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Tag: World Journal of Stem Cells

  • Dissecting molecular mechanisms underlying ferroptosis in human umbilical cord mesenchymal stem cells: Role of cystathionine γ-lyase/hydrogen sulfide pathway

    Dissecting molecular mechanisms underlying ferroptosis in human umbilical cord mesenchymal stem cells: Role of cystathionine γ-lyase/hydrogen sulfide pathway

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    BACKGROUND

    Ferroptosis can induce low retention and engraftment after mesenchymal stem cell (MSC) delivery, which is considered a major challenge to the effectiveness of MSC-based pulmonary arterial hypertension (PAH) therapy. Interestingly, the cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway may contribute to mediating ferroptosis. However, the influence of the CSE/H2S pathway on ferroptosis in human umbilical cord MSCs (HUCMSCs) remains unclear.

    AIM

    To clarify whether the effect of HUCMSCs on vascular remodelling in PAH mice is affected by CSE/H2S pathway-mediated ferroptosis, and to investigate the functions of the CSE/H2S pathway in ferroptosis in HUCMSCs and the underlying mechanisms.

    METHODS

    Erastin and ferrostatin-1 (Fer-1) were used to induce and inhibit ferroptosis, respectively. HUCMSCs were transfected with a vector to overexpress or inhibit expression of CSE. A PAH mouse model was established using 4-wk-old male BALB/c nude mice under hypoxic conditions, and pulmonary pressure and vascular remodelling were measured. The survival of HUCMSCs after delivery was observed by in vivo bioluminescence imaging. Cell viability, iron accumulation, reactive oxygen species production, cystine uptake, and lipid peroxidation in HUCMSCs were tested. Ferroptosis-related proteins and S-sulfhydrated Kelch-like ECH-associating protein 1 (Keap1) were detected by western blot analysis.

    RESULTS

    In vivo, CSE overexpression improved cell survival after erastin-treated HUCMSC delivery in mice with hypoxia-induced PAH. In vitro, CSE overexpression improved H2S production and ferroptosis-related indexes, such as cell viability, iron level, reactive oxygen species production, cystine uptake, lipid peroxidation, mitochondrial membrane density, and ferroptosis-related protein expression, in erastin-treated HUCMSCs. In contrast, in vivo, CSE inhibition decreased cell survival after Fer-1-treated HUCMSC delivery and aggravated vascular remodelling in PAH mice. In vitro, CSE inhibition decreased H2S levels and restored ferroptosis in Fer-1-treated HUCMSCs. Interestingly, upregulation of the CSE/H2S pathway induced Keap1 S-sulfhydration, which contributed to the inhibition of ferroptosis.

    CONCLUSION

    Regulation of the CSE/H2S pathway in HUCMSCs contributes to the inhibition of ferroptosis and improves the suppressive effect on vascular remodelling in mice with hypoxia-induced PAH. Moreover, the protective effect of the CSE/H2S pathway against ferroptosis in HUCMSCs is mediated via S-sulfhydrated Keap1/nuclear factor erythroid 2-related factor 2 signalling. The present study may provide a novel therapeutic avenue for improving the protective capacity of transplanted MSCs in PAH.

    Key Words: Human umbilical cord mesenchymal stem cells, Cystathionine γ-lyase/hydrogen sulfide pathway, Ferroptosis, Pulmonary arterial hypertension, S-sulfhydration

     

    Core Tip: Regulation of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in human umbilical cord mesenchymal stem cells (HUCMSCs) contributes to the inhibition of ferroptosis and improves the suppressive effect of HUCMSCs on vascular remodelling in hypoxia-induced pulmonary arterial hypertension (PAH) mice. Moreover, the protective effect of the CSE/H2S pathway against ferroptosis in HUCMSCs was mediated via S-sulfhydrated Kelch-like ECH-associating protein 1/nuclear factor erythroid 2-related factor 2 signalling. The present study may provide a novel therapeutic avenue for improving the protective capacity of transplanted MSCs in PAH.

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  • How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

    How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

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    Intervertebral disc (ID) degeneration (IDD) is one of the main causes of chronic low back pain, and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID. The environment in which the ID is located is harsh, with almost no vascular distribution within the disc, and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate. The stability of its internal environment also plays an important role in preventing IDD. The main feature of disc degeneration is a decrease in the number of cells. Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner. The main purpose is to promote their regeneration. The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix. The treatment of disc degeneration with stem cells has achieved good efficacy, and the current challenge is how to improve this efficacy. Here, we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles, enhancement of therapeutic effects when stem cells are mixed with related substances, and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions. We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.

