Stem Cell Reviews and Reports

Ratajczak, Mariusz Z.

doi: 10.1007/s12015-023-10669-0pmid: 38150083

Borlongan, Mia C.; Saha, Dipongkor; Wang, Hongbin

doi: 10.1007/s12015-023-10639-6pmid: 37861969

Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.Graphical abstract[graphic not available: see fulltext]

Moreno-Londoño, Angela Patricia; Robles-Flores, Martha

doi: 10.1007/s12015-023-10647-6pmid: 37922108

CD133 protein has been one of the most used surface markers to select and identify cancer cells with stem-like features. However, its expression is not restricted to tumoral cells; it is also expressed in differentiated cells and stem/progenitor cells in various normal tissues. CD133 participates in several cellular processes, in part orchestrating signal transduction of essential pathways that frequently are dysregulated in cancer, such as PI3K/Akt signaling and the Wnt/β-catenin pathway. CD133 expression correlates with enhanced cell self-renewal, migration, invasion, and survival under stress conditions in cancer. Aside from the intrinsic cell mechanisms that regulate CD133 expression in each cellular type, extrinsic factors from the surrounding niche can also impact CD33 levels. The enhanced CD133 expression in cells can confer adaptive advantages by amplifying the activation of a specific signaling pathway in a context-dependent manner. In this review, we do not only describe the CD133 physiological functions known so far, but importantly, we analyze how the microenvironment changes impact the regulation of CD133 functions emphasizing its value as a marker of cell adaptability beyond a cancer-stem cell marker.Graphical Abstract[graphic not available: see fulltext]

Sarabia-Sánchez, Miguel Angel; Robles-Flores, Martha

doi: 10.1007/s12015-023-10610-5pmid: 37804416

Tissue homeostasis is crucial for multicellular organisms, wherein the loss of cells is compensated by generating new cells with the capacity for proliferation and differentiation. At the origin of these populations are the stem cells, which have the potential to give rise to cells with both capabilities, and persevere for a long time through the self-renewal and quiescence. Since the discovery of stem cells, an enormous effort has been focused on learning about their functions and the molecular regulation behind them. Wnt signaling is widely recognized as essential for normal and cancer stem cell. Moreover, β-catenin-dependent Wnt pathway, referred to as canonical, has gained attention, while β-catenin-independent Wnt pathways, known as non-canonical, have remained conspicuously less explored. However, recent evidence about non-canonical Wnt pathways in stem cells begins to lay the foundations of a conceivably vast field, and on which we aim to explain this in the present review. In this regard, we addressed the different aspects in which non-canonical Wnt pathways impact the properties of stem cells, both under normal conditions and also under disease, specifically in cancer.Graphical abstract[graphic not available: see fulltext]

Khatun, Masuma; Lundin, Karolina; Naillat, Florence; Loog, Liisa; Saarela, Ulla; Tuuri, Timo; Salumets, Andres; Piltonen, Terhi T.; Tapanainen, Juha S.

doi: 10.1007/s12015-023-10627-wpmid: 37768523

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine condition among women with pleiotropic sequelae possessing reproductive, metabolic, and psychological characteristics. Although the exact origin of PCOS is elusive, it is known to be a complex multigenic disorder with a genetic, epigenetic, and environmental background. However, the pathogenesis of PCOS, and the role of genetic variants in increasing the risk of the condition, are still unknown due to the lack of an appropriate study model. Since the debut of induced pluripotent stem cell (iPSC) technology, the ability of reprogrammed somatic cells to self-renew and their potential for multidirectional differentiation have made them excellent tools to study different disease mechanisms. Recently, researchers have succeeded in establishing human in vitro PCOS disease models utilizing iPSC lines from heterogeneous PCOS patient groups (iPSCPCOS). The current review sets out to summarize, for the first time, our current knowledge of the implications and challenges of iPSC technology in comprehending PCOS pathogenesis and tissue-specific disease mechanisms. Additionally, we suggest that the analysis of polygenic risk prediction based on genome-wide association studies (GWAS) could, theoretically, be utilized when creating iPSC lines as an additional research tool to identify women who are genetically susceptible to PCOS. Taken together, iPSCPCOS may provide a new paradigm for the exploration of PCOS tissue-specific disease mechanisms.Graphical Abstract[graphic not available: see fulltext]

