Frontiers in Cell and Developmental Biology最新文献

Ferroptosis is a novel form of regulated cell death. Compared with other types of cell death, it shows great differences in structure and biochemistry. This type of cell death is receiving increasing attention. For example, studies have found that it plays a key role in the development of neurodegenerative diseases underlying brain atrophy, such as Alzheimer's disease (AD). AD is a chronic and worsening neurodegenerative disease. It poses a serious threat to the health and quality of life of the elderly. The pathology of AD is mainly the presence of extracellular beta-amyloid (Aβ) plaques and intracellular tau-based nerve fiber entanglement (NFTs). Although there are a large number of studies and interventions for AD, so far, no clinical drugs have been found that can stop the pathological progression of AD or cure it. Currently, treatment strategies for this disease only focus on alleviating clinical symptoms and do not achieve slowing disease progression or curing it. Ferroptosis is gradually considered to play a key role in the occurrence and development of AD. Research based on the AD model confirms that neuronal ferroptosis can be inhibited through pharmacology to reverse cognitive disorders. In this review, we first describe the key molecular mechanisms of ferroptosis, and then discuss how these mechanisms operate and develop in AD. Then, we give a detailed introduction to the latest treatments for AD, including iron chelators, antioxidants, and specific ferroptosis inhibitors. What is noteworthy is that this article emphasizes the analysis of the mechanisms of iron metabolism disorders, as well as the introduction of new drugs for the prevention, rather than the alleviation of AD.

The cellular and molecular programs underlying neurogenesis are deeply conserved in metazoans. In vertebrates, neural progenitor and glial lineages converged within the astroglia lineage, which can alternate between stem cell activity and homeostatic states that support neuronal function. In mammals, astroglia migrated into the parenchyma, where they further diversified both between and within regions and specialized in homeostatic support, while only two restricted populations retained neurogenic activity in the ventricular-subventricular (V-SVZ) and subgranular zones. Nevertheless, parenchymal astroglia maintain a latent neurogenic potential that can be reactivated under specific conditions, engaging a program identical to that of niche astroglia. Despite this widespread potential, the regenerative capacity of the mammalian brain is highly reduced compared with non-mammalian vertebrates. The regionalization of the embryonic progenitors into domains of committed progenitors is preserved in adult vertebrates, but while non-mammalian vertebrates continue to generate the same neuron types, in mammals, periventricular domains constituting the V-SVZ converge to generate olfactory bulb interneurons. Cortical and striatal astrocytes also converge toward related neuronal identities, resembling a population of transient developmental neurons. Thus, when astroglia colonized the parenchyma, they carried the niche with them, but their neurogenic potential may have shifted from a reservoir for regeneration to one for plasticity. Paraphrasing Santiago Ramón y Cajal, it is for the science of the future to change, if possible, this harsh evolutionary choice.

Cell-cell communication coordinates signalling between cells to guide context-dependent cell fate decisions such as proliferation, differentiation, and lineage specification. Such communication mechanisms are poorly understood in regulating the stem cell states. In this study, we investigate how cell-cell communication regulates cell fate transitions in heterogeneous embryonic stem cell populations, with a particular focus on totipotent-like cells that resemble the two-cell stage embryo. Using single-cell RNA sequencing in combination with computational frameworks, we map ligand-receptor interactions and model downstream regulatory effects across various stem cell states. We functionally validate the predictions by selectively perturbing signalling pathways under specific culture conditions. Our data reveal the key roles of BMP and NODAL (TGF-β) signalling in mediating intercellular communication to shape stem cell identity and heterogeneity. These findings enhance our understanding of the signalling logic that governs early developmental cell fate decisions, providing new insights into stem cell biology with broad implications for regenerative medicine and developmental modelling.

Introduction: Single-cell RNA-sequencing analyses have revealed the existence of two distinct capillary cell populations in the human lung: general capillary cells (CAP1) and alveolar capillary cells (CAP2). Studies in mouse have shown that the splicing of Vegf-a evolves during embryonic development, creating a temporal pattern of expression for different isoforms, which contributes to the formation of pulmonary capillaries. Moreover, it was demonstrated that murine Vegf-a188 isoform promotes the emergence of CAP2 in vitro. Human homologs of these VEGF-A isoforms exist; however, their role in this process remains elusive. This study investigates the role of VEGF-A and its isoforms in the differentiation of lung capillaries during human prenatal development.

Methods: A cohort of human prenatal tissues, aged from the late pseudoglandular to early canalicular stages of development (10-20 weeks of gestation), was used to study the emergence of CAP2 markers (TBX2, SOSTDC1, EDNRB, HPGD, APLN) in correlation with the expression of the different VEGF-A isoforms (VEGF-A121, VEGF-A145, VEGF-A165, VEGF-A189).

