Multifunctional fluorescent molecules with organelle-targeting capabilities and high phototherapeutic efficacy have been regarded as promising materials for real-time tumor diagnosis and non-invasive treatment in the clinic. In this study, we developed a near-infrared (NIR) emissive photosensitizer, DACNPy+, which exhibits mitochondrial targeting ability, laser-triggered type I and type II reactive oxygen species (ROS) generation, and aggregation-induced emission (AIE) properties. After being encapsulated by platelet membranes and liposomal membranes, DACNPy+ was formulated into biomimetic nanoparticles termed DFL, which demonstrated remarkable tumor-targeting capabilities and in vivo long-term tumor tracking. Upon laser irradiation, DFL disintegrated within the lysosomes of cancer cells, releasing DACNPy+ and target mitochondria, thereby achieving mitochondria-targeted photodynamic therapy (PDT). This process resulted in mitochondrial dysfunction and disruption of cellular homeostasis. Notably, the highly efficient PDT successfully sensitized radiotherapy, forming a synergistic therapeutic system with "1 + 1 > 2" effect for effective killing of cancer stem cells and tumor ablation. This work offers a novel alternative to traditional clinical theranostics strategies.

Littoral cell angioma (LCA) is a rare primary splenic vascular neoplasm originating from the littoral cells of the reticuloendothelial system. Splenectomy is the accepted mode of definitive diagnosis and treatment. With fewer than 200 reported cases, LCA remains poorly understood. Herein, we provide an enhanced insight into its histology and highlight the role of nuclear imaging in aiding LCA diagnosis. A 63-year-old female with a history of stage II multiple myeloma (MM) and rheumatoid arthritis was incidentally found to have a slowly enlarging splenic mass over a 6-year period. Given her candidacy for autologous hematopoietic stem cell transplantation for MM, further evaluation of the splenic lesion was pursued using nuclear medicine (NM) liver-spleen scan, which revealed a photopenic region consistent with a benign hemorrhagic mass. Subsequent splenectomy and histopathological analysis confirmed the diagnosis of LCA, with immunohistochemistry demonstrating CD68+ and CD31+ expression, highlighting LCA's unique dual histiocytic and endothelial character. This case highlights the diagnostic challenge posed by LCA due to its nonspecific clinical presentation and imaging findings. While splenectomy remains the gold standard for diagnosis, our findings suggest that NM liver-spleen scan imaging may aid in differentiating LCA from malignant splenic masses preoperatively. Furthermore, this case reinforces the association between LCA and hematologic malignancies, supporting the hypothesis that immune dysregulation may play a role in its pathogenesis. This underscores the importance of considering LCA in the differential diagnosis of splenic masses, particularly in cases involving a history of malignancy and/or immune system abnormalities.

Chronic myelomonocytic leukaemias (CMML) are myeloid neoplasms characterized by a sustained increase in monocyte counts in the peripheral blood, accompanied by dysplasia, abnormal proliferation, chromosomal anomalies and somatic mutations of haematopoietic cells. More than 95% of CMML patients harbour somatic mutations. CMML must be separated from other myeloid neoplasms and reactive monocytosis. The clinical presentation of CMML varies, but most frequently shows signs and symptoms of haematopoietic insufficiency or myeloproliferation. Robust instruments are available for assessing the prognosis of patients with CMML, such as the CMML-specific prognostic scoring system molecular. Treatment options for patients with CMML are still inadequate and generally less effective than those for other myeloid neoplasms. The only curative approach is allogeneic stem cell transplantation. This article explains essential aspects of CMML pathophysiology and provides an overview of diagnostic considerations, prognostic assessment and therapeutic options.