Panda, Debarchan; Nayak, Sunita

doi: 10.1007/s12015-023-10640-zpmid: 37867186

Diabetic foot ulcer (DFU) is a complication from incomplete or prolonged wound healing, at times requires amputation, putting substantial health and socioeconomic burden. Wound healing is a dynamic overlapping process that can be regulated by arrays of molecular factors showing redundancy in function. However, dysregulation in the mechanism of angiogenesis, extra cellular matrix (ECM) formation and immune modulation are the major causes for impair wound healing in hyperglycaemic patients. Despite development of wound care research, there is a lack of well-accepted targeted therapy with multidisciplinary approach for DFU treatment. Stem cell therapy holds a promising outcome both in preclinical and clinical trials because of its ability to promote healing via regeneration and specialized tissue differentiation. Among different types of stem cells, regenerative potential of mesenchymal stem cell (MSC) is well demonstrated in both experimental and clinical trial. Still there is a huge knowledge gap among medical practitioners for deciding the best stem cell source, administration route, and safety. This review strengthens the fact that why stem cell therapy is a promising candidate to treat DFU and cited multiple tissue engineering and biomaterial-based approaches for delivering stem cells and their aftermath paracrine events. Based on the pre-clinical and clinical studies, the review tried to come up with optimum stem cell source and delivery route for the treatment of DFU. At last, the review glances on possible direction to enhance therapeutics strategy for the same, including different approaches like: phytocompounds, exosomes, scaffold geometry, cell preconditioning and licensing etc. Graphical Abstract[graphic not available: see fulltext]

Liu, Wenxiu; Wang, Qian; Bai, Yanrui; Xiao, Han; Li, Zhunduo; Wang, Yan; Wang, Qi; Yang, Jing; Sun, Hui

doi: 10.1007/s12015-023-10651-wpmid: 37938407

To accurately reveal the scenario and mecahnism of gastrointestinal diseases, the establishment of in vitro models of intestinal diseases and drug screening platforms have become the focus of attention. Over the past few decades, animal models and immortalized cell lines have provided valuable but limited insights into gastrointestinal research. In recent years, the development of intestinal organoid culture system has revolutionized in vitro studies of intestinal diseases. Intestinal organoids are derived from self-renewal and self-organization intestinal stem cells (ISCs), which can replicate the genetic characteristics, functions, and structures of the original tissues. Consequently, they provide new stragety for studying various intestinal diseases in vitro. In the review, we will discuss the culture techniques of intestinal organoids and describe the use of intestinal organoids as research tools for intestinal diseases. The role of intestinal epithelial cells (IECs) played in the pathogenesis of inflammatory bowel diseases (IBD) and the treatment of intestinal epithelial dysfunction will be highlighted. Besides, we review the current knowledge on using intestinal organoids as models to study the pathogenesis of IBD caused by epithelial dysfunction and to develop new therapeutic approaches. Finally, we shed light on the current challenges of using intestinal organoids as in vitro models.Graphical Abstract[graphic not available: see fulltext]

Akat, Ayberk; Karaöz, Erdal

doi: 10.1007/s12015-023-10653-8pmid: 37955832

Duchenne Muscular Dystrophy (DMD) is an inherited genetic disorder characterized by progressive degeneration of muscle tissue, leading to functional disability and premature death. Despite extensive research efforts, the discovery of a cure for DMD continues to be elusive, emphasizing the need to investigate novel treatment approaches. Cellular therapies have emerged as prospective approaches to address the underlying pathophysiology of DMD. This review provides an examination of the present situation regarding cell-based therapies, including CD133 + cells, muscle precursor cells, mesoangioblasts, bone marrow-derived mononuclear cells, mesenchymal stem cells, cardiosphere-derived cells, and dystrophin-expressing chimeric cells. A total of 12 studies were found eligible to be included as they were completed cell therapy clinical trials, clinical applications, or case reports with quantitative results. The evaluation encompassed an examination of limitations and potential advancements in this particular area of research, along with an assessment of the safety and effectiveness of cell-based therapies in the context of DMD. In general, the available data indicates that diverse cell therapy approaches may present a new, safe, and efficacious treatment modality for patients diagnosed with DMD. However, further studies are required to comprehensively understand the most advantageous treatment approach and therapeutic capacity.Graphical Abstract[graphic not available: see fulltext]