    Key Words: Mesenchymal stem cells, Intervertebral disc degeneration, Extracellular vesicles, Nucleus pulposus cells, Tissue regeneration

     

    Core Tip: Mesenchymal stem cells have a strong self-renewal capacity and multidirectional differentiation potential, and their secreted vesicles promote regeneration of myeloid cells, increase extracellular matrix production, and alleviate inflammatory status. We reviewed the current relevant targets of stem cell exosomes for the treatment of intervertebral discs and the adjuvant tools used in conjunction with stem cell therapy. This will help to improve the therapeutic efficacy of stem cells and their exosomes, which will also contribute to development of more efficient treatment strategies and approaches for the restoration of disc degeneration.

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  • Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells

    Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells

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    BACKGROUND

    Mesenchymal stem cells (MSCs) have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties. However, MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects, and therefore, their therapeutic efficacy is reduced. In this challenging context, an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.

    AIM

    To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.

    METHODS

    Umbilical cord MSCs (UC-MSCs) were pretreated with hypoxia (2% O2) exposure and inflammatory factors (interleukin-1β, tumor necrosis factor-α, interferon-γ) for 24 h. Flow cytometry, polymerase chain reaction, enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.

    RESULTS

    Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability, proliferation or size. In addition, pretreatment significantly decreased the expression of coagulation-related tissue factors but did not affect the expression of other surface markers. Similarly, mitochondrial function and integrity were retained. Although pretreatment promoted UC-MSC apoptosis and senescence, it increased the expression of genes and proteins related to immune regulation. Pretreatment increased peripheral blood mononuclear cell and natural killer (NK) cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.

    CONCLUSION

    In summary, hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.

    Key Words: Mesenchymal stem cells, Umbilical cord, Preconditioning, Hypoxia, Inflammatory factors, Immune regulation

     

    Core Tip: Mesenchymal stem cells (MSCs) are potential candidates for treating many immune diseases due to their unique immunomodulatory abilities, but low survival rates and weakened function after venous transplantation reduces their treatment potential. Therefore, our study reveals a combination pretreatment method based on in vitro hypoxia exposure and inflammatory factor treatment that simulates the harsh in vivo environment to protect MSCs from injury after intravenous transfusion and promote high immunosuppressive effects of MSCs.

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  • Quercetin ameliorates oxidative stress-induced senescence in rat nucleus pulposus-derived mesenchymal stem cells via the miR-34a-5p/SIRT1 axis

    Quercetin ameliorates oxidative stress-induced senescence in rat nucleus pulposus-derived mesenchymal stem cells via the miR-34a-5p/SIRT1 axis

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    BACKGROUND

    Intervertebral disc degeneration (IDD) is a main contributor to low back pain. Oxidative stress, which is highly associated with the progression of IDD, increases senescence of nucleus pulposus-derived mesenchymal stem cells (NPMSCs) and weakens the differentiation ability of NPMSCs in degenerated intervertebral discs (IVDs). Quercetin (Que) has been demonstrated to reduce oxidative stress in diverse degenerative diseases.

    AIM

    To investigate the role of Que in oxidative stress-induced NPMSC damage and to elucidate the underlying mechanism.

    METHODS

    In vitro, NPMSCs were isolated from rat tails. Senescence-associated β-galactosidase (SA-β-Gal) staining, cell cycle, reactive oxygen species (ROS), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and western blot analyses were used to evaluated the protective effects of Que. Meanwhile the relationship between miR-34a-5p and Sirtuins 1 (SIRT1) was evaluated by dual-luciferase reporter assay. To explore whether Que modulates tert-butyl hydroperoxide (TBHP)-induced senescence of NPMSCs via the miR-34a-5p/SIRT1 pathway, we used adenovirus vectors to overexpress and downregulate the expression of miR-34a-5p and used SIRT1 siRNA to knockdown SIRT1 expression. In vivo, a puncture-induced rat IDD model was constructed, and X rays and histological analysis were used to assess whether Que could alleviate IDD in vivo.

