This study aimed to investigate the effects and underlying mechanisms of compressive force on the osteogenic differentiation of human dental follicle stem cells (DFSCs) and to explore its potential role in orthodontically induced inflammatory root resorption (OIIRR). Human DFSCs (hDFSCs) were subjected to a compressive force of 2 g/cm2. Western blot and quantitative real-time polymerase chain reaction were used to quantify the expression levels of biglycan (BGN), Runt related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and components of the bone morphogenetic protein (BMP)2/Smad1 signaling pathway in hDFSCs. To elucidate the regulatory role of the BGN/BMP2/Smad1 signaling pathway, a BGN overexpression plasmid and a BMP signaling activator were utilized. In addition, a mouse OIIRR model was established to determine the involvement of the BGN/BMP2/Smad1 signaling axis in vivo. Under compressive force, the mRNA and protein expression levels of ALP, RUNX2, and components of the BGN/BMP2/Smad1 signaling pathway were downregulated. Overexpression of BGN significantly upregulated BMP2 and phosphorylated Smad1 expression (P < 0.05) and enhanced the osteogenic differentiation of hDFSCs. Furthermore, activation of the BMP2/Smad1 signaling pathway using sb4 also reversed the compressive force-induced decline in osteogenic differentiation of hDFSCs. In vivo, the expression levels of the BGN/BMP2/Smad1 signaling axis and the osteogenic markers were significantly reduced on the compressive side of periodontal tissue compared with the control group (P < 0.01). BGN plays a crucial role in the osteogenic differentiation of hDFSCs under compressive force via the BMP2/Smad1 signaling axis and may contribute to the occurrence of OIIRR in mice.

Elevated succinate accumulation has been demonstrated to be associated with metabolic and inflammatory disorders. Our previous study revealed that adipose-derived stem cells (ADSC) from obese individuals exhibit high succinate, reduced biological activity, and mitochondrial dysfunction. However, the precise role of succinate in these processes remains unclear. Here, we investigated the effects of excess succinate on cellular biological activity, immunomodulatory capacity, and mitochondrial function of ADSC. We found that elevated succinate levels in ADSC decreased proliferation and differentiation potential, while promoting M1 macrophage polarization. Furthermore, succinate accumulation impaired mitochondrial biogenesis and metabolism, increasing in reactive oxygen species (ROS) production and inflammatory responses. Transcriptome sequencing analysis further confirmed that succinate upregulated inflammatory pathways, suppressed mitochondrial biogenesis and metabolism, and enhanced cellular apoptosis and senescence, accompanied by reduced DNA replication and repair. Overall, these findings imply that succinate accumulation in ADSC triggers inflammatory response and mitochondrial dysfunction, potentially contributing to a decline of cellular biological activity. Targeting succinate may offer therapeutic potential for metabolic disorders.

Stem cells are located in a well-structured and specialized microenvironment called the niche. The niche provides signaling molecules to control the survival, self-renewal, and differentiation of stem cells. As tissues generally contain different types of stem cells, it is important to understand how these stem cells are coordinately regulated by various signaling pathways. The Drosophila testis niche serves as an excellent model for studying such processes, because it harbors 2 types of stem cells, germline stem cells and somatic cyst stem cells. In this review, we summarize the roles of key signaling pathways in stem cell maintenance and differentiation in the Drosophila testis.

The loss of the intrinsic "mechano-electro-biochemical" cascade effect in critical-sized bone defects (CSBDs) impedes the bone self-healing process. Traditional strategies cannot provide bionic electrical output, thereby failing to sufficiently activate the "mechano-electro-biochemical" cascade effect in situ and limiting the repair efficiency of CSBDs. Here, a bionic, self-adhesive, and biodegradable triboelectric nanogenerator (TENG) called PPCs-TENG using silk-fibroin-derived peptide (Cs)-grafted polydopamine-polyacrylamide (PPCs) as the electrode layer is fabricated. It provides bionic electrical stimulation (bio-ES) in response to the host's motion status. It reestablishes the resting potential during host rest and generates real-time biofeedback action potential during host movement. Further, it activates the "mechano-electro-biochemical" cascade effect for accelerating the repair of CSBDs. The bio-ES generated from PPCs-TENG enriches extracellular osteogenesis-related biochemical factors at the CSBD site. It also activates the intracellular mechanosensitive protein Piezo1, thereby promoting calcium signaling and intracellular mechano-transduction pathways. This activation enhances the proliferation and migration of bone marrow stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs), and promotes osteogenic differentiation in BMSCs and angiogenesis in HUVECs. In vivo tests demonstrate that PPCs-TENG significantly accelerates the repair of CSBDs in situ.

