Stem Cell Reviews and Reports最新文献

Investigation of toxicological profile and possible side effects of engineered nanomaterials (ENMs) is of high importance. Historically, two-dimensional (2D) cell culture was used to study the toxicity of the ENMs, but due to their inability to simulate in vivo cell behavior, three-dimensional (3D) cell culture systems have been developed. Nanotoxicity studies initiate with in vitro experiments and continue with in vivo studies, which are very challenging and sometimes accompanied by conflicting data due to the in vitro-in vivo gap. Thus, scientists are turning their attention to microfabrication techniques and engineered systems "called organ-on-a-chips", which act as an intermediate between in vivo and in vitro systems. The present account tries to review the classical study models and suitably cover the emerging 3D culture models including scaffold-free and scaffold-based 3D cell cultures, 3D co-culture with direct contact and without cell-cell contact methods as well as microfluidic-based tissue chips and organoids. Overall, this review aims to give readers a better insight about the ENMs' toxicology and fill the gaps between the knowledge and practical techniques. Hopefully, the presented information will resolve the issues of 2D in vitro cultures and display the clinically relevant responses to the concerns of therapeutic ENMs.

Cancer Stem Cells (CSCs) represent a heterogeneous group of tumor cells that possess the innate ability to self-renew and differentiate, which also contributes to their resistance to first-line therapies. What sets CSCs apart from others is their crucial role in the recurrence of cancer, metastasis, and varied clinical responses against anti-cancer drugs, which makes them challenging to target. In recent years, there has been growing evidence that therapies capable of eliminating CSC niches or specifically targeting their core survival mechanisms are a potential means of providing a sustainable, long-term response to therapy and increasing disease-free survival rates. Bioactive compounds from natural sources have gained immense interest for their bio-efficacy, low toxicity profiles, and wide therapeutic index (TI), especially with their broad-spectrum ability of targeting multiple pathways while having little or no systemic side effects. Bioactive compounds can target major signaling pathways (Wnt/β-catenin, Notch, Hippo-YAP/TAZ, Hedgehog, PI3K/Akt/mTOR, NF-κB) to induce apoptosis, inhibit epithelial-mesenchymal transition (EMT), disrupt cancer stem cell niches, and other effects that suggest they resensitize to chemotherapeutic agents. Plant-derived biologics may be used as unique strategies targeting CSCs or as adjuncts reconstituted with custom conventional treatment plans, to mitigate drug resistance with mechanisms that involve targeting CSC metabolism, blocking protective autophagy, and the epigenetic landscape. The use of nanotechnology for targeted delivery of bioactive compounds is anticipated to provide better stability, bioavailability, and tumor accumulation. In this review, we outline a range of approaches using bioactive compounds for the eradication of CSCs, focusing on the mechanisms by which they work, the preclinical and clinical evidence supporting them, and their role in combination therapy approaches. This review also gives a comprehensive understanding of various other strategies and latest advancements that do not directly target the CSCs, including differentiation therapy, metabolic targeting, and immunomodulation, which, when used in conjunction with bioactive compounds, may resensitize the drug-resistant CSC population. We also discuss the therapeutic and translational potential of bioactive compounds and the future possibilities of combination, multi-targeted, CSC-based treatment strategies to eliminate tumor recurrences and improve cancer outcomes for patients.

Ovarian cancer (OC) remains the deadliest gynecological malignancy, characterized by late diagnosis, tumor heterogeneity, and chemotherapy resistance, contributing to poor survival rates. This comprehensive review explores the potential of chimeric antigen receptor (CAR)-T and CAR-natural killer (NK) cell therapies as emerging immunotherapies for OC. We examine key tumor-associated antigens, including folate receptor alpha (FRα), mesothelin (MSLN), HER2, EpCAM, MUC16, Tn-glycopeptide, TAG-72, and LGR5, which are overexpressed in OC and have shown promise in preclinical studies and early clinical trials for inducing tumor regression without MHC restrictions. While CAR-T cells have demonstrated significant antitumor cytotoxicity in preclinical models, their application in solid tumors like OC faces challenges, including immunosuppressive tumor microenvironments, antigen escape, cytokine release syndrome, and neurotoxicity. CAR-NK cells offer potential advantages, such as reduced toxicity, off-the-shelf availability, and efficacy against heterogeneous tumors, making them a promising complementary approach. This review discusses current research on dosing regimens and combination strategies involving checkpoint inhibitors, chemotherapy, and radiotherapy, as well as responses across histological subtypes. Drawing from ongoing early-phase trials and innovative approaches like CRISPR editing and dual-targeting, we highlight the progress and challenges in developing CAR-based therapies, underscoring their potential while emphasizing the need for further research to establish clinical efficacy in OC.

