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Tag: World Journal of Stem Cells

  • 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

    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.

    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

    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.

    World Journal of Stem Cells

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  • Mammalian Ste20-like kinase 1 inhibition as a cellular mediator of anoikis in mouse bone marrow mesenchymal stem cells

    Mammalian Ste20-like kinase 1 inhibition as a cellular mediator of anoikis in mouse bone marrow mesenchymal stem cells

    BACKGROUND

    The low survival rate of mesenchymal stem cells (MSCs) caused by anoikis, a form of apoptosis, limits the therapeutic efficacy of MSCs. As a proapoptotic molecule, mammalian Ste20-like kinase 1 (Mst1) can increase the production of reactive oxygen species (ROS), thereby promoting anoikis. Recently, we found that Mst1 inhibition could protect mouse bone marrow MSCs (mBMSCs) from H2O2-induced cell apoptosis by inducing autophagy and reducing ROS production. However, the influence of Mst1 inhibition on anoikis in mBMSCs remains unclear.

    AIM

    To investigate the mechanisms by which Mst1 inhibition acts on anoikis in isolated mBMSCs.

    METHODS

    Poly-2-hydroxyethyl methacrylate-induced anoikis was used following the silencing of Mst1 expression by short hairpin RNA (shRNA) adenovirus transfection. Integrin (ITGs) were tested by flow cytometry. Autophagy and ITGα5β1 were inhibited using 3-methyladenine and small interfering RNA, respectively. The alterations in anoikis were measured by Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling and anoikis assays. The levels of the anoikis-related proteins ITGα5, ITGβ1, and phospho-focal adhesion kinase and the activation of caspase 3 and the autophagy-related proteins microtubules associated protein 1 light chain 3 II/I, Beclin1 and p62 were detected by Western blotting.

    RESULTS

    In isolated mBMSCs, Mst1 expression was upregulated, and Mst1 inhibition significantly reduced cell apoptosis, induced autophagy and decreased ROS levels. Mechanistically, we found that Mst1 inhibition could upregulate ITGα5 and ITGβ1 expression but not ITGα4, ITGαv, or ITGβ3 expression. Moreover, autophagy induced by upregulated ITGα5β1 expression following Mst1 inhibition played an essential role in the protective efficacy of Mst1 inhibition in averting anoikis.

    CONCLUSION

    Mst1 inhibition ameliorated autophagy formation, increased ITGα5β1 expression, and decreased the excessive production of ROS, thereby reducing cell apoptosis in isolated mBMSCs. Based on these results, Mst1 inhibition may provide a promising strategy to overcome anoikis of implanted MSCs.

    Key Words: Mouse bone marrow mesenchymal stem cell, Mammalian sterile 20-like kinase 1, Anoikis, Integrin, Autophagy, Reactive oxygen species

     

    Core Tip: In isolated mouse bone marrow mesenchymal stem cell (mBMSCs), Mammalian sterile 20-like kinase 1 (Mst1) inhibition could ameliorate not only autophagy formation but also upregulate integrin (ITG) α5β1 expression (but not ITGα4, ITGαv, or ITGβ3). In addition, Mst1 inhibition-induced autophagy could scavenge the excessive production of ITGα5β1-triggered ROS. Therefore, Mst1 inhibition-based infusion may improve the survival of MSCs, thereby serving as an ideal candidate for clinical transplantation in pulmonary arterial hypertension.

    World Journal of Stem Cells

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  • Clinical trials using dental stem cells: 2022 update

    Clinical trials using dental stem cells: 2022 update

    For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.

    Core Tip: Since dental pulp stem cells were first isolated and identified in 2000, a variety of dental stem cells (DSCs) have been reported. DSCs have shown satisfactory clinical effects in the treatment of a variety of diseases and have great potential for clinical application. This paper will summarize DSC-based clinical trials and put forward the current limitations and perspectives to accelerate and extend the clinical application of DSCs.

    World Journal of Stem Cells

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  • Mesenchymal stem cells in ischemic tissue regeneration

    Mesenchymal stem cells in ischemic tissue regeneration

    Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.

    Core Tip: Mesenchymal stem cell (MSC) transplantation is an innovative therapy with positive therapeutic effects for many ischemic diseases. Ischemia of an area is defined as insufficient blood supply to specific tissues and various organs or individual parts of the body. The leading cause of tissue ischemia is the narrowing or blockage of the lumen of an artery, most often due to the formation of atherosclerotic plaques, thrombus, or spasms of a specific artery. Here, the potential therapeutic mechanisms of MSCs in ischemic diseases were discussed, along with examples of preclinical and clinical studies.