This study revealed that adipose-derived mesenchymal stem cell-facilitated ciprofloxacin therapy effectively protected the kidney parenchyma and functional integrity against acute pyelonephritis damage in rodents. In vitro studies revealed that adipose-derived mesenchymal stem cell-derived media significantly suppressed the number of bacterial colony formation units (P < 0.0001). Additionally, the combination of adipose-derived mesenchymal stem cell-ciprofloxacin was superior to either treatment alone on suppressing lipopolysaccharide-induced inflammatory reactions in macrophages and peripheral blood-derived mononuclear cells and attenuated lipopolysaccharide-induced apoptosis/DNA damage in uroepithelial cells (Simian virus Hydrologic Unit Code 1) (all P < 0.0001). Sprague-Dawley rats were categorized into groups 1 (sham-control)/2 (acute pyelonephritis)/3 (acute pyelonephritis-ciprofloxacin)/4 (acute pyelonephritis- adipose-derived mesenchymal stem cell)/5 (acute pyelonephritis-adipose-derived mesenchymal stem cell-ciprofloxacin), and kidneys were harvested by day 5 after acute pyelonephritis induction. The in vivo results revealed that the day-5 mortality rate and creatinine levels at days 2 and 5 were significantly greater in group 2 than in groups 1 and 5 (P = 0.01), whereas the kidney injury score and inflammatory cell infiltration in the kidney were highest in group 2, lowest in group 1, and significantly greater in groups 3 and 4 than in group 5; however, there was no difference between groups 3 and 4 (all P < 0.0001). The upstream inflammatory signaling (toll-like receptor-4, myeloid differentiation primary response 88, tumor necrosis factor receptor associated factor 6 and nuclear factor-kappa B) and downstream inflammatory signaling (tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6) biomarkers exhibited identical patterns of kidney injury scores among the groups (all P < 0.0001). The results of the present study showed that adipose-derived mesenchymal stem cell-facilitated ciprofloxacin reduced inflammatory signaling-induced kidney parenchymal damage and acute pyelonephritis-induced mortality and preserved kidney function.

Adult glioblastoma (GBM) is a highly malignant tumor with a poor prognosis and high mortality rate. As versatile 3D culture systems in vitro, organoid models are emerging as a promising new tool for GBM research and combat. However, Matrigel, the most used extracellular matrix, is animal-derived with a complex composition and significant batch-to-batch variability, requiring further optimization for GBM organoid construction. Hydrogels, high-affinity polymers, have been widely employed in organoid construction for their customizable properties. In the present study, we selected and tested several commonly used hydrogel materials-hyaluronic acid methacryloyl (HAMA), chitosan methacryloyl (CSMA), and gelatin methacryloyl (GelMA)-for the construction of GBM organoids. To address the limitations of a single Matrigel, we combined Matrigel with different hydrogels and found that hydrogels influenced glioblastoma stem cells and organoid formation in distinct ways. Matrigel-HAMA (MH) promoted the formation of independent spherical clones but with a significantly lower glioblastoma stem cell (GSC) proliferation rate. GelMA-HAMA(GH) could replace Matrigel preserving the characteristics and proliferative capacity of GSCs and supported the formation of more compact spherical clones than MH did. Further experimentation with ribosomal inhibitor CX5461 and CX5461 + IFNβ indicated that GH-based GBM organoid model constituted an efficient system for GBM drug testing, discovery, and precision medicine.

&lt;b&gt;Background and Objective:&lt;/b&gt; Diabetic foot ulcers (DFUs) remain a critical clinical problem and stem cell-derived secretome reared under hypoxic conditions has been shown to play a significant role in tissue repair via immunomodulation. This study aimed to evaluate the secretome of human mesenchymal stem cell gel (SH-MSC gel) in DFU patients with grades 2 and 3 through reduced wound volume and modulation of CD163 and NF-κB p50 mRNA expression. &lt;b&gt;Materials and Methods:&lt;/b&gt; A prospective, randomized controlled clinical trial involved 16 DFU patients with grades 2 and 3. Participants received either a placebo gel or an intervention gel containing secretome from Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) cultured under hypoxic conditions. All patients received standard wound care. Primary outcomes included changes in wound volume and expression levels of CD163 and NF-κB p50 mRNA in wound tissue, assessed using quantitative PCR. The Shapiro-Wilk test assessed normality and for normally distributed data, paired t-tests (within-group) and unpaired t-tests (between-group) were used. One-way ANOVA compared means across groups, while the Kruskal-Wallis test followed by &lt;i&gt;post hoc&lt;/i&gt; analysis was employed for non-parametric data (p<0.05). Statistical analysis was performed using GraphPad Prism 10. &lt;b&gt;Results:&lt;/b&gt; Baseline characteristics of participants did not show significant differences between the groups. Treatment with SH-MSC gel significantly enhanced wound healing compared to the placebo group, evidenced by a marked reduction in wound volume after 7 days (95% CI (0.467 to 1.18), p<0.001). The CD163 mRNA expression significantly increased in the SH-MSC gel group post-treatment (95% CI (-2.20 to -1.11), p<0.001), while NF-κB p50 mRNA expression significantly decreased (95% CI (0.349 to 0.688), p<0.001). &lt;b&gt;Conclusion:&lt;/b&gt; The clinical trial results suggested that SH-MSC gel effectively improves wound healing in DFUs. Further research is warranted to explore additional inflammatory markers to better understand DFU treatment.

