs target genes were obtained. The target genes were mainly involved in biological processes such as regulation of cell size, positive regulation of cellular catabolic process and small GTPase-mediated signal transduction; positive regulation of genes involved in cellular components such as growth cone, site of polarized growth, and distal axon; and molecular functions such as small GTPase binding and Ras GTPase binding. In pathway analysis, target genes regulated by six DERs were mainly enriched in axon guidance, endocytosis, and Ras and cGMP-dependent protein kinase G signaling pathways. Finally, 19 hub genes were identified via the PPI network.

Conclusion:Our study provides a theoretical basis for treating nerve repair by OEC-derived EVs.

Current Stem Cell Research & Therapy. 2024;19(1):116-125
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Knockdown of VASH2 Inhibits the Stemness and EMT Process by Regulating ZEB2 in Colorectal Cancer

Shayimu P., Yin C., Zeng X., Jiapaer R.

Resumo

Introduction:VASH2 is associated with the malignant progression of a variety of tumors, but the role and mechanism of VASH2 in colorectal cancer are still unclear.

Methods:We analyzed the expression of VASH2 in colorectal cancer from the TCGA database and also analyzed the relationship between VASH2 expression and survival of colorectal cancer patients in the PrognoScan database. We verified the role of VASH2 in colorectal cancer through transfecting si-VASH2 into colorectal cancer cells and detecting cell viability by CCK8, cell migration by wound healing assay, and cell invasion by Transwell assay. ZEB2, Vimentin, and E- cadherin protein expression were examined by Western-Blot assay. Cell sphere-forming ability was determined by sphere formation assay, and we further confirmed the mechanism of VASH2 in colorectal cancer progression by rescue assays.

Results:Colorectal cancer has a high expression of VASH2, and its expression is associated with a poorer patient survival rate. The vitality, migration, invasion, EMT, and tumor stemness of colorectal cancer cells were all decreased by VASH2 knockdown. These alternations were attenuated by ZEB2 overexpression.

Conclusion:Our experiments confirmed that VASH2 affects colorectal cancer cell proliferation, migration, invasion, EMT, and seed bovine stemness by regulating ZEB2 expression.

Current Stem Cell Research & Therapy. 2024;19(1):126-132
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