    World Journal of Stem Cells

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  • Barriers to mesenchymal stromal cells for low back pain

    Barriers to mesenchymal stromal cells for low back pain

    Intervertebral disc degeneration is the main cause of low back pain. In the past 20 years, the injection of mesenchymal stromal cells (MSCs) into the nucleus pulposus of the degenerative disc has become the main approach for the treatment of low back pain. Despite the progress made in this field, there are still many barriers to overcome. First, intervertebral disc is a highly complex load-bearing composite tissue composed of annulus fibrosus, nucleus pulposus and cartilaginous endplates. Any structural damage will change its overall biomechanical function, thereby causing progressive degeneration of the entire intervertebral disc. Therefore, MSC-based treatment strategies should not only target the degenerated nucleus pulposus but also include degenerated annulus fibrosus or cartilaginous endplates. Second, to date, there has been relatively little research on the basic biology of annulus fibrosus and cartilaginous endplates, although their pathological changes such as annular tears or fissures, Modic changes, or Schmorl’s nodes are more commonly associated with low back pain. Given the high complexity of the structure and composition of the annulus fibrosus and cartilaginous endplates, it remains an open question whether any regeneration techniques are available to achieve their restorative regeneration. Finally, due to the harsh microenvironment of the degenerated intervertebral disc, the delivered MSCs die quickly. Taken together, current MSC-based regenerative medicine therapies to regenerate the entire disc complex by targeting the degenerated nucleus pulposus alone are unlikely to be successful.

    Core Tip: Intervertebral disc is a highly complex weight-bearing tissue, and its degeneration is a major cause of low back pain. Current mesenchymal stromal cell-based clinical trials are difficult to succeed because the repair only targets the degenerated nucleus pulposus, and the transplanted cells die rapidly.

    World Journal of Stem Cells

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  • SPOC domain-containing protein 1 regulates the proliferation and apoptosis of human spermatogonial stem cells through adenylate kinase 4

    SPOC domain-containing protein 1 regulates the proliferation and apoptosis of human spermatogonial stem cells through adenylate kinase 4

    BACKGROUND

    Spermatogonial stem cells (SSCs) are the origin of male spermatogenesis, which can reconstruct germ cell lineage in mice. However, the application of SSCs for male fertility restoration is hindered due to the unclear mechanisms of proliferation and self-renewal in humans.

    AIM

    To investigate the role and mechanism of SPOC domain-containing protein 1 (SPOCD1) in human SSC proliferation.

    METHODS

    We analyzed publicly available human testis single-cell RNA sequencing (RNA-seq) data and found that SPOCD1 is predominantly expressed in SSCs in the early developmental stages. Small interfering RNA was applied to suppress SPOCD1 expression to detect the impacts of SPOCD1 inhibition on SSC proliferation and apoptosis. Subsequently, we explored the target genes of SPOCD1 using RNA-seq and confirmed their role by restoring the expression of the target genes. In addition, we examined SPOCD1 expression in some non-obstructive azoospermia (NOA) patients to explore the correlation between SPOCD1 and NOA.

    RESULTS

    The uniform manifold approximation and projection clustering and pseudotime analysis showed that SPOCD1 was highly expressed in the early stages of SSC, and immunohistological results showed that SPOCD1 was mainly localized in glial cell line-derived neurotrophic factor family receptor alpha-1 positive SSCs. SPOCD1 knockdown significantly inhibited cell proliferation and promoted apoptosis. RNA-seq results showed that SPOCD1 knockdown significantly downregulated genes such as adenylate kinase 4 (AK4). Overexpression of AK4 in SPOCD1 knockdown cells partially reversed the phenotypic changes, indicating that AK4 is a functional target gene of SPOCD1. In addition, we found a significant downregulation of SPOCD1 expression in some NOA patients, suggesting that the downregulation of SPOCD1 may be relevant for NOA.

    CONCLUSION

    Our study broadens the understanding of human SSC fate determination and may offer new theories on the etiology of male infertility.

    Core Tip: In this study, we reported the dominant expression of SPOC domain-containing protein 1 (SPOCD1) in human spermatogonial stem cells (SSCs). Knockdown of SPOCD1 in SSC caused a significant decrease in proliferation and self-renewal, and the induction of apoptosis. RNA sequencing showed that SPOCD1 knockdown caused significant downregulation of genes such as adenylate kinase 4 (AK4), and overexpression of AK4 in SPOCD1-knockdown cells reversed the phenotypic alterations induced by SPOCD knockdown. Additionally, we found significant downregulation of SPOCD1 in non-obstructive azoospermia patients. These results broaden our understanding of human SSC fate determination and provide new theories on the etiology of male infertility.

    World Journal of Stem Cells

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  • Optimal concentration of mesenchymal stem cells for fracture healing in a rat model with long bone fracture

    Optimal concentration of mesenchymal stem cells for fracture healing in a rat model with long bone fracture

    BACKGROUND

    There is still no consensus on which concentration of mesenchymal stem cells (MSCs) to use for promoting fracture healing in a rat model of long bone fracture.

    AIM

    To assess the optimal concentration of MSCs for promoting fracture healing in a rat model.

    METHODS

    Wistar rats were divided into four groups according to MSC concentrations: Normal saline (C), 2.5 × 106 (L), 5.0 × 106 (M), and 10.0 × 106 (H) groups. The MSCs were injected directly into the fracture site. The rats were sacrificed at 2 and 6 wk post-fracture. New bone formation [bone volume (BV) and percentage BV (PBV)] was evaluated using micro-computed tomography (CT). Histological analysis was performed to evaluate fracture healing score. The protein expression of factors related to MSC migration [stromal cell-derived factor 1 (SDF-1), transforming growth factor-beta 1 (TGF-β1)] and angiogenesis [vascular endothelial growth factor (VEGF)] was evaluated using western blot analysis. The expression of cytokines associated with osteogenesis [bone morphogenetic protein-2 (BMP-2), TGF-β1 and VEGF] was evaluated using real-time polymerase chain reaction.

