Intrauterine adhesions (IUA) and endometriosis are debilitating gynecological disorders that impair endometrial function and fertility. IUA, typically caused by iatrogenic trauma to the basal endometrium, leads to fibrosis and infertility, whereas endometriosis, characterized by ectopic endometrial growth, induces chronic inflammation, pain, and subfertility. Current treatments, such as surgical adhesiolysis for IUA and hormonal suppression for endometriosis, frequently fail to address underlying pathological mechanisms, including aberrant fibrosis, inflammatory cascades, and impaired tissue regeneration. Recently, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach. Their therapeutic benefits are mediated primarily through paracrine actions, which modulate immune responses, promote tissue repair, and attenuate inflammation and fibrosis. Recent studies have further highlighted the potential of MSC-derived exosomes (MSC-Exos) as a cell-free alternative. In this review, we comprehensively summarize current evidence from animal models and clinical studies on the application of MSCs and MSC-Exos in treating IUA and endometriosis, focusing on their therapeutic potential, mechanisms of action, and future directions. We also discuss remaining challenges and promising strategies to overcome them, thereby positioning MSC-based therapies as transformative options for endometrial restoration and disease management.

This study aimed to recapitulate adipose-tumor interactions within the colorectal cancer (CRC) tumor microenvironment (TME) and to elucidate the role of adipose-derived stem cells (ADSCs) in regulating CRC progression through cytokine-mediated signaling. Human ADSCs were isolated from adipose tissue and directly cocultured with CRC cells using an oxygen-permeable, PDMS-based 3D coculture chip, followed by cytokine profiling of conditioned media, immunofluorescence analysis of spheroids, FACS-based cell separation, and molecular analyzes including western blotting, qPCR, and immunoprecipitation to interrogate HIF-1-related mechanisms. The results revealed that cancer-associated ADSCs secrete CCL8, which markedly enhances CRC cell migration. Mechanistically, ADSC-derived CCL8 activated the ERK signaling pathway in CRC cells, leading to increased HIF-1α protein accumulation without significant changes in protein stability. This was accompanied by enhanced interaction between HIF-1α and the transcriptional cofactor p300. Consequently, HIF-1α transcriptional activity was increased, resulting in the upregulation of downstream epithelial-mesenchymal transition markers and promoting a pro-migratory and aggressive cancer phenotype. These effects were particularly pronounced in the coculture system, where intensified crosstalk between ADSCs and cancer cells amplifies oncogenic signaling within the TME. Collectively, these findings demonstrate that ADSC-derived CCL8 functions as a key mediator of adipose-tumor crosstalk in CRC progression by driving HIF-1α-dependent signaling pathways. Furthermore, the PDMS-based 3D coculture platform employed in this study provides a robust and physiologically relevant experimental system for dissecting complex cell-cell interactions and cytokine-driven mechanisms within the TME of CRC.

To explore the promotion of dynamic distraction on osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMMSCs) in three-dimensional culture.

Several recent advances in microphysiological systems or organ-on-chip technology have demonstrated its potential for replacing traditional in vitro and animal models in the coming years. Despite the physiological relevance and cost-effectiveness of organ chips, there are several hurdles that must be overcome for widespread adoption for biological studies. Many manufacturing and scalability challenges have been overcome by a transition from polydimethylsiloxane to thermoplastics. However, challenges have arisen in these sealed, brittle systems related to end-point tissue analyses, harvest, and high-resolution imaging, which is particularly difficult for multilayer organ chips. Here, we present low-cost organ chips that are fluidically sealed but demountable, fabricated using a cut-and-assemble method without the need for cleanroom technologies. We have validated the capabilities of this method by demonstrating the culture of human aortic smooth muscle cells and induced pluripotent stem cell-derived neural cells, encapsulated in gelatin methacryloyl (GelMA) hydrogel on chip, for up to 27 days. The three-dimensional (3D) culture layer of the organ chip was removed, and high-resolution images were obtained following immunostaining. Furthermore, these organ chips facilitate rapid redesign and manufacture for alternative tissue and/or interface systems. To the best of our knowledge, this is the first innervated organ chip with multiple removable cell culture layers, as well as the first humanized nerve-artery model that includes a 3D hydrogel culture. In future work, these unique features of our platform can be utilized for investigating the crosstalk mechanisms between different cell types in coculture.Impact StatementWe present here a new method for fabricating low-cost demountable organ-on-a-chip platforms. This method leverages our recent cut-and-assemble method for layered three-dimensional organ chips comprised of gas impermeable thermoplastics.

