Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.

Purinergic receptors participate, in almost every cell type, in controlling metabolic activities and many physiological functions including signal transmission, proliferation and differentiation. While most of P2Y receptors induce transient elevations of intracellular calcium concentration by activation of intracellular calcium pools and forward these signals as waves which can also be transmitted into neighboring cells, P2X receptors produce calcium spikes which also include activation of voltage-operating calcium channels. P2Y and P2X receptors induce calcium transients that activate transcription factors responsible for the progress of differentiation through mediators including calmodulin and calcineurin. Expression of P2X2 as well as of P2X7 receptors increases in differentiating neurons and glial cells, respectively. Gene expression silencing assays indicate that these receptors are important for the progress of differentiation and neuronal or glial fate determination. Metabotropic receptors, mostly P2Y1 and P2Y2 subtypes, act on embryonic cells or cells at the neural progenitor stage by inducing proliferation as well as by regulation of neural differentiation through NFAT translocation. The scope of this review is to discuss the roles of purinergic receptor-induced calcium spike and wave activity and its codification in neurodevelopmental and neurodifferentiation processes.

Complex organoid co-culture systems that resemble tissue microenvironments are emerging as a powerful model for precision-medicine. Despite intrinsic in vitro limitations, patient-derived three-dimensional models closely recapitulate tissue architecture, cellular heterogeneity, and microenvironmental interactions. Organoid platforms integrate stromal, vascular, microbial, and immune elements, therefore, supporting mechanistic studies of disease, preclinical assessment of therapeutics, and individualized ex-vivo prediction of treatment response. However clinical translation remains challenging based on methodological obstacles, particularly those related to components of vascular and immune integration. Computerassisted analysis of organoid systems -be such analysis deterministic (i.e. classical image analysis) or AI-based -remains a critical bottleneck in the road map to full exploitation of what organoid co-culture systems might be able to deliver. The contributions in this Research Topic delineate a translational trajectory from mechanistic studies of barrier biology to engineered ex vivo immunotherapy assays and to organoid development for non-oncologic tissue repair. Collectively, they demonstrate the field's potential to advance precision medicine while exposing enduring methodological, bioengineering, and validation challenges that must be addressed for clinical translation.From Barrier Integrity to Therapeutic Resistance: Organoid Approaches to IFN-I (Edited by Talita Glaser) Type I interferons can help or harm the gut associated functionality. Therefore detailed, studies are needed to separate protective effects from damaging ones in inflammatory bowel disease (IBD). King et al. show that patient-derived intestinal organoids can offer a physiologically relevant platform to interrogate epithelial-specific IFN-I signaling (King et al., 2025). With addition of immune and microbial components, these models might enable systematic comparison of transient versus sustained IFN-I exposure, allowing the assessment of effects on tight-junction integrity, epithelial proliferation, apoptosis, cellular turnover, and reparative programs. The authors prioritize epithelial barrier assays with immune and microbial partners to model signaling driving treatment failure. King et al. note that that interspecies differences between murine and human organoids can alter interferon-stimulated gene expression and cytokine sensitivity, a consideration that should inform experimental design and translational interpretation.Predicting Anti-PD-1 Response in Colorectal Cancer Using Patient-Derived Microtumors (Edited by Talita Glaser) Nguyen et al. describe a media-perfused 3D ex vivo platform that co-cultures patient-derived colorectal microtumors with autologous peripheral blood mononuclear cells (PBMCs) to functionally screen PD-1 blockade (Nguyen et al., 2025). The system preserves tissue architecture, endogenous tumor-infiltrating lymphocytes (TILs) and viability, and allows interstitial immune migration within bioconjugated liquid-like solid microgels. Using interferon-gamma (IFN-γ) measurements, confocal/TUNEL imaging, multiplexed ion beam imaging (MIBI), and whole-exome sequencing (WES), they report an MSI (microsatellite-instable) case with robust IFN-γ induction, immune infiltration and tumor apoptosis after pembrolizumab; an MSS (microsatellite-stable) case harboring a DNA polymerase epsilon (POLE) A456P exonuclease mutation with ultrahigh tumor mutational burden (TMB; ≈ 236 muts/Mb) showing ex vivo PD-1 sensitivity, particularly in microtumor-only cultures; and heterogeneous outcomes among other POLE-mutated tumors, underscoring variant pathogenicity and the importance of spatial immune context. The observed attenuation of response upon adding autologous PBMCs suggests peripheral suppressive populations (e.g., myeloid-derived suppressor cells, MDSCs) may modulate efficacy. Strengths include multimodal functional and spatial readouts and clear translational relevance. Limitations are small cohort size and absence of systemic physiology. Prospective validation linking ex vivo readouts to clinical responses, TCR clonotype tracking, single-cell profiling, and interrogation of myeloid suppression are warranted to establish clinical utility for personalizing immunotherapy in colorectal cancer (CRC).Talita Glaser) Jiao et. al provide a concise review of osteochondral organoids as transformative platforms for osteoarthritis (OA) research, highlighting their capacity to recapitulate cartilage-bone interfaces, multicellular crosstalk, and pathomimetic processes relevant to disease progression and repair (Jiao et al., 2025). The authors synthesize advances in cell sourcing (MSCs, iPSC-derived progenitors), engineered matrices (natural, synthetic, gradient and DNA-based hydrogels), and bio fabrication (3D/4D bioprinting, microfluidics, integrated printing-chip systems) that enable graded osteochondral architectures and functional maturation. They emphasize applications in mechanistic modeling, gene-edited disease phenotypes, high-throughput drug screening, and regenerative implantation while underscoring persistent translational barriers: vascularization, immune compatibility, reproducibility under GMP, and safety concerns (e.g., residual pluripotent cells). Jiao et al. advocate interdisciplinary integration-organ-on-chip platforms, multi-omics, and AI-driven design and quality controlto generate standardized, patient-specific models that bridge preclinical discovery and clinical translation. Overall, the review positions osteochondral organoids as a promising route toward precision OA therapeutics, contingent on resolving key bioengineering and regulatory challenge.Jiang Xin-Yi and colleagues review organoid technology as a promising transformative platform for cancer research and precision therapy (Xin-Yi et al., 2025a;b). As three-dimensional, patient-derived mini-tissues, tumor...