    RESULTS

    Micro-CT showed that BV and PBV was significantly increased in groups M and H compared to that in group C at 6 wk post-fracture (P = 0.040, P = 0.009; P = 0.004, P = 0.001, respectively). Significantly more cartilaginous tissue and immature bone were formed in groups M and H than in group C at 2 and 6 wk post-fracture (P = 0.018, P = 0.010; P = 0.032, P = 0.050, respectively). At 2 wk post-fracture, SDF-1, TGF-β1 and VEGF expression were significantly higher in groups M and H than in group L (P = 0.031, P = 0.014; P < 0.001, P < 0.001; P = 0.025, P < 0.001, respectively). BMP-2 and VEGF expression were significantly higher in groups M and H than in group C at 6 wk post-fracture (P = 0.037, P = 0.038; P = 0.021, P = 0.010). Compared to group L, TGF-β1 expression was significantly higher in groups H (P = 0.016). There were no significant differences in expression levels of chemokines related to MSC migration, angiogenesis and cytokines associated with osteogenesis between M and H groups at 2 and 6 wk post-fracture.

    CONCLUSION

    The administration of at least 5.0 × 106 MSCs was optimal to promote fracture healing in a rat model of long bone fractures.

    Core Tip: This study focused on the optimal concentration of mesenchymal stem cells (MSCs) that affect fracture healing in a rat model of long bone shaft fracture. Factors related to the homing effect of MSCs, osteogenesis and angiogenesis were analyzed by in vivo (radiographic and histologic evaluation) as well as in vitro (reverse transcriptase-polymerase chain reaction and western blot analysis). Among the various concentrations used, the administration of at least 5.0 × 106 MSCs was optimal to promote the therapeutic effect on fracture healing.

    World Journal of Stem Cells

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  • Biomaterial application strategies to enhance stem cell-based therapy for ischemic stroke

    Biomaterial application strategies to enhance stem cell-based therapy for ischemic stroke

    BACKGROUND

    Ischemic stroke is a condition in which an occluded blood vessel interrupts blood flow to the brain and causes irreversible neuronal cell death. Transplantation of regenerative stem cells has been proposed as a novel therapy to restore damaged neural circuitry after ischemic stroke attack. However, limitations such as low cell survival rates after transplantation remain significant challenges to stem cell-based therapy for ischemic stroke in the clinical setting. In order to enhance the therapeutic efficacy of transplanted stem cells, several biomaterials have been developed to provide a supportable cellular microenvironment or functional modification on the stem cells to optimize their reparative roles in injured tissues or organs.

    AIM

    To discuss state-of-the-art functional biomaterials that could enhance the therapeutic potential of stem cell-based treatment for ischemic stroke and provide detailed insights into the mechanisms underlying these biomaterial approaches.

    METHODS

    The PubMed, Science Direct and Scopus literature databases were searched using the keywords of “biomaterial” and “ischemic stroke”. All topically-relevant articles were then screened to identify those with focused relevance to in vivo, in vitro and clinical studies related to “stem cells” OR “progenitor cells” OR “undifferentiated cells” published in English during the years of 2011 to 2022. The systematic search was conducted up to September 30, 2022.

    RESULTS

    A total of 19 articles matched all the inclusion criteria. The data contained within this collection of papers comprehensively represented 19 types of biomaterials applied on seven different types of stem/progenitor cells, namely mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, neural progenitor cells, endothelial progenitor cells, neuroepithelial progenitor cells, and neuroblasts. The potential major benefits gained from the application of biomaterials in stem cell-based therapy were noted as induction of structural and functional modifications, increased stem cell retention rate in the hostile ischemic microenvironment, and promoting the secretion of important cytokines for reparative mechanisms.

    CONCLUSION

    Biomaterials have a relatively high potential for enhancing stem cell therapy. Nonetheless, there is a scarcity of evidence from human clinical studies for the efficacy of this bioengineered cell therapy, highlighting that it is still too early to draw a definitive conclusion on efficacy and safety for patient usage. Future in-depth clinical investigations are necessary to realize translation of this therapy into a more conscientious and judicious evidence-based therapy for clinical application.

    Core Tip: Ischemic stroke is becoming a significant health issue globally. An increasing number of studies have proposed the applications of regenerative stem cells for the treatment of this neurodegenerative disease. We critically reviewed the literature on biomaterial application to enhance the therapeutic potential of stem/progenitor cell therapy for ischemic stroke. Despite the limited evidence collected to translate this evidence into clinical practice, it is postulated that application of stem cells as regenerative treatment for stroke is practicable and beneficial for stroke patients, especially those in the chronic phase of stroke which could not be cured by any other established means.

    World Journal of Stem Cells

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