The absence of induced pluripotent stem cell (iPSC) lines derived from Emirati patients with developmental disease hampers region-specific disease modeling and therapeutic research. Herein, we describe the creation of an iPSC line from peripheral blood mononuclear cells obtained from a 21-year-old Emirati female patient with ventricular septal defect (VSD) using Sendai virus-mediated delivery of reprogramming factors. The resulting line, UAEUi001-A, exhibited typical colony morphology, was mycoplasma negative, successfully generated embryoid bodies), and demonstrated strong alkaline phosphatase activity. These iPSCs were further characterized for pluripotency potential and their differentiation potential into the three germ layers under in vitro culture conditions through immunostaining using stage-specific markers. To the best our knowledge, this is the first reported generation of an iPSC line from an Emirati patient with VSD. Overall, this iPSC line may serve as a valuable model for establishing an Emirati-specific iPSC repository, supporting disease modeling and drug discovery relevant to the Emirati population.Impact StatementThis study establishes the first induced pluripotent stem cell (iPSC) line derived from an Emirati patient with ventricular septal defect, addressing a critical gap in region-specific disease models. It provides a valuable platform for understanding developmental cardiac disorders in underrepresented populations and supports the development of precision medicine and targeted therapeutic strategies relevant to the Emirati population.

R-Loops are three-stranded DNA/RNA hybrids implicated in immune responses. Their role in mesenchymal stem cell differentiation, particularly in dental pulp regeneration under inflammation, remains unclear.

Chronic systemic inflammation is a key driver of disease progression in rheumatoid arthritis and chronic kidney disease (CKD), particularly in patients undergoing long-term hemodialysis. Persistent elevation of proinflammatory cytokines contributes to pain, anemia, endothelial dysfunction, and increased cardiovascular risk, while therapeutic options are often limited by comorbidities and drug intolerance. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may offer an alternative strategy for systemic inflammatory control. We report on the case of a 56-year-old woman with juvenile-onset rheumatoid arthritis and dialysis-dependent CKD who received three consecutive systemic administrations of MSCs. Baseline evaluation demonstrated elevated inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Following treatment, inflammatory parameters were consistently reduced, which was accompanied by improvement in hemoglobin levels and favorable trends in renal function markers. Additionally, pain assessment scores (Western Ontario and McMaster Universities Arthritis Index, Knee Injury and Osteoarthritis Outcome Score, Visual Analogue Scale) showed clinically significant improvement. The patient also reported significant subjective pain relief and improved overall well-being. Although limited by its single-case design, this report supports the biological plausibility of systemic MSC therapy as a potential immunomodulatory approach in patients with overlapping autoimmune and uremia-associated chronic inflammation. Further controlled studies are warranted.

Insulin substantially promotes the growth of malignant cells that overexpress the insulin receptor (INSR), and insulin excess has been recognised as a cancer-promoting factor in patients. Interferon-induced transmembrane protein 1 (IFITM1) is also overexpressed in various cancers. In this study, we investigate the association between insulin signalling-induced IFITM1 expression and multiple myeloma (MM) aggressiveness. We observed that expression of both INSR and IFITM1 was significantly elevated in symptomatic MM patients compared with those with monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM). Notably, IFITM1-but not INSR-expression correlated with prognosis following autologous stem cell transplantation and bortezomib-based induction therapy. Further analysis revealed that IFITM1 expression in bone marrow plasma cells was associated with the concentrations of insulin and insulin-like growth factor 2 (IGF-II) in the bone marrow microenvironment. Insulin and IGF-II enhanced MM cell proliferation through IFITM1 upregulation, whereas suppression of IFITM1 abrogated the proliferative effects of these ligands. Moreover, insulin and IGF-II attenuated apoptosis and the inhibition of cell migration induced by the proteasome inhibitors (PIs) bortezomib and carfilzomib, and these effects were reversed by IFITM1 knockdown. The ability of insulin to reduce bortezomib-induced apoptosis and G2/M phase cell cycle arrest was likewise dependent on IFITM1 expression. Collectively, these findings suggest that insulin-induced IFITM1 plays a pivotal role in MM progression and resistance to bortezomib, highlighting IFITM1 as a potential prognostic biomarker and therapeutic target.