Peri-bone fibroblasts play a crucial role in regulating bone regeneration during early fracture healing. Inspired by the synergy between osteoblasts and fibroblasts at fracture sites, a biomimetic three-dimensional (3D) indirect co-culture system is developed, comprising a 3D scaffold and co-cultured cells. To mimic cellular interactions in the fracture healing zone, the scaffold features an inner-outer ring structure with communication channels that support indirect cell co-culture. This setup provides fibroblasts and osteoblasts with a 3D culture environment resembling the in vivo extracellular matrix, enhancing intercellular signaling while minimizing risks of direct contact. Mechanically tunable bioinks are formulated by incorporating hyaluronic acid methacrylate (HAMA) hydrogel into gelatin methacryloyl (GelMA) hydrogel to construct the scaffold. The optimal co-culture ratio is established in vitro, where fibroblasts are found to regulate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via zinc ion transport mechanisms. In vivo validations are conducted, including ectopic bone formation in nude mice and bone regeneration in rat cranial defect and tooth extraction socket models. This 3D indirect co-culture system enhances osteogenesis by promoting functional fibroblast-osteoblast interactions, offering a novel platform for co-culture studies and a promising strategy for clinical bone regeneration applications.

The small intestine is essential for digestion, nutrient absorption, immune regulation, and microbial balance. Its epithelial lining, containing specialized cells like Paneth and tuft cells, is crucial for maintaining intestinal homeostasis. Paneth cells produce antimicrobial peptides and growth factors that support microbial regulation and intestinal stem cells, while tuft cells act as chemosensors, detecting environmental changes and modulating immune responses. Along with immune cells such as intraepithelial lymphocytes, innate lymphoid cells, T cells, and macrophages, they form a strong defense system that protects the epithelial barrier. Disruptions in this balance contribute to chronic inflammation, microbial dysbiosis, and compromised barrier function-key features of inflammatory bowel disease, celiac disease, and metabolic syndromes. Furthermore, dysfunctions in the small intestine and immune cells are linked to systemic diseases like obesity, diabetes, and autoimmune disorders. Recent research highlights promising therapeutic strategies, including modulation of epithelial and immune cell functions, probiotics, and gene editing to restore gut health and address systemic effects. This review emphasizes the pivotal roles of small intestinal epithelia and immune cells in maintaining intestinal homeostasis, their involvement in disease development, and emerging treatments for intestinal and systemic disorders.

In this paper, we explore several fundamental theoretical issues in cell-based neural architecture search, including whether different architectures in search space are equally important in terms of the minimal training loss they can achieve, and whether an optimal cell found by architecture search is still optimal when using it in a cell stack. We model the directed acyclic graph (DAG) of a cell as a stem path plus multiple bypass edges. For single cells, we prove that the training loss is always decreased or at least maintained if skip connections are added into bypass edges in a greedy order and learnable operations are added into bypass edges in any order. We also prove that for some architectures with special weights, a learnable operation is worse than a skip connection in the sense that when adding them separately in the same bypass, a learnable operation will lead to a architecture with higher or equal training loss. Then, when stacking multiple identical cells during architecture evaluation, we prove that an optimal cell structure formed by adding bypass edges greedily will yield an optimal cell stack. These theoretical results are verified with experimental results on NAS-BENCH-201 dataset. Finally, when additional metrics such as network size are taken into account, we design examples to demonstrate that an optimal cell obtained by architecture search may be not optimal again in cell stack, and allowing non-tied cell structures in a cell stack may produce better result. These theoretical results increase our understanding of search space and partly justify the cell-based architecture search paradigm.

Acute radiation-induced dermatitis refers to skin lesions that usually appear within 90 days of the start of radiotherapy. Although various treatments are available, none have proven fully effective. Exosomes produced by adipose-derived stem cells play crucial roles in enhancing cell regeneration, promoting angiogenesis, regulating inflammation and remodeling the extracellular matrix. Hyaluronic acid, a major extracellular matrix component, is synthesized by hyaluronic acid synthase, with hyaluronic acid synthase 1 being particularly critical for skin repair. This study aimed to investigate whether exosomes derived from adipose-derived stem cells can protect against radiation-induced acute skin damage and to elucidate the underlying mechanisms involving hyaluronic acid synthase 1.