    RESULTS

    We found that TBHP can cause NPMSCs senescence changes, such as reduced cell proliferation ability, increased SA-β-Gal activity, cell cycle arrest, the accumulation of ROS, and increased expression of senescence-related proteins. While abovementioned senescence indicators were significantly alleviated by Que treatment. Que decreased the expression levels of senescence-related proteins (p16, p21, and p53) and senescence-associated secreted phenotype (SASP), including IL-1β, IL-6, and MMP-13, and it increased the expression of SIRT1. In addition, the protective effects of Que on cell senescence were partially reversed by miR-34a-5p overexpression and SIRT1 knockdown. In vivo, X-ray, and histological analyses indicated that Que alleviated IDD in a puncture-induced rat model.

    CONCLUSION

    In summary, the present study provides evidence that Que reduces oxidative stress-induced senescence of NPMSCs via the miR-34a/SIRT1 signaling pathway, suggesting that Que may be a potential agent for the treatment of IDD.

    Core Tip: In our article, we provide the evidence that quercetin (Que) can prevent oxidative stress induced senescence of nucleus pulposus-derived mesenchymal stem cells via miR-34a/SIRT1 signaling pathway. Moreover, Que could ameliorate the progression of intervertebral disc degeneration (IDD) in rat model. Thus, Que can be considered as a potential agent for the treatment of IDD.

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  • Up-to-date meta-analysis of long-term evaluations of mesenchymal stem cell therapy for complex perianal fistula

    Up-to-date meta-analysis of long-term evaluations of mesenchymal stem cell therapy for complex perianal fistula

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    BACKGROUND

    Local mesenchymal stem cell (MSC) therapy for complex perianal fistulas (PFs) has shown considerable promise. But, the long-term safety and efficacy of MSC therapy in complex PFs remain unknown.

    AIM

    To explore the long-term effectiveness and safety of local MSC therapy for complex PFs.

    METHODS

    Sources included the PubMed, EMBASE, and Cochrane Library databases. A standard meta-analysis was performed using RevMan 5.3.

    RESULTS

    After screening, 6 studies met the inclusion criteria. MSC therapy was associated with an improved long-term healing rate (HR) compared with the control condition [odds ratio (OR) = 2.13; 95% confidence interval (95%CI): 1.34 to 3.38; P = 0.001]. Compared with fibrin glue (FG) therapy alone, MSC plus FG therapy was associated with an improved long-term HR (OR = 2.30; 95%CI: 1.21 to 4.36; P = 0.01). When magnetic resonance imaging was used to evaluate fistula healing, MSC therapy was found to achieve a higher long-term HR than the control treatment (OR = 2.79; 95%CI: 1.37 to 5.67; P = 0.005). There were no significant differences in long-term safety (OR = 0.77; 95%CI: 0.27 to 2.24; P = 0.64).

    CONCLUSION

    Our study indicated that local MSC therapy promotes long-term and sustained healing of complex PFs and that this method is safe.

    Core Tip: The long-term safety and efficacy of mesenchymal stem cell (MSC) therapy for complex perianal fistulas (PFs) remain unknown. So, we explored the long-term effectiveness and safety of local MSC therapy for complex PFs. We found that MSC treatment is a safe and effective method that can significantly improve the long-term healing of complex PFs, and this method confers no risk of MSC-related adverse events.

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  • Mastering the craft: Creating an insightful and widely-cited literature review

    Mastering the craft: Creating an insightful and widely-cited literature review

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    The art of constructing an insightful literature review manuscript has witnessed an exemplar in the work of Oz et al (2023), wherein concept progression harmoniously merges with figures and tables. Reflecting on retrospective data science, it is evident that well-cited articles can wield a transformative influence on the Journal Citation Reports Impact Factor score, as exemplified by Robert Weinberg’s landmark on cancer (Hanahan and Weinberg, 2011). Here, we aim to spotlight a commendable contribution by Tuba Oz, Ajeet Kaushik, and Małgorzata Kujawska in this issue while pivoting towards identifying the hallmarks of a subpar literature review-elements that hinder rather than promote advancement. The hurdles and roadblocks encountered within subpar literature reviews are multifold. Anticipation of emerging trends, identification of challenges, and exploration of solutions remain conspicuously absent. Original Contributions fail to surface amidst the vast sea of pre-existing literature, with noticeable gaps amplified by the lack of illustrative figures and tables. The manuscript, at times, assumes a skeletal form, reflecting an attempt to accommodate an excess of references, leading to convoluted sentences laden with citations. In contrast, a potent solution lies in adopting a comprehensive approach. A nuanced and critical evaluation of sources can culminate in a robust discussion, surpassing the mere summarization of conclusions drawn by others. This approach, often dismissed, holds the potential to elevate clarity, coherence, and logical flow, ultimately inviting engaged readership and coveted citations. The critical necessity of integrating visionary insights is underscored and achieved through a rigorous analysis of pivotal concepts and innovative ideas. Examples can be harnessed to elucidate the application of these solutions. We advocate a paradigm shift, urging literature review writers to embrace the readers’ perspective. A literature review’s purpose extends beyond providing a comprehensive panorama; it should illuminate avenues for concept development within a specific field of interest. By achieving this balance, literature reviews stand to captivate a devoted readership, paving the way for manuscripts that are both widely read and frequently cited. The pathway forward requires a fusion of astute analysis and visionary insights, shaping the future of literature review composition.