Results: RT-qPCR analyses revealed a simultaneous expression of certain VEGF-A isoforms with several CAP2 markers, which peaked at around 18-20 weeks of gestation. Human prenatal lung explants were then treated with recombinant proteins of the different VEGF-A isoforms to study their impact on EC proliferation, as well as on the expression of CAP2 markers. While most of the isoforms did not impact EC proliferation, except for VEGF-A189 which downregulated it, almost all of them upregulated the expression of APLN, a major CAP2 marker. By using fluorescence in situ hybridization, we showed that this increase of expression was specific to the ECs. However, most of the isoforms induced a downregulation of EDNRB and HPGD. They also did not impact the expression of SOSTDC1 and TBX2.

Discussion: Our study shows that the different VEGF-A isoforms do not have the same effect on human lung capillary differentiation as those observed with their homologs in mice, highlighting the importance of studying this process in the human model. Moreover, while it demonstrated that VEGF-A isoforms can induce APLN expression in ECs, it also revealed that CAP2 differentiation is most likely a multifactorial process, not only involving VEGF-A.

Oral submucosal fibrosis (OSF) is a chronic and progressive fibrosis disease and causes sclerosis in oral mucosal tissue with a higher potential of malignant transformation. It is characterized by excessive production and deposition of extracellular matrix. The major behavioral cause of OSF is chewing areca nut, and the symptoms include severe burning sensation, ulceration, restricted mouth opening, and more. However, despite significant advancements in biochemical and molecular techniques in recent years, no specific and targeted antifibrotic treatment strategies have been approved, potentially due to the complicated molecular mechanism that initiates and drives the fibrotic events, which remains to be completely understood. In this review, we aimed to discuss the epidemiology, etiology, and risk factors associated with the OSF, with special emphasis on the recent developments such as the use of flavored areca nut, etc. Then we highlight the OSF pathogenesis with special emphasis on the role of TGF-b, epithelial-mesenchymal transition, and other processes such as dysregulation of collagen metabolism and angiogenesis. We also mentioned the role of hypoxia-induced pathogenesis, which recently has been more in focus. Next, apart from traditional diagnosis methods, i.e., clinical evaluation and histopathology, we also discussed newer techniques such as biomarkers present in serum, saliva, and tissue biopsies. Afterwards, we mention ongoing traditional and modern treatments in clinical settings, such as the use of natural compounds, anti-fibrotic agents, targeted therapy, and more. We also discussed the role of emerging new therapeutic targets and how targeting them can overcome the current limitations. Moving ahead, we discussed how next-generation sequencing and artificial intelligence have improved our understanding of OSF pathophysiology. We conclude with a discussion of future perspectives and potential ways for developing novel OSF treatment or management.

Introduction: Calcium and iron are essential bioelements regulating neuronal function and survival. Dysregulation of calcium signaling and iron homeostasis is implicated in Alzheimer's disease (AD), contributing to oxidative stress, synaptic dysfunction, and neurodegeneration. Previously, using in vitro cell-based models and transgenic mice, we demonstrated that CAMKK2, a calcium/calmodulin-dependent protein kinase, regulates iron transport via transferrin (TF) and transferrin receptor (TFRC). While excessive iron deposition is a hallmark of AD brains, the mechanisms underlying its dysregulation remain poorly understood. In a prior study of postmortem temporal cortex tissues, we showed that CAMKK2/TF/TFRC protein levels were significantly reduced in AD compared to cognitively normal (CN) individuals, and that increased iron accumulation in AD correlated with reduced TF/TFRC levels. This follow-up study aimed to assess CAMKK2/TF/TFRC protein levels in hippocampal tissues - an early site of AD pathology - and examine their relationship with tau (MAPT) aggregation in AD, Parkinson's disease (PD), and frontotemporal dementia (FTD).

Methods: Postmortem hippocampal tissues from 29 CN individuals and patients diagnosed with AD/FTD/PD (N = 73/7/9 respectively) were analyzed. CAMKK2/TF/TFRC/MAPT levels were quantified using Western blotting. Correlation analyses evaluated associations among these proteins and with age, sex, and postmortem interval (PMI). Isoelectric focusing (IEF) was used to assess post-translational modifications of CAMKK2 and TF.

Results: CAMKK2 and TF levels were significantly reduced in AD, FTD, and PD hippocampi compared to CN controls. TFRC reduction was specific to late onset AD, suggesting a later event. MAPT levels were significantly elevated in AD, with high molecular weight smears indicating tau aggregation. CAMKK2 and MAPT were positively correlated in CN but not in AD, indicating disease-specific disruption. TF and CAMKK2 were also positively correlated in CN but attenuated in AD. No significant changes in CAMKK2 or TF charge states were detected.