The increasing prevalence of Diabetes Mellitus (DM) correlates with a rising incidence of Diabetic Kidney Disease (DKD). DKD, a multifactorial condition, is characterized by activation of the renin-angiotensin-aldosterone system (RAAS), with angiotensin II playing a significant role in podocyte injury. While conventional treatments show potential in mitigating DKD progression, a combination of strategies is required to both impede its development and repair damaged structures.

The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance.

Despite the natural ability of bone repair, its limitations have led to advanced organic-inorganic-based biomimetic scaffolds and sustained drug release approaches. Particularly, dexamethasone (DEX), a widely used synthetic glucocorticoid, has been shown to increase the expression of bone-related genes during the osteogenesis process. This study aims to develop a hybrid 3D-printed scaffold for controlled delivery of dexamethasone. Hence, hybrid scaffolds were fabricated using a layer-by-layer 3D-printing of combined materials comprising polycaprolactone (PCL)-nanohydroxyapatite (nHA) composite, and DEX-loaded PCL microparticles embedded in the alginate-gelatin hydrogel. Encapsulation efficiency, loading capacity, and in vitro kinetics of DEX release were evaluated. Osteogenic differentiation of human endometrial mesenchymal stem cells (hEnMSCs) on DEX-loaded hybrid scaffolds was assessed by evaluating osteogenic gene expression levels (collagen I, osteonectin, RUNX2), alkaline phosphatase (ALP) activity, and scaffold mineralization. The hybrid scaffolds exhibited favorable morphology, mechanical-properties, biocompatibility, and biodegradability, enhancing osteogenesis of hEnMSCs. DEX-loaded PCL microparticles within hybrid scaffolds exhibited a controlled release pattern and promoted osteogenic differentiation during the sustained release period through a significant increase in osteonectin and COL1A1 expression. Also, increased mineralization was demonstrated by SEM and alizarin red staining. This study proposes that drug-loaded 3D-printed hybrid organic-inorganic nanocomposite scaffolds are promising for advanced bone tissue engineering applications.

Mitochondria are traditionally known as the cells' powerhouses; however, their roles go far beyond energy suppliers. They are involved in intracellular signaling and thus play a crucial role in shaping cells' destiny and functionality, including immune cells. Mitochondria can be actively exchanged between immune and non-immune cells via mechanisms such as nanotubes and extracellular vesicles. The mitochondria transfer from immune cells to different cells is associated with physiological and pathological processes, including inflammatory disorders, cardiovascular diseases, diabetes, and cancer. On the other hand, mitochondrial transfer from mesenchymal stem cells, bone marrow-derived stem cells, and adipocytes to immune cells significantly affects their functions. Mitochondrial transfer can prevent exhaustion/senescence in immune cells through intracellular signaling pathways and metabolic reprogramming. Thus, it is emerging as a promising therapeutic strategy for immune system diseases, especially those involving inflammation and autoimmune components. Transferring healthy mitochondria into damaged or dysfunctional cells can restore mitochondrial function, which is crucial for cellular energy production, immune regulation, and inflammation control. Also, mitochondrial transfer may enhance the potential of current therapeutic immune cell-based therapies such as CAR-T cell therapy.

Umbilical Cord-derived Mesenchymal Stromal Cells (UC-MSCs) display high immunoregulatory properties, offering new perspectives to treat severe immune and inflammatory diseases. However, the heterogeneity of their biological properties remains a challenge to predict clinical response. The aim of our study is to evaluate a strategy based on the constitution of a pool of several pre-selected donors to reduce the biological variability of UC-MSCs and improve their immunomodulatory properties.

Stem cells from human exfoliated deciduous teeth (SHED) can differentiate into functioning neurons and oligodendrocytes and exhibit immunomodulatory and regenerative properties. This study aimed to compare the growth and size of SHED cultured in human platelet lysate (hPL) and fetal bovine serum (FBS), with the goal of evaluating their potential use in regenerative medicine.

Notch signaling is a widely preserved communication pathway that supports essential cellular functions by allowing adjacent cells to interact. The Notch signaling pathway consists of Notch ligands (DSL proteins), Notch receptors, DNA-binding proteins, and downstream target genes. Hepatocellular carcinoma (HCC) represents the predominant cause of cancer-related deaths globally and poses a significant threat to human health. For highly malignant HCC, current treatment options, including chemotherapy, radiotherapy, immunotherapy, targeted therapies, and surgical procedures, often have poor prognoses. Therefore, there is a need to explore additional therapeutic strategies. Many studies have found that abnormal activation of the Notch signaling pathway contributes to tumor initiation and progression by promoting HCC proliferation, metastasis, stem cell-like properties, and drug resistance. In this research, we reveal the composition and activation mechanisms of the Notch signaling pathway, as well as the molecular mechanism underlying its aberrant activation in HCC. Furthermore, we summarize recent advances in targeting Notch signaling for the treatment of HCC. This review aims to highlight the promising potential of investigating the Notch pathway as a therapeutic target in HCC.