    Core Tip: This manuscript highlights a remarkable literature review, demonstrating a seamless fusion of concept progression with figures and tables. Reflecting on data science, it reveals how influential articles can impact the Journal Citation Report Impact Factor. We focus on identifying elements hindering effective literature reviews. Key challenges include absent trend anticipation, gaps in original contributions, and skeletal content. To address this, we propose a comprehensive approach involving critical evaluation, fostering clarity, coherence, and reader engagement. Integration of visionary insights and examples further enhances the impact, emphasizing the importance of concept development and paving the way for influential literature reviews.

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  • Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression

    Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression

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    BACKGROUND

    The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the “license” of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear.

    AIM

    To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.

    METHODS

    We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis.

    RESULTS

    Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice.

    CONCLUSION

    Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.

    Core Tip: Our study showed that interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) significantly induced programmed cell death protein 1 ligand 1 (PD-L1) expression in human umbilical-cord-mesenchymal stem cells (hUC-MSCs), and pretreated hUC-MSCs exhibited stronger immunomodulatory capacity. Signaling pathway analysis showed that TNF-α up-regulated IFN-γ receptor expression in hUC-MSCs through nuclear factor kappa-B pathway, and then promoted IFN-γ -mediated activation of JAK/STAT1/interferon regulatory factor 1 pathway and PD-L1 expression. In ulcerative colitis mice, hUC-MSCs pretreated with IFN-γ and TNF-α exhibited stronger immunosuppressive ability through high expression of PD-L1, effectively inhibited the inflammation in the colon of mice.

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  • Constitutive aryl hydrocarbon receptor facilitates the regenerative potential of mouse bone marrow mesenchymal stromal cells

    Constitutive aryl hydrocarbon receptor facilitates the regenerative potential of mouse bone marrow mesenchymal stromal cells

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    BACKGROUND

    Bone marrow mesenchymal stromal cells (BMSCs) are the commonly used seed cells in tissue engineering. Aryl hydrocarbon receptor (AhR) is a transcription factor involved in various cellular processes. However, the function of constitutive AhR in BMSCs remains unclear.

    AIM

    To investigate the role of AhR in the osteogenic and macrophage-modulating potential of mouse BMSCs (mBMSCs) and the underlying mechanism.

    METHODS

    Immunochemistry and immunofluorescent staining were used to observe the expression of AhR in mouse bone marrow tissue and mBMSCs. The overexpression or knockdown of AhR was achieved by lentivirus-mediated plasmid. The osteogenic potential was observed by alkaline phosphatase and alizarin red staining. The mRNA and protein levels of osteogenic markers were detected by quantitative polymerase chain reaction (qPCR) and western blot. After coculture with different mBMSCs, the cluster of differentiation (CD) 86 and CD206 expressions levels in RAW 264.7 cells were analyzed by flow cytometry. To explore the underlying molecular mechanism, the interaction of AhR with signal transducer and activator of transcription 3 (STAT3) was observed by co-immunoprecipitation and phosphorylation of STAT3 was detected by western blot.

    RESULTS

    AhR expressions in mouse bone marrow tissue and isolated mBMSCs were detected. AhR overexpression enhanced the osteogenic potential of mBMSCs while AhR knockdown suppressed it. The ratio of CD86+ RAW 264.7 cells cocultured with AhR-overexpressed mBMSCs was reduced and that of CD206+ cells was increased. AhR directly interacted with STAT3. AhR overexpression increased the phosphorylation of STAT3. After inhibition of STAT3 via stattic, the promotive effects of AhR overexpression on the osteogenic differentiation and macrophage-modulating were partially counteracted.