The expanding worldwide population has increased the meat demand, prompting efforts to find alternatives. A promising approach is the cultivation of animal cells on edible biomaterials for cultured meat production. However, those biomaterials face challenges in their mechanical properties, cytotoxicity, and ability to support optimal cell growth. In this study, we focused on optimizing plant-edible hydrogels as a 3D environment for the growth of bovine myoblast cells. We prepared alginate hydrogel (A) to be enriched with soybean protein (S.A) and tapioca starch (T.A), developing Group 1 hydrogels. Aiming to enhance their elasticity, xanthan gum (XG) was incorporated into Group 1, generating alginate-xanthan gum (Ax), soybean-alginate-xanthan gum (S.Ax), and tapioca-alginate-xanthan gum (T.Ax) Group 2 hydrogels. Both groups were assessed for physical and chemical analyses, rheological testing, cell viability assays, immunofluorescence staining, gene expression, and flavor profiling. Our findings showed that all hydrogels maintained their crosslinking for up to 7 days except Ax and T.Ax, which showed degradation of 57.39% and 36.03%, respectively. Both groups represented swelling characteristics, porosity, protein adsorption, and cooking capabilities. Moreover, A and S.A exhibited viscous properties with slow stress relaxation, whereas T.A displayed rapid relaxation and viscoelastic behavior. Successfully, Group 2 demonstrated faster stress relaxation and sufficient elasticity. Bovine myoblast cells showed no significant toxicity and could proliferate, expressing paired box 7 (PAX-7) marker in both groups. At the differentiation stage, desmin expression indicated the intermediate differentiation of the muscle cells for up to 7 days in both groups. Besides S.A and S.Ax scaffolds exhibit the nearest metabolic similarity to beef among the plant-based scaffolds. These findings suggest that the hydrogels enriched with protein and starch holding the potential for culture meat production.

Bioactive cytokines such as vascular endothelial growth factor (VEGF) and Activin A are critical for the differentiation of stem cells into vascular endothelial cells and cardiomyocytes. However, production of the cytokines using conventional Escherichia coli or mammalian cell expression systems carries risks of immunogenicity and viral contamination. In this study, we developed a VEGF and Activin A plant expression system and demonstrated that plant-expressed VEGF and Activin A are as active as their commercial counterparts. We also showed that plant-expressed VEGF and Activin A are as efficient as human recombinant counterparts in inducing endothelial cells and cardiomyocytes from human pluripotent stem cells. These results suggest that plant-expressed VEGF and Activin A are promising alternatives for the safe and efficient production of cardiac cells, specifically cardiomyocytes and endothelial cells, for stem cell-based regenerative medicine.

Flt3 gene expression is known to occur at a specific development stage of hematopoiesis in mice. Flt3-Cre reporter mice have been utilized in lineage tracing studies. This review systematically evaluates different Flt3-Cre reporter constructs, focusing on labeling efficiency and consistency with endogenous Flt3 expression patterns. We discuss the strengths and limitations associated with employing marker gene expression in lineage tracing. Furthermore, this lineage tracing strategy is compared with clonal tracing strategies such as barcoding and single-cell transplantation. Finally, we propose comparing hematopoietic stem cells identified by barcoding with those identified by transplantation to know the relationship between HSCs in non-stress and stress conditions. HIGHLIGHTS: • Flt3-Cre reporter mice are excellent models to understand hematopoiesis but may not necessarily reflect endogenous expression of Flt3. • The labeling efficiency significantly differs among the Flt3-Cre reporter mice.