Discussion: CAMKK2 downregulation and impaired iron transport appear to be shared features across multiple neurodegenerative diseases, but their decoupling from tau pathology seems specific to AD. These findings position CAMKK2 as a molecular gatekeeper linking calcium signaling, iron metabolism, and tau aggregation. Future studies should focus on elucidating the mechanisms underlying CAMKK2 downregulation to better understand its role in AD pathogenesis.

Background: The effects of menstrual blood-derived mesenchymal stromal cell secretome (S-MenSC) on macrophage polarization remain unclear. This study studied the impact of secretomes from basal MenSCs (S-bMenSCs) and those preconditioned with IFNγ and TNFα (S-pMenSCs) on human monocytes and macrophages in vitro.

Methods: S-MenSCs were used to assess their effects on three stages of monocyte-derived cell maturation: i. monocyte differentiation; ii. polarization of monocyte-derived macrophages (MDMs) toward M1-like or M2-like phenotypes; and iii. reprogramming of pre-polarized M1 or M2 macrophages. Surface markers were analyzed by flow cytometry and cytokine gene expression by RT-qPCR. In addition, a proteomic profiling was performed to identify proteins involved in the observed effects.

Results: Our results confirmed the capacity of S-MenSCs of modulating innate immune response and in particular macrophage polarization. More concretely, the in vitro experiments showed that: i. both secretomes partly promoted monocyte differentiation into an M1-like phenotype; ii. during macrophage polarization, S-bMenSCs partially limited the shift to an M1 phenotype, whereas treatment with S-pMenSCs boosted it; and, iii. in the pre-polarized macrophages, S-bMenSCs reinforced M1 traits, whereas S-pMenSCs promote partial phenotype switching. Finally, proteomic analysis revealed significant differences in the composition of both secretomes, comprising key proteins associated with macrophage polarization.

Conclusion: These findings extend the knowledge on the immunomodulatory capacity of the S-MenSC, supporting that MenSCs, particularly when preconditioned, may play a significant role in regulating macrophage polarization, and, thus, modulating the inflammatory response.

Introduction: High-power microwave (HPM) exposure can produce biological effects in cells, but the specific characteristics and mechanisms of these effects in ocular tissues remain poorly defined. This study aimed to investigate the biological responses of human corneal epithelial cells (HCE-T) to 4.3 GHz HPM exposure, with a focus on moderate-dose effects.

Methods: HCE-T cells were exposed to 4.3 GHz HPM at average specific absorption rates (SARs) of 1.64, 3.28, and 8.2 W/kg. Cellular responses were evaluated by measuring cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and apoptosis at multiple time points. Transcriptomic analysis was performed to identify underlying molecular pathways.

Results: Moderate-dose exposure (3.28 W/kg) resulted in the most pronounced cellular effects, including early and significant ROS elevation, marked collapse of mitochondrial membrane potential, the highest apoptosis rate, and sustained inhibition of proliferation. Transcriptomic profiling showed strong suppression of the mTOR signaling pathway, upregulation of TSC2, and activation of Polycomb-mediated chromatin remodeling, suggestive of autophagy induction and irreversible cell cycle arrest. In contrast, low-dose exposure (1.64 W/kg) primarily activated DNA repair and adaptive pathways, while high-dose exposure (8.2 W/kg) predominantly disrupted metabolic and membrane signaling with a trend toward recovery.

Discussion: These findings demonstrate that moderate-dose 4.3 GHz HPM exposure induces a uniquely strong stress response in HCE-T cells, characterized by oxidative stress, mitochondrial dysfunction, and activation of stress-related signaling pathways. These results highlight the importance of considering specific exposure conditions in assessing HPM bioeffects and ocular safety.

Liquid-liquid phase separation (LLPS) is a crucial process that influences the spatial organization of cells. Dysregulation of this process can contribute to serious adverse outcomes, including neurodegenerative diseases, developmental disorders, and impaired immune responses. While various studies have explored how factors like physicochemical properties, molecular structures, and post-translational modifications (PTMs) affect the formation of condensates, current knowledge remains fragmented and lacks a cohesive framework. This review aims to systematically compile the principles regulating LLPS, focusing on the interplay between physico-chemical parameters, PTMs, and molecular sequence characteristics. Building on this foundation, we will also examine the significance of physiological phase separation and its connection to pathological phase transitions, such as the conversion from a liquid to a solid state.