    CONCLUSION

    AhR plays a beneficial role in the regenerative potential of mBMSCs partially by increasing phosphorylation of STAT3.

    Core Tip: Aryl hydrocarbon receptor (AhR) was positively expressed in murine bone marrow tissue and bone marrow mesenchymal stromal cells (BMSCs). In vitro, overexpression of AhR enhanced the osteogenic potential of mouse BMSCs. Additionally, AhR-overexpressed BMSCs had an increased ability to polarize macrophages to an anti-inflammatory phenotype. While knockdown of AhR showed the opposite effects. Mechanistically, the beneficial effects of AhR were partially dependent on increased phosphorylation of signal transducer and activator of transcription 3. This study suggests that AhR might be a target for achieving optimal bone regeneration in mouse BMSCs-based tissue engineering.

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  • Wnt signaling pathway inhibitor promotes mesenchymal stem cells differentiation into cardiac progenitor cells in vitro and improves cardiomyopathy in vivo

    Wnt signaling pathway inhibitor promotes mesenchymal stem cells differentiation into cardiac progenitor cells in vitro and improves cardiomyopathy in vivo

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    BACKGROUND

    Cardiovascular diseases particularly myocardial infarction (MI) are the leading cause of mortality and morbidity around the globe. As cardiac tissue possesses very limited regeneration potential, therefore use of a potent small molecule, inhibitor Wnt production-4 (IWP-4) for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration. Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo. Mesenchymal stem cells (MSCs) derived from the human umbilical cord have the potential to regenerate cardiac tissue, as they are easy to isolate and possess multilineage differentiation capability. IWP-4 may promote the differentiation of MSCs into the cardiac lineage.

    AIM

    To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects.

    METHODS

    Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology, immunophenotyping of surface markers specific to MSCs, as well as by tri-lineage differentiation capability. Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4. MSCs were treated with 5 μM IWP-4 at two different time intervals. Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels. The MI rat model was developed. IWP-4 treated as well as untreated MSCs were implanted in the MI model, then the cardiac function was analyzed via echocardiography. MSCs were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) dye for tracking, while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry.

    RESULTS

    MSCs were isolated and characterized. Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5 μM concentration. Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation. Cardiac function was restored in the IWP-4 treated group in comparison to the MI group. Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye. Histological analysis confirmed the significant reduction in fibrotic area, and improved left ventricular wall thickness in IWP-4 treated MSC group.

    CONCLUSION

    Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation. These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing, survival, and differentiation at the infarcted region, increased left ventricular wall thickness, and reduced infarct size.

    Core Tip: This study highlights the role of Wnt signaling pathway in the differentiation of mesenchymal stem cells (MSCs) into cardiac progenitor cells and the therapeutic potential of MSCs conditioned with inhibitor Wnt production-4 (IWP-4) for the treatment of heart disease. Further studies are required to comprehend the mode of action of IWP-4 on MSCs and to assess its potency and safety in human clinical trials. Nevertheless, this research is an exciting step forward for new treatments for heart diseases and is more focused on the importance of continued investment in the development of innovative therapies for this devastating condition.

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  • Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use

    Different priming strategies improve distinct therapeutic capabilities of mesenchymal stromal/stem cells: Potential implications for their clinical use

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    Mesenchymal stromal/stem cells (MSCs) have shown significant therapeutic potential, and have therefore been extensively investigated in preclinical studies of regenerative medicine. However, while MSCs have been shown to be safe as a cellular treatment, they have usually been therapeutically ineffective in human diseases. In fact, in many clinical trials it has been shown that MSCs have moderate or poor efficacy. This inefficacy appears to be ascribable primarily to the heterogeneity of MSCs. Recently, specific priming strategies have been used to improve the therapeutic properties of MSCs. In this review, we explore the literature on the principal priming approaches used to enhance the preclinical inefficacy of MSCs. We found that different priming strategies have been used to direct the therapeutic effects of MSCs toward specific pathological processes. Particularly, while hypoxic priming can be used primarily for the treatment of acute diseases, inflammatory cytokines can be used mainly to prime MSCs in order to treat chronic immune-related disorders. The shift in approach from regeneration to inflammation implies, in MSCs, a shift in the production of functional factors that stimulate regenerative or anti-inflammatory pathways. The opportunity to fine-tune the therapeutic properties of MSCs through different priming strategies could conceivably pave the way for optimizing their therapeutic potential.