Santilli, Francesca; Fabrizi, Jessica; Santacroce, Costantino; Caissutti, Daniela; Spinello, Zaira; Candelise, Niccolò; Lancia, Loreto; Pulcini, Fanny; Delle Monache, Simona; Mattei, Vincenzo

doi: 10.1007/s12015-023-10652-9pmid: 37962698

Mesenchymal stem cells (MSCs) are well known for their beneficial effects, differentiation capacity and regenerative potential. Dental-derived MSCs (DSCs) are more easily accessible and have a non-invasive isolation method rather than MSCs isolated from other sources (umbilical cord, bone marrow, and adipose tissue). In addition, DSCs appear to have a relevant neuro-regenerative potential due to their neural crest origin. However, it is now known that the beneficial effects of MSCs depend, at least in part, on their secretome, referring to all the bioactive molecules (neurotrophic factors) released in the conditioned medium (CM) or in the extracellular vesicles (EVs) in particular exosomes (Exos). In this review, we described the similarities and differences between various DSCs. Our focus was on the secretome of DSCs and their applications in cell therapy for neurological disorders. For neuro-regenerative purposes, the secretome of different DSCs has been tested. Among these, the secretome of dental pulp stem cells and stem cells from human exfoliated deciduous teeth have been the most widely studied. Both CM and Exos obtained from DSCs have been shown to promote neurite outgrowth and neuroprotective effects as well as their combination with scaffold materials (to improve their functional integration in the tissue). For these reasons, the secretome obtained from DSCs in combination with scaffold materials may represent a promising tissue engineering approach for neuroprotective and neuro-regenerative treatments.Graphical Abstract[graphic not available: see fulltext]

Mahmoud, Marwa; Abdel-Rasheed, Mazen; Galal, Eman Reda; El-Awady, Rehab R.

doi: 10.1007/s12015-023-10654-7pmid: 37962697

Human adipose tissue-derived stem/stromal cells (hASCs) are adult multipotent mesenchymal stem/stromal cells with immunomodulatory capacities. Here, we present up-to-date knowledge on the impact of different experimental and donor-related factors on hASC immunoregulatory functions in vitro. The experimental determinants include the immunological status of hASCs relative to target immune cells, contact vs. contactless interaction, and oxygen tension. Factors such as the ratio of hASCs to immune cells, the cellular context, the immune cell activation status, and coculture duration are also discussed. Conditioning of hASCs with different approaches before interaction with immune cells, hASC culture in xenogenic or xenofree culture medium, hASC culture in two-dimension vs. three-dimension with biomaterials, and the hASC passage number are among the experimental parameters that greatly may impact the hASC immunosuppressive potential in vitro, thus, they are also considered. Moreover, the influence of donor-related characteristics such as age, sex, and health status on hASC immunomodulation in vitro is reviewed. By analysis of the literature studies, most of the indicated determinants have been investigated in broad non-standardized ranges, so the results are not univocal. Clear conclusions cannot be drawn for the fine-tuned scenarios of many important factors to set a standard hASC immunopotency assay. Such variability needs to be carefully considered in further standardized research. Importantly, field experts’ opinions may help to make it clearer.Graphical AbstractParameters that promote ASC immunosuppression on immune cells. Activation of immune cells induces their proliferation and differentiation and presence of ASCs modulates/suppresses such consequences. Augmented immunosuppressive effects of ASCs can be introduced in direct contact with the immune cells and via complementing the repeatedly reported experimental settings (texts in grey shapes). Abbreviations: ASCs: adipose tissue-derived stem/stromal cells, IFN-ɤ: Interferon gamma, MLR: Mixed lymphocyte reaction, TNF: Tumor necrosis factor.[graphic not available: see fulltext]