Effective skeletal muscle regeneration requires muscle stem cells (MuSCs) to continuously interpret and respond to signals from their surrounding microenvironment. These niche-derived cues, including inflammatory, extracellular matrix, paracrine, metabolic, and biomechanical signals, direct MuSC progression through quiescence, activation, proliferation, and differentiation by reshaping gene expression programs. Increasing evidence suggests that transcriptional enhancers serve as a key regulatory interface through which environmental information is translated into transcriptional output. Enhancer activity is governed by the coordinated action of lineage-defining transcription factors, histone modifiers, chromatin remodelers, transcriptional coactivators, and architectural proteins that together regulate chromatin accessibility, enhancer-promoter communication, and gene activation. Recent work has shown that enhancer landscapes and three-dimensional genome organization are highly dynamic during muscle regeneration and become altered in aging and disease. In this review, we examine how enhancer-associated mechanisms enable MuSCs to interpret niche-derived signals, highlighting the roles of transcription factor networks, chromatin remodeling complexes, and enhancer-promoter interactions in coordinating gene expression. We further discuss how disruption of enhancer regulation contributes to impaired regeneration in aging and muscular dystrophy, where altered chromatin states and genome organization lead to aberrant transcriptional responses. Understanding how these regulatory elements integrate complex environmental signals will be essential for defining the mechanisms underlying muscle regeneration and may provide new avenues for therapeutic intervention.

Microglia, the immune cells of the central nervous system (CNS), quickly respond to neurodegeneration by proliferating and migrating to areas of disease, phagocytosing debris, and releasing cytokines to initiate inflammation. Critically, the mechanisms underlying these microglial functions remain only partly understood. One molecular regulator of interest is complement protein C1q, the initiator molecule of the complement cascade that increases 300-fold in healthy aging and accumulates with neurodegeneration. We have previously reported that exogenous C1q treatment alters inflammatory gene expression and cell function in human induced pluripotent stem cell-derived microglia (iMG). Here, we test the hypothesis that C1q induced cell changes are modulated by novel C1q receptor, CD44. We first confirmed expression of five novel C1q receptors at the RNA and protein levels, and then validated C1q-receptor binding on the iMG cell surface using proximity ligation assay. Based on these results, we selected CD44 as an initial target and generated CD44 knockout iMG to test the role of CD44 in the iMG response to C1q. We demonstrate that C1q-CD44 interactions regulate changes in microglial phagocytosis, proliferation, and migration. These data suggest C1q interacts with CD44 to modulate microglial functions that are critical to health and disease, thus informing future directions to test whether these interactions are altered in neurodegenerative disease.

Iron is an indispensable trace element for maintaining normal physiological functions in the body, participating in key biological processes such as energy metabolism, DNA synthesis, and damage repair. Under normal physiological conditions, cells tightly regulate iron homeostasis to prevent iron overload-induced oxidative stress and DNA damage. In contrast, tumor cells undergo iron metabolic reprogramming to adapt to their aberrant proliferation and elevated metabolic levels. By upregulating iron uptake and storage pathways, they elevate intracellular iron levels, providing essential cofactors for accelerated DNA synthesis and mitochondrial energy production, thereby meeting the material and energy demands of malignant growth. As an essential regulator of iron acquisition, transferrin receptor 1 (TFR1) binds transferrin (TF) and enters the cell through clathrin-mediated endocytosis to deliver ferric iron (Fe³⁺). Internalized TFR1 returns to the cytoplasmic membrane via the recycling pathway, sustaining surface receptor levels and enabling continued iron uptake. Owing to this mechanism, TFR1 has emerged as a prominent target for anticancer drug development. This review focuses on the molecular mechanisms regulating TFR1, from transcriptional regulation to translational expression, with a focus on its biological roles in iron metabolism and malignant progression. Furthermore, we summarize various TFR1-targeted antitumor strategies based on current research, providing a theoretical foundation for the development of novel anticancer therapeutics.