    Core Tip: Mesenchymal stromal/stem cells (MSCs) have demonstrated promising therapeutic results in the field of regenerative medicine. However, due to their heterogeneity, the application of MSCs in clinical trials has shown moderate or poor efficacy. Here, we review data on the principal priming approaches for enhancing the therapeutic potential of MSCs. We found that different priming strategies can modify MSC properties and, in this case some therapeutic effects on different disease models can be obtained in relation to dose and/or combination of the priming factors used. The production of priming type-specific functional factors in MSCs could pave the way toward implementing new MSC-based therapies.

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  • Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges

    Cell transplantation therapies for spinal cord injury focusing on bone marrow mesenchymal stem cells: Advances and challenges

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    Spinal cord injury (SCI) is a devastating condition with complex pathological mechanisms that lead to sensory, motor, and autonomic dysfunction below the site of injury. To date, no effective therapy is available for the treatment of SCI. Recently, bone marrow-derived mesenchymal stem cells (BMMSCs) have been considered to be the most promising source for cellular therapies following SCI. The objective of the present review is to summarize the most recent insights into the cellular and molecular mechanism using BMMSC therapy to treat SCI. In this work, we review the specific mechanism of BMMSCs in SCI repair mainly from the following aspects: Neuroprotection, axon sprouting and/or regeneration, myelin regeneration, inhibitory microenvironments, glial scar formation, immunomodulation, and angiogenesis. Additionally, we summarize the latest evidence on the application of BMMSCs in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.

    Core Tip: In this work, we review the specific mechanism of bone marrow-derived mesenchymal stem cell (BMMSC) in spinal cord injury (SCI) repair mainly from the following aspects: Neuroprotection, neuronal circuit, axon sprouting and or regeneration, myelin regeneration, inhibitory microenvironment, glial scar formation, immunomodulation, and angiogenesis. Additionally, we also summarize the latest evidence on application of BMMSC in clinical trials and further discuss the challenges and future directions for stem cell therapy in SCI models.

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  • Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression

    Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression

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    Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

    Core Tip: Mesenchymal stem cells (MSCs), the main cell population of the bone marrow (BM) stroma, can influence BM microenvironment through their paracrine activity, involving both soluble factors and extracellular vesicles, but also through direct communication. Being the BM the predominant localization of multiple myeloma cells (MM), finding the appropriate conditions at this niche, is key for the survival and expansion of tumour cells and thus, for the progression of the disease. Since the activity of BM-MSCs could determine the fate of MM cells at BM, these cells could be interesting targets for the design of new antitumor drugs.

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  • Modulation of stem cell fate in intestinal homeostasis, injury and repair

    Modulation of stem cell fate in intestinal homeostasis, injury and repair

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    The mammalian intestinal epithelium constitutes the largest barrier against the external environment and makes flexible responses to various types of stimuli. Epithelial cells are fast-renewed to counteract constant damage and disrupted barrier function to maintain their integrity. The homeostatic repair and regeneration of the intestinal epithelium are governed by the Lgr5+ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to the different epithelial cell types. Protracted biological and physicochemical stress may challenge epithelial integrity and the function of ISCs. The field of ISCs is thus of interest for complete mucosal healing, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel diseases. Here, we review the current understanding of the signals and mechanisms that control homeostasis and regeneration of the intestinal epithelium. We focus on recent insights into the intrinsic and extrinsic elements involved in the process of intestinal homeostasis, injury, and repair, which fine-tune the balance between self-renewal and cell fate specification in ISCs. Deciphering the regulatory machinery that modulates stem cell fate would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.

    Core Tip: The homeostatic repair and regeneration of the intestinal epithelium upon injury are governed by the Lgr5+ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to different epithelial cell types. We review the current understanding of the intrinsic niche signaling and extrinsic stimulating factors that control homeostasis and regeneration of the ISCs. Deciphering the regulatory machinery that modulates stem cell fate, and formulating strategies for better repair and regeneration would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.

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  • Human pluripotent stem cell-derived extracellular vesicles: From now to the future

    Human pluripotent stem cell-derived extracellular vesicles: From now to the future

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    Extracellular vesicles (EVs) are nanometric particles that enclose cell-derived bioactive molecules in a lipid bilayer and serve as intercellular communication tools. Accordingly, in various biological contexts, EVs are reported to engage in immune modulation, senescence, and cell proliferation and differentiation. Therefore, EVs could be key elements for potential off-the-shelf cell-free therapy. Little has been studied regarding EVs derived from human pluripotent stem cells (hPSC-EVs), even though hPSCs offer good opportunities for induction of tissue regeneration and unlimited proliferative ability. In this review article, we provide an overview of studies using hPSC-EVs, focusing on identifying the conditions in which the cells are cultivated for the isolation of EVs, how they are characterized, and applications already demonstrated. The topics reported in this article highlight the incipient status of the studies in the field and the significance of hPSC-EVs’ prospective applications as PSC-derived cell-free therapy products.

