Stem Cell Reviews and Reports最新文献

Mesenchymal stem cells (MSCs) are highly valuable for their potential in cell therapy and tissue engineering because of their self-renewal, multilineage differentiation, and immunomodulatory capabilities. Adipose-derived mesenchymal stem cells (AD-MSCs) are advantageous in regenerative medicine because of their accessibility and ease of isolation. However, the clinical application of MSCs faces challenges related to large-scale culture (LSC) expansion, which is required to generate enough cells for transplantation but also decreases their therapeutic properties. This review assesses the impact of LSC on MSC functionality, differentiation potential, and immunomodulatory properties, and identifies key factors, such as metabolic shifts, genetic instability, and altered secretory profiles, that can compromise their therapeutic potential. We explored how prolonged in vitro passaging decreases MSC functionality and increases the risk of genetic alterations. In addition, strategies to preserve the efficacy of MSCs during scaling are discussed. A comprehensive literature review was conducted using PubMed, focusing on in vitro and in vivo studies that evaluated the effects of LSC on MSCs. These findings provide insights into optimizing culture protocols to maintain the clinical efficacy of AD-MSCs in regenerative therapies, addressing the critical need to balance large-scale expansion and functional integrity.

Background: Takotsubo syndrome (TTS), also known as stress-induced cardiomyopathy, is characterized by transient left ventricular dysfunction often triggered by emotional or physical stress. Catecholamines are believed to play a pivotal role in the pathogenesis of TTS, including endothelial dysfunction. This study aimed to elucidate the catecholamine-induced endothelial dysfunction using patient-specific induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) from TTS patients.

Methods: hiPSC-ECs derived from a TTS patient (TTS-hiPSC-ECs) and three healthy donors (HD-hiPSC-ECs) were treated with epinephrine (Epi), Lipopolysaccharide (LPS), or a combination of both, and cell functional responses were evaluated.

Results: Epi exposure significantly impaired endothelial cell functions, evidenced by reduced cell migration, nitric oxide (NO) production, Dil-Ac-LDL uptake, mitochondrial membrane potential (MMP), ATP production, and inhibited tube formation and wound healing in both HD-hiPSC-ECs and TTS-hiPSC-ECs. Additionally, catecholamine treatment resulted in increased concentrations of endothelin-1 (ET-1), angiotensin II (Ang II), and reactive oxygen species (ROS) in the supernatants of both cell types. Elevated Mincle expression and pro-inflammatory cytokines, including IL-6 and IL-1β, along with reduced IL-4 protein expression, were observed in both HD-hiPSC-ECs and TTS-hiPSC-ECs. Furthermore, LPS treatment enhanced Mincle, IL-6, and IL-1β protein expression and reduced IL-4 levels in both cell types. The combination of LPS and Epi enhanced not only the level of those inflammatory factors but also the PI3K/NF-κB signaling pathway in both HD-hiPSC-ECs and TTS-hiPSC-ECs. Strikingly, TTS-hiPSC-ECs showed abnormal features even without an Epi challenge.

Conclusions: The study first reveals functional abnormalities of hiPSC-ECs from a TTS patient and underscores the critical involvement of inflammatory signaling in catecholamine-induced endothelial dysfunction in TTS.

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.