The central nervous system (CNS) has a limited regenerative capacity, rendering traumatic injuries such as spinal cord injury (SCI) and traumatic brain injury (TBI) highly disabling and difficult to treat. These insults trigger complex pathophysiological cascades, including extensive cell death, sustained inflammation, and the formation of a hostile inhibitory microenvironment that compromises neural plasticity and hampers tissue regeneration. The multifactorial nature of these mechanisms, together with a fragmented understanding of CNS plasticity, has hindered the development of effective therapeutic interventions.

Chimeric antigen receptor T-cell (CAR-T cell) therapy is highly effective for relapsed/refractory multiple myeloma (R/R MM), but hematologic toxicity and the need for blood transfusions remain common. This study examined the patterns of transfusion needs in patients receiving CAR-T cell therapy, analyzed risk factors, and assessed the effects of transfusions on clinical outcomes.

Multiple interacting factors within the tumor microenvironment, including mechanical pressure, extracellular matrix components, hypoxia, and vascular architecture, are known to promote cancer progression. Although fibronectin 1 functions as a critical extracellular matrix glycoprotein in colorectal cancer, its specific interaction with mechanical pressure is not well characterized.

Oocyte aneuploidy is a major contributor to age-related fertility decline, but the effective treatments are still unavailable. The spindle assembly checkpoint (SAC), which functions to maintain chromosomal euploidy in oocytes, may become impaired with aging, manifesting primarily as an aberrant acceleration of meiotic progression. In the present study, we investigated the effects, effective components, and molecular mechanisms of the secretome of mesenchymal stem cells (MSC-sec) in reducing aneuploidy by alleviating the accelerated meiotic progression of aged mouse oocytes.

Nicotinamide N-methyltransferase (NNMT) is a methyltransferase that uses S-adenosyl-L-methionine (SAM, cofactor) to catalyze the N-methylation of nicotinamide (NAM, substrate), yielding 1-methylnicotinamide (MNAM) and S-adenosyl-homocysteine (SAH). By consuming SAM and generating SAH, NNMT establishes a cellular "methylation sink" that couples metabolic reprogramming to epigenetic remodeling across DNA, RNA and proteins. Accumulating evidence shows that NNMT is upregulated in multiple malignancies, across both cancer cells and stromal lineages such as cancer-associated fibroblasts and pericytes. Its activity correlates with key hallmarks of cancer progression, including tumor growth, metastasis potential, metabolic rewiring, immune evasion, angiogenesis, maintenance of stem-like states, and resistance to therapy (including chemotherapy, targeted agents, and radiotherapy). These properties nominate NNMT as a candidate biomarker for diagnosis and stratification and as a tractable therapeutic node. We synthesize current knowledge of NNMT-driven cellular and microenvironmental mechanisms in tumorigenesis and progression, and summarize emerging therapeutic strategies, which include competitive inhibitors targeting the substrate or cofactor binding sites, microenvironment-activated prodrugs, and rational combinations with immune checkpoint blockade and targeted therapy to provide a conceptual and translational framework for developing NNMT-directed interventions.