With advancements in radiotherapy technologies, the detrimental effects of ionizing radiation on biological systems, particularly the hematopoietic system, have caused significant concern. N6-methyladenosine (m6A), the most pervasive representative of post-transcriptional modifications, plays critical roles in diverse biological events. Non-coding RNA comprises the vast majority of the human genome. This study aimed to explore the role of long non-coding RNA (lncRNA) m6A modification in γ-ray irradiation-induced hematopoietic injury. By using mouse models, it was found that γ-radiation rapidly damaged hematopoietic bone marrow cells (BMCs), triggering apoptosis, oxidative stress and DNA damage, along with up-regulation of m6A Reader proteins. We revealed the time-conditioned landscape of lncRNA m6A methylome of BMCs in the short term after radiation and found that a dynamic "change-then-recover" trend involved. LncRNA Snhg15 was identified as a key regulator through integration analysis of the methylome and transcriptome data. Its m6A modification was closely related to progression of radiation injury in BMCs. Further research demonstrated that the novel m6A Reader LRPPRC could interact with the modification site of Snhg15, stabilize Snhg15 and promote its expression, thereby exacerbating radiation-induced injury to BMCs both in vitro and in vivo. Knockdown of Lrpprc or Snhg15 could alleviate the radiation injury to the hematopoietic system. Additionally, the LRPPRC-Snhg15 axis was involved in the radio-protective efficacy of gut microbiota-derived valeric acid. These findings uncover a novel mechanism by which m6A-modified lncRNA Snhg15 is stabilized by LRPPRC modulates γ-irradiation-induced hematopoietic injury, providing potential therapeutic targets for the prevention and treatment of radiation injuries.

Adenosine deaminase type 2 deficiency (DADA2) is caused by bi-allelic loss-of-function mutations in ADA2. While anti-TNF therapy is effective for the autoinflamatory and vasculitic components of the disease it does not correct marrow failure or immunodeficiency. Allogeneic stem cell transplantation (HSCT) offers a potential cure but is limited by challenges such as graft-versus-host-disease and donor availability. We previously demonstrated that lentiviral-mediated ADA2 gene therapy could restore ADA2 enzyme activity in patient-derived cells, correct macrophage inflammatory activation and reduce endothelial activation in vitro. Here, we evaluated the biodistribution and engraftment potential of lentivirally transduced healthy donor and patient-derived haematopoietic stem cells (HSC) in vivo using a humanised NBSGW mouse model. Transduced healthy HSC retained multilineage differentiation and engraftment capacity, without functional impairment. PCR analysis confirmed the absence of viral integration in non-haematopoietic organs, and histology showed no abnormal tissue changes, underscoring the safety and precision of this approach. In DADA2 patient-derived HSC, ADA2 transduction restored protein expression and enzyme activity, supporting improved cellular function and enhanced engraftment potential. These findings provide a strong foundation for advancing ADA2 gene therapy as a therapeutic strategy for DADA2, bringing it closer to clinical application.

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. The FA cellular phenotype is marked by a defective DNA double-strand break repair. Alongside this defect, FA cells exhibit mitochondrial dysfunction and redox unbalance. In addition, FA cells display an altered microRNA profile, including miR-29a-3p, which plays a crucial role in hematopoiesis by supporting the self-renewal, lineage commitment, and differentiation of hematopoietic stem cells (HSCs). In this study, we demonstrate that miR-29a-3p is downregulated in lymphoblasts and fibroblasts mutated for the FANC-A gene, leading to hyperactivation of PI3K/AKT pathway due to the overexpression of its target genes, FOXO3, SGK1, and IGF1, and resulting in altered mitochondrial metabolism and insufficient antioxidant response. In addition, miR-29a-3p downregulation appears associated with hyperactivation of the TGF-β signal. By contrast, FA cells transfected with miR-29a-3p show an improvement in mitochondrial metabolism, oxidative stress response, and DNA damage accumulation, by inhibiting the PI3K/AKT pathway and modulating the TGF-β pathway through a feedback mechanism. In conclusion, our results highlight the central role of miR-29a-3p in FA cells, suggesting that it is a promising molecular target to address several mechanisms based on FA pathogenesis.

Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.

The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque (Macaca fascicularis) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.

Objective:To investigate the impact of Waardenburg syndrome（WS） -associated Sox10 p.S100Rfs*9 mutation on inner ear function and its mechanism in noise-induced hearing impairment. Methods:A mice model carrying the Sox10 p.S100Rfs*9 mutation was established using CRISPR-Cas9 gene editing technology. Auditory phenotypes were assessed under baseline conditions and after noise exposure（96 dB SPL, 2 hours）. Auditory brainstem response（ABR） tests were performed to evaluate hearing function, combined with immunofluorescence staining of cochlear basilar membrane whole-mounts to observe hair cells and ribbon synapses. Transcriptome sequencing was conducted to analyze molecular mechanisms. Results:Sox10 p.S100Rfs*9 heterozygous mice exhibited normal hearing thresholds with characteristic ventral pigmentation abnormalities under baseline conditions. Following noise exposure, mutant mice showed significantly higher ABR thresholds at 24 000 Hz compared to wild-type controls（[60.00±6.12]vs[48.13±4.28]dB SPL, P<0.000 1）, and a significant reduction in ribbon synapses（CtBP2-positive puncta） in the basal turn（[55.0±2.3]vs[64.8±3.3]per inner hair cell, P=0.006 6）, while hair cell morphology and number remained intact. Transcriptome analysis revealed altered expression of genes involved in immune regulation, membrane structures, ion channels, and neuroactive ligand-receptor interactions. Conclusion:The Sox10 p.S100Rfs*9 mutation does not alter baseline hearing function but significantly increases inner ear susceptibility to noise damage, primarily manifested as enhanced ribbon synapse vulnerability, especially in high-frequency regions. This gene-environment interaction reveals that Sox10 haploinsufficiency may compromise noise tolerance by affecting synaptic stability and inner ear protective mechanisms. These findings provide new perspectives on the phenotypic heterogeneity in WS patients and theoretical basis for individualized noise protection strategies for patients carrying SOX10 mutations.

In patients with non-muscle invasive bladder cancer, the standard immunotherapy involves intravesical Bacillus Calmette-Guérin (BCG). However, its success requires repeated doses, and ∼50% of patients do not benefit. Using a preclinical orthotopic bladder cancer model, we found that a single intravesical dose of combined BCG and β-glucan immunotherapy eradicated aggressive tumors, resulting in 100% survival. Through single-cell transcriptomic/epigenomic analysis, flow cytometry, and intravital imaging, we show that BCG and β-glucan reprogrammed hematopoietic stem and progenitor cells with imprinting in innate immune cells, particularly neutrophils. Reprogrammed neutrophils exhibited increased reactive oxygen species (ROS) production and infiltration into the tumor core, reducing tumor vascularization and growth. The tumor microenvironment can convert neutrophils into protumor cells; BCG and β-glucan prevented this conversion, promoting sustained antitumoral activity. These findings support β-glucan as a safe, effective adjuvant to enhance BCG immunotherapy in bladder cancer and other solid tumors.

Increased use of titanium (Ti) and its alloys in implant manufacture is due to their biocompatibility and mechanical properties. However, their biological inertness must be considered. Surface modifications are essential for accelerating osteointegration and bone healing. Herein, calcium phosphate (brushite, CaHPO4.2H2O) was deposited on an additive-manufactured Ti6Al4V alloy substrate by electrochemical deposition technique. X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy confirmed the presence of brushite on the Ti6Al4V substrate. Scanning electron microscopy (SEM) and cross-section micrograph observations confirmed the homogeneity of the coating's coverage, composed of microcrystals approximately 1-3 μm thick and 10 μm long. EDXS analysis revealed pure brushite stoichiometric values, and tensile adhesion tests demonstrated good adhesion to the substrate. The coating demonstrated a rapid dissolution in MES (pH 5.5) and HEPES (pH 7.4) buffer solutions. Human mesenchymal stem cells (hMSCs) cultured with brushite-coated Ti alloy in osteogenic medium showed normal proliferation and increased biomineralization with SP7 mRNA upregulation. To explore how Brushite improved bone healing, we performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics analysis of hMSCs secretome from co-cultures with Ti alloys, for 7 and 14 days. Brushite promoted secretion of osteogenic and bone matrix factors. Factors involved in blood clotting (e.g. FII, FV, FX), mitochondrial biogenesis, energy metabolism (e.g. mitochondrial ATP synthase), lipid metabolism (e.g. apolipoproteins) and cellular stress response (e.g. heat shock proteins) were enriched. Increased specific chromatin-related proteins suggest chromatin's role in enhancing bone regeneration. Secretome profiling showed the unique role of brushite Ti alloys in bone regeneration, encouraging further study.