    Core Tip: The research on extracellular vesicles (EVs) derived from different cell types, such as adult stem cells, has shown potential in the treatment of various pathologies. However, little has been explored regarding EVs derived from human pluripotent stem cells (hPSC-EVs). In this review, we provide an overview of studies carried out on these EVs, highlighting methodologies used for the culture of hPSCs for isolating EVs, their characteristics, and potential applications. We note the potential of hPSC-EVs as future acellular therapies. However, studies are in the infancy, and more research is needed to confirm their benefits.

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    World Journal of Stem Cells

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  • How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

    How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

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    Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

    Core Tip: Colorectal cancer (CRC) represents one of the most prevalent tumors worldwide. The tumor microenvironment (TME) through its proinflammatory role, among others, actively participates in CRC progression and the disturbance of gut microbiota (dysbiosis) can influence this inflammatory process. CRC stem cells (CCSC) are a tumor cell subpopulation that drives CRC initiation, progression and treatment failure. The features and behavior of CCSC are modulated by several factors including TME and gut microbiota. Here, we will give an overview of the synergistic interaction among TME and intestinal microorganisms that condition the CRC environment and shape CCSC characteristics allowing CRC evolution.

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    World Journal of Stem Cells

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  • Tissue-specific cancer stem/progenitor cells: Therapeutic implications

    Tissue-specific cancer stem/progenitor cells: Therapeutic implications

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    Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs’ resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.

    Core Tip: Therapeutic approaches targeting cancer stem cell (CSC) markers hold great promise toward developing effective anti-cancer treatment. Tissue-specific CSCs (TSCSCs) possess unique expression profile that allows for their identification, isolation, and targeting. TSCSCs, isolated from patient tumor tissues, were shown to form organ analogs or patient-derived organoids (PDOs) under specific culturing conditions in vitro. These models simulate the original tumor characteristics in a three-dimensional culture dish. As such, PDOs have the potential to be used in patient-specific in vitro drug clinical trials and proof-of-concept studies on CSC-targeted therapies.

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    World Journal of Stem Cells

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  • Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges

    Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges

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    Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.

    Core Tip: Tongue squamous cell carcinoma is one of the most common and aggressive oral cavity carcinomas, particularly among the Indian population. Despite various treatment strategies employed, the survival rates of the patients remain poor. A rare population i.e., cancer stem cells (CSCs), plays an important role in resistance, recurrence as well as metastasis which are factors responsible for the poor survival outcome. In this review, we discuss the recent findings regarding cell signaling pathways and markers associated with the CSCs and the need to gain a deeper understanding on the properties of the CSCs.

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    World Journal of Stem Cells

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  • Advancements in adipose-derived stem cell therapy for skin fibrosis

    Advancements in adipose-derived stem cell therapy for skin fibrosis

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    Pathological scarring and scleroderma, which are the most common conditions of skin fibrosis, pathologically manifest as fibroblast proliferation and extracellular matrix (ECM) hyperplasia. Fibroblast proliferation and ECM hyperplasia lead to fibrotic tissue remodeling, causing an exaggerated and prolonged wound-healing response. The pathogenesis of these diseases has not been fully clarified and is unfortunately accompanied by exceptionally high medical needs and poor treatment effects. Currently, a promising and relatively low-cost treatment has emerged-adipose-derived stem cell (ASC) therapy as a branch of stem cell therapy, including ASCs and their derivatives-purified ASC, stromal vascular fraction, ASC-conditioned medium, ASC exosomes, etc., which are rich in sources and easy to obtain. ASCs have been widely used in therapeutic settings for patients, primarily for the defection of soft tissues, such as breast enhancement and facial contouring. In the field of skin regeneration, ASC therapy has become a hot research topic because it is beneficial for reversing skin fibrosis. The ability of ASCs to control profibrotic factors as well as anti-inflammatory and immunomodulatory actions will be discussed in this review, as well as their new applications in the treatment of skin fibrosis. Although the long-term effect of ASC therapy is still unclear, ASCs have emerged as one of the most promising systemic antifibrotic therapies under development.

