Stem Cell Reviews and Reports最新文献

Fracture healing is a complex process driven by endogenous regenerative mechanisms, with early biological responses playing a pivotal role in determining healing outcomes. During this critical phase, the body establishes a dynamic equilibrium across multiple systems, akin to the precise calibration of a biological clock. The inflammatory response is tightly regulated through the interplay of pro- and anti-inflammatory signals, ensuring efficient immune cell recruitment for necrotic tissue clearance while preventing excessive inflammation that could compromise surrounding tissues. Simultaneously, the coagulation cascade maintains a delicate balance between clot formation and anticoagulation, facilitating hemostasis and repair initiation while mitigating thrombotic risks. Energy metabolism is similarly fine-tuned, with coordinated anabolic and catabolic activity providing the necessary substrates and energy for regeneration. These interconnected processes collectively drive the phenotypic transformation of cells from diverse lineages, ultimately shaping the trajectory of fracture healing. In this review article, we propose an integrated 'biological orchestration' framework. Rather than viewing these systems in isolation, we discuss the intricate crosstalk among inflammatory homeostasis, coagulation balance, and metabolic adaptation. Additionally, we provide a multi-dimensional exploration of the fracture healing process, encompassing the microenvironment, intra-osseous dynamics, and the regulatory influence of surrounding tissues. By elucidating the temporal orchestration of these systems, this review offers theoretical insights that may inform the development of precise therapeutic strategies for bone regeneration.

Despite advances in surgical resection, radiation, and chemotherapy, glioblastoma remains a lethal condition driven by intrinsic heterogeneity, therapy resistance, and an immunosuppressive tumour microenvironment. Mesenchymal stromal cells (MSCs) and their secretomes, comprising cytokines, growth factors, and extracellular vesicles, have emerged as promising therapeutic candidates due to their tumour-homing properties and anti-inflammatory and immunomodulatory potential. However, recent evidence reveals a paradox: MSC secretomes exhibit both anti-inflammatory/immunomodulatory potential and pro-tumorigenic activities, depending on MSC source, passage number, and environmental and manufacturing contexts. In this review, we critically examine the molecular mechanisms underlying these opposing effects, synthesising evidence on how MSC source, donor variability, passage number, and environmental priming/licensing (e.g., hypoxia, inflammatory licensing) dictate secretome composition and function. We identify critical manufacturing determinants, including the necessity for upper passage limits and standardised isolation protocols, and propose a translational framework that integrates mechanism-based potency assays, such as nuclear factor-κB (NF-κB) reporter systems and multi-donor mixed lymphocyte reactions, to predict clinical activity. Establishing these robust quality controls and mechanistic release and rejection criteria will be essential to resolve the functional plasticity of secretomes and enable the safe translation of MSC-based therapies for glioblastoma.

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.