This study aimed to assess the impact of human amniotic epithelial stem cells-conditioned medium (hAECs-CM) on the healing of burn wounds and the reduction of inflammation in a mouse model of deep second degree burns. The findings indicated that hAECs-CM markedly enhanced the primary metrics of burn wound healing within a brief duration of 14 days. The rate of wound healing was substantially greater than that of the control group following 21 days of treatment with daily administration of hAECs-CM. The CD31 concentration was markedly elevated in burn tissues treated with hAECs-CM, whereas the myeloperoxidase (MPO) level was reduced. Simultaneously, the antibacterial efficacy of hAECs-CM was assessed, indicating that hAECs-CM may alleviate infections generated by burns. HE and Masson staining results indicated that the treatment markedly diminished inflammation and collagen deposition relative to the model group, while both connective tissue and neovascularization were enhanced in the dermis of the hAECs-CM-BI group. In conclusion, the utilization of hAECs-CM may expedite the wound healing process and mitigate burn infections.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions marked by severe inflammation, oxidative stress, and disruption of the alveolar-capillary barrier. The limited efficacy of current therapies highlights the urgent need for novel approaches targeting key pathological mechanisms. Excessive generation of reactive oxygen species (ROS) and resulting cascade of amplified inflammatory responses is a key factor in the progression of ALI/ARDS. Herein, we successfully regulated the immune homeostasis-mediated inflammatory response to alleviate ALI based on the inhalable CoAl-LDH (CAL) nanosheets with good biocompatibility and exciting ROS scavenging capabilities. Transcriptomic analysis combined with single-cell sequencing reanalysis revealed, for the first time, that CAL binds to damaged DNA and effectively inhibits the cGAS-STING pathway-mediated inflammatory response. Furthermore, incorporating the cGAS-STING pathway inhibitor C176 into CAL greatly enhanced this inhibition to reduce inflammation and mitigate the lung tissue damage. These results suggest that regulation of immune homeostasis with multifunctional nanosheets may be a promising paradigm for managing ALI/ARDS in clinical settings.

Aging results in a decline in cellular and molecular functions. One of the hallmarks of aging is stem cell exhaustion which impacts self-renewal and differentiation. We employ the Drosophila larval lymph gland (LG) to investigate the impact of genetic perturbation of cellular homeostasis on hematopoiesis. LG consists of a Posterior Signalling Center (PSC) - a stem cell niche that maintains Medullary Zone (MZ) prohemocytes whereas Cortical Zone (CZ) consists of differentiated hemocytes. We employ over-activation of Toll or Imd pathway for disrupting cellular homeostasis whereas over-express Foxo or Atg8 for balancing it. Genetic perturbation of cellular homeostasis displays hallmarks of aging. Induction of Toll or Imd pathway locally and systemically leads to a decreased niche size and increased differentiation whereas Foxo or Atg8 over-expression shows an opposite trend. We show that the Integrated Stress Response (ISR) pathway is induced upon Toll or Imd over-activation and LG's with ISR perturbation show increased hemocyte differentiation. Genetic epistasis shows that ectopic over-expression of ISR components upon Imd activation can rescue hematopoietic defects. Overall, our study explores how genetic perturbation of cellular homeostasis can impact hematopoiesis. Our research has implications in understanding how abrogation of cellular homeostatic mechanisms may lead to onset of malignancies.