    Core Tip: Pathological scarring and scleroderma are the most common conditions of skin fibrosis with high medical needs and poor therapeutic effects. Adipose-derived stem cell (ASC) therapy has emerged as a promising treatment for skin fibrosis. Here, we discuss the possible mechanism of skin fibrosis as well as the latest research about the mechanism of ASC therapy and its application in treating these conditions. ASC therapy provides a brand-new insight into the treatment of skin fibrosis.

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    World Journal of Stem Cells

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  • Stromal cell-derived factor-1α regulates chondrogenic differentiation via activation of the Wnt/β-catenin pathway in mesenchymal stem cells

    Stromal cell-derived factor-1α regulates chondrogenic differentiation via activation of the Wnt/β-catenin pathway in mesenchymal stem cells

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    BACKGROUND

    Mesenchymal stem cells (MSCs) have been applied to treat degenerative articular diseases, and stromal cell-derived factor-1α (SDF-1α) may enhance their therapeutic efficacy. However, the regulatory effects of SDF-1α on cartilage differentiation remain largely unknown. Identifying the specific regulatory effects of SDF-1α on MSCs will provide a useful target for the treatment of degenerative articular diseases.

    AIM

    To explore the role and mechanism of SDF-1α in cartilage differentiation of MSCs and primary chondrocytes.

    METHODS

    The expression level of C-X-C chemokine receptor 4 (CXCR4) in MSCs was assessed by immunofluorescence. MSCs treated with SDF-1α were stained for alkaline phosphatase (ALP) and with Alcian blue to observe differentiation. Western blot analysis was used to examine the expression of SRY-box transcription factor 9, aggrecan, collagen II, runt-related transcription factor 2, collagen X, and matrix metalloproteinase (MMP)13 in untreated MSCs, of aggrecan, collagen II, collagen X, and MMP13 in SDF-1α-treated primary chondrocytes, of glycogen synthase kinase 3β (GSK3β) p-GSK3β and β-catenin expression in SDF-1α-treated MSCs, and of aggrecan, collagen X, and MMP13 in SDF-1α-treated MSCs in the presence or absence of ICG-001 (SDF-1α inhibitor).

    RESULTS

    Immunofluorescence showed CXCR4 expression in the membranes of MSCs. ALP stain was intensified in MSCs treated with SDF-1α for 14 d. The SDF-1α treatment promoted expression of collagen X and MMP13 during cartilage differentiation, whereas it had no effect on the expression of collagen II or aggrecan nor on the formation of cartilage matrix in MSCs. Further, those SDF-1α-mediated effects on MSCs were validated in primary chondrocytes. SDF-1α promoted the expression of p-GSK3β and β-catenin in MSCs. And, finally, inhibition of this pathway by ICG-001 (5 µmol/L) neutralized the SDF-1α-mediated up-regulation of collagen X and MMP13 expression in MSCs.

    CONCLUSION

    SDF-1α may promote hypertrophic cartilage differentiation in MSCs by activating the Wnt/β-catenin pathway. These findings provide further evidence for the use of MSCs and SDF-1α in the treatment of cartilage degeneration and osteoarthritis.

    Core Tip: In this study, we investigated the effect of stromal cell-derived factor-1α (SDF-1α) on the differentiation of bone marrow mesenchymal stem cells (MSCs) and primary chondrocytes in vitro. We demonstrated that SDF-1α promotes the chondrogenic differentiation of MSCs, and similar results were observed in primary chondrocytes. In addition, SDF-1α also activates the Wnt/β-catenin pathway to regulate chondrocyte hypertrophy and maturation in MSCs.

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    World Journal of Stem Cells

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  • Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations

    Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations

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    Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

    Core Tip: Colorectal cancer (CRC) represents one of the most prevalent tumors worldwide. The tumor microenvironment (TME) through its proinflammatory role, among others, actively participates in CRC progression and the disturbance of gut microbiota (dysbiosis) can influence this inflammatory process. CRC stem cells (CCSC) are a tumor cell subpopulation that drives CRC initiation, progression and treatment failure. The features and behavior of CCSC are modulated by several factors including TME and gut microbiota. Here, we will give an overview of the synergistic interaction among TME and intestinal microorganisms that condition the CRC environment and shape CCSC characteristics allowing CRC evolution.

    [ad_2]

    World Journal of Stem Cells

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