Over the past two decades there have been remarkable advances in stem cell biology, bioengineering, and lung regenerative research, transforming our understanding of pulmonary biology from development to repair, and disease. Strategies using endogenous lung progenitor cells, pluripotent stem cell technologies, and engineered tissue platforms have become central tools for interrogating lung biology. Major breakthroughs have included the identification of diverse cell populations that coordinate lung homeostasis and repair, facilitated by the extensive adoption of single cell, multiomic and spatialomics approaches. Simultaneous progress in biomaterials, organoid systems, decellularized lung scaffolds, and lung-on-chip platforms has uncovered how extracellular matrix composition, mechanical forces, and tissue architecture contribute to the regulation of cell fate and function. These advances have enabled increasingly physiologically relevant in vitro, and ex vivo models while informing tissue engineering strategies aimed ultimately at functional lung replacement. Translation toward the clinic has advanced through both cell-based and cell-free therapeutic strategies. Early efforts focused largely on mesenchymal stromal cell-based approaches and extracellular vesicles, which have demonstrated safety and context-dependent efficacy in inflammatory lung diseases, alongside emerging preclinical evidence of functional engraftment of induced pluripotent stem cell-derived lung lineages. The past twenty years of progress, captured at the 20th Anniversary Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, highlights the power of interdisciplinary collaboration in advancing lung regeneration from foundational discovery toward therapeutic reality.

WNT proteins have been recognized as key regulators of skeletal health. However, developing WNT-associated bone anabolic agents is clinically challenging and expensive. Here we identify the reconstructed thumb and index domains of WNT7B (WNT7BRTID) as a WNT-derived bone anabolic peptide via Alphafold-empowered sequence prediction and in silico docking screening. In aged mice and pigs models of osteoporosis, WNT7BRTID peptides demonstrate therapeutic potential by improving the osteogenic potential of mesenchymal stromal/stem cells (MSCs) and enhancing bone regeneration. Using single-cell sequencing, transgenic lineage tracking and biochemical approaches, we show that WNT7BRTID harnesses the function and osteogenic lineage generation of intrinsic tissue-residual MSCs without needing MSC transplantation to repair a critical-sized defect effectively. Mechanistically, WNT7BRTID activates non-canonical Ca2+-NFAT signalling through RECK/GPR124 to drive its bone anabolic effects, independent of canonical Wnt/β-catenin signalling known for its oncogenic effects. Our results suggest that WNT7BRTID could work as bone anabolic agent for alleviating bone loss in aging and for fracture repair by promoting MSC function via Ca2+-NFAT signalling.

Alternative splicing is essential for the production of diverse messenger RNAs from a single gene. However our understanding of alternative splicing and its regulation during processes such as osteoblast differentiation remains incomplete. Using differentiating hMSC-TERT4 cells as a model, we performed deep short- and long-read RNA sequencing, revealing a highly integrated multiphasic differentiation program. Analysis for splicing revealed extensive changes during lineage commitment, in genes associated with known transcriptional regulators including RUNX2, TEAD1, CTNNB1 and NFATC4. During late-stage matrix osteoblast differentiation (maturation), splicing changes occurred in genes encoding cytoskeletal and extracellular matrix proteins, and Golgi and vesicle trafficking proteins. Analysis of proteomic and phosphoproteomic profiles confirmed the presence of alternative splicing in proteins participating in these biological processes as well as in RNA splicing and autophagy, with splicing involving a variety of protein domains, regions and PTM sites. Together, the transcriptomic and protein splicing landscapes provide a comprehensive description of how mesenchymal stromal cells progressively acquire an osteoblastic phenotype.

Regeneration of the dentin-pulp complex is essential for tooth integrity and function. However, the inherent cell heterogeneity limits our understanding of lineage-specific subsets critical for efficient odontogenesis and regenerative outcomes. Here, we demonstrated that CD24+ human dental papilla cells (hDPCs) exhibit robust odontogenic differentiation capacity and drive coordinated regeneration of well-vascularized pulp and structurally integrated dentin tissues in both ectopic murine and preclinical in situ minipig models, significantly outperforming conventional dental pulp stem cells. Mechanistically, we delineate a BMP2/SIRT1 axis where elevated BMP signaling sustains SIRT1 expression and promotes mitochondrial metabolism and odontogenic capacity. Furthermore, BMP signaling induces VEGF expression, enhancing neovascularization via paracrine effects. CD24 is also a downstream marker of BMP signaling, though it does not directly mediate differentiation. Together, CD24+ hDPCs represent a regeneration-competent subpopulation that integrates mitochondrial metabolism and signaling crosstalk to enable coordinated dentin-pulp regeneration, representing a translationally relevant cell source for dental tissue engineering.