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder affecting salivary and lacrimal glands, leading to distressing ocular symptoms. Existing therapeutic approaches for SS-associated dry eye syndrome (DES) show insufficient efficacy. This study investigates the use of topical MSC-derived exosomes in primary SS-related DES.

Oral squamous cell carcinoma (OSCC) is a common carcinoma in Indian population, wherein one-third of global OSCC cases are from India. The five-year survival rate is poor due to late diagnosis. Oral tongue squamous cell carcinoma (OTSCC) is the second-most common OSCC. An in vitro cell line model is a valuable tool to get a deeper understanding of the molecular mechanisms involved in therapy resistance and disease progression. We report establishment of three OTSCC cell lines from advanced stage treatment naïve Indian patient samples, such as ACOTSC120, ACOSTC132, and ACOTSC140. All three OTSCC cell lines showed epithelial morphology, which was confirmed by Keratin-14 staining. The cell lines showed in vitro spheroid-forming and in vivo tumorigenic potential. The STR of the cell lines ensured their human origin and novelty when compared to DSMZ cell line database. The karyotype of the cell lines showed aneuploidy and further confirmed their human origin. These cell lines showed the presence of cancer stem cell (CSCs) population, i.e., the ALDHbr/CD44+ population. These cell lines thus provide a model to help understand the biology of disease and its progression.

Human induced pluripotent stem cells (hiPSCs)-derived neuronal networks on multi-electrode arrays (MEAs) are a powerful tool for studying neurological disorders. The electric activity patterns of these networks differ between healthy and patient-derived neurons, reflecting underlying pathology. However, elucidating these underlying molecular mechanisms requires strenuous additional experiments. Computational models can link observable network activity to underlying mechanisms by estimating biophysical model parameters that simulate the experimental observations, but this is challenging. Here, we address this challenge using simulation-based inference (SBI), a machine-learning approach, to automatically estimate all model parameters that can explain network activity. We show how SBI can accurately estimate parameters that replicate the activity of healthy hiPSC-derived neuronal networks, pinpoint molecular mechanisms affected by pharmacological agents, and identify key disease mechanisms in patient-derived neuronal networks. This demonstrates SBI's potential to automate and enhance the discovery of in vitro disease mechanisms from MEA measurements, advancing research with hiPSC-derived neuronal networks.

Existing immunodeficient pig models have demonstrated limited success in supporting robust human haematopoietic engraftment and multilineage differentiation. Here we hypothesize that the targeted deletion of integrin-associated protein (Cd47) in severe combined immunodeficient pigs, with deletions in the X-linked interleukin-2 receptor gamma chain and recombination activating gene 1, would enable long-term haematopoietic engraftment following transplantation with human haematopoietic stem/progenitor cells. In Cd47-deficient pigs, we observed high levels of human haematopoietic chimerism in the blood and spleen, with functional T and B lymphocytes, natural killer and myeloid cells, as well as robust thymopoiesis. Our findings suggest that severe combined immunodeficient pigs with Cd47 deletion represent an improved preclinical model for studying human haematopoiesis, disease mechanisms and therapies, and offer potential as a bioreactor for large-scale production of human immune cells.

Age-related hearing loss (ARHL) is among the most prevalent and complex disorders in older adults. However, the pathogenesis of ARHL remains poorly understood. Using a single-cell transcriptomic landscape of mouse cochlea at five time points (1, 2, 5, 12 and 15 months), we found that the levels of human antigen R (HuR)-a classical RNA-binding protein-increase with age. Here we show that HuR is specifically transported from the nucleus to the cytoplasm in hair cells in both aging mice and nonhuman primates. HuR overexpression in cochlea could successfully alleviate ARHL in aged mice. Meanwhile, HuR deficiency led to premature hearing dysfunction characterized by degeneration of stereocilia and the subsequent loss of hair cells. RNA immunoprecipitation sequencing analysis revealed that HuR can bind to messenger RNAs that enable stereocilia maintenance, including Gnai3. Adeno-associated virus-mediated Gnai3 overexpression partially rescues the hearing defects in HuR-deficient mice. Taken together, these findings indicate that HuR is a potential therapeutic target for ARHL.