Human invariant natural killer T (iNKT) cells are a conserved population of innate-like T cells that are activated by glycolipid antigens. In addition to their well-known role in anti-tumor function, iNKT cells are also involved in regulating and maintaining hematopoiesis in the bone marrow. Here, we present the reprogramming of human CD4⁺Vα24⁺Vβ11⁺ iNKT cells into induced pluripotent stem cells (iNKT-iPSCs) and describe a novel chemically defined, feeder-free 3D spheroid method for generating CD34⁺ cells from iNKT-iPSCs, followed by their re-differentiation into functional Vα24⁺Vβ11⁺ iNKT cells (i-iNKT) with pro-hematopoietic activity. The i-iNKT cells showed specific binding to CD1d tetramers loaded with the lipid antigen α-galactosylceramide and had a similar transcription factor profile to that of somatic CD4⁺ iNKT cells. Additionally, in response to CD3 stimulation, the i-iNKT cells produced cytokines with hematopoietic potential and promoted expansion/differentiation of myeloid progenitors. These findings suggest the feasibility of using iPSCs as off-the-shelf i-iNKT cell sources to enhance the hematopoietic activity of bone marrow after hematopoietic stem cell (HSC) transplantation.

Ischemic stroke is one of the leading causes of disability and mortality worldwide, posing a significant threat to human health. Neural stem cells possess the remarkable capabilities of self-renewal and differentiation into diverse neural cell types, endowing them with significant potential for the restoration of damaged neural tissues and functions. Exosomes, which carry a multitude of bioactive substances, serve as crucial tools for intercellular communication. Neural stem cell-derived exosomes are capable of engaging in the modulation of various physiological functions, presenting a highly promising novel approach for the treatment of ischemic stroke. This paper elaborates on the pathophysiological mechanisms of ischemic stroke, the engineering strategies for exosomes, and the prospects and limitations of neural stem cell transplantation therapies. It systematically reviews the potential roles of neural stem cell-derived exosomes in the treatment of ischemic stroke. Studies have shown that neural stem cell-derived exosomes can contribute to brain targeting, promote neural regeneration and angiogenesis, suppress neuroinflammation, and enhance the integrity of the blood-brain barrier in the treatment of ischemic stroke. However, their efficacy is constrained by insufficient targeting precision and limited cargo content. To improve the therapeutic efficacy of neural stem cell-derived exosomes, strategies such as surface modification and cargo loading can be employed. These include attaching targeting peptides, proteins, and antibodies to the exosome surface via chemical modification and genetic engineering, as well as loading small-molecule drugs and nanomaterials. Furthermore, accelerating the clinical translation of exosomes requires strict adherence to Good Manufacturing Practices. Neural stem cell-derived exosomes hold substantial potential in the treatment of ischemic stroke, which is expected to promote the development of the field of neural regeneration and bring new hope for more central nervous system diseases.

Mesenchymal stromal cells (MSCs) have gained significant attention in regenerative medicine for their potential in treating a variety of diseases even intractable ones, due to their ability to differentiate into various cell types and promote tissue repair. In addition to their regenerative properties, MSCs possess potent immunomodulatory effects, which make them particularly promising for treating orthopedic conditions and musculoskeletal disorders complicated by chronic inflammation, infection, or other comorbidities. This review explores the immunomodulatory mechanisms of MSCs and their role in facilitating bone and cartilage repair in conditions such as fractures, osteoarthritis, and tendon injuries. We examine the key mechanisms by which MSCs regulate the immune responses, including the paracrine activity by secreting cytokines, growth factors and extracellular vesicles on one hand, and modulation of immune cell activities through direct cell-cell contact. Furthermore, this review examines how comorbidities impact MSC function and quality and explores the potential of MSCs in treating orthopedic conditions complicated by diabetes, obesity, smoking, and infections, which can hinder the healing process. The challenges of translating MSC-based therapies into orthopaedic clinical practice are also discussed, particularly concerning MSC source selection, optimal dosing strategies and long-term safety and efficacy. Finally, we highlight emerging strategies aimed at enhancing the immunomodulatory effects of MSCs, such as preconditioning, genetic modifications, biomaterial-based delivery systems and combination therapies. A profound understanding of MSC immunomodulatory mechanisms can pave the way toward optimizing their application in orthopedic cell therapy and tissue engineering and enhancing clinical outcomes for patients with complex healing conditions.