Degenerative ocular disorders, glaucoma, cataracts and age-related macular degeneration, are major contributors to global blindness and visual impairment. Other conditions, such as limbal stem cell deficiency, dry eye disease and retinitis pigmentosa, lead to significant ocular distress and progressive vision loss, profoundly affecting patients’ quality of life. Conventional therapies primarily focus on symptom management and slowing disease progression, offering limited potential for tissue restoration. In recent years, stem cell therapy and regenerative medicine have emerged as promising strategies to address these limitations. Mesenchymal Stem Cells (MSCs) induced Pluripotent Stem Cells (iPSCs) and other progenitor cells have demonstrated the capacity to differentiate into ocular-specific cell types, modulate inflammation, secrete neurotrophic factors and promote tissue repair. Preclinical studies and early clinical trials have shown encouraging results in corneal regeneration, retinal repair and optic nerve protection, highlighting the translational potential of these therapies. Despite these advances, challenges remain, including optimizing cell sourcing, delivery methods, immune compatibility and long-term safety. This review provides a comprehensive overview of current stem cell-based approaches in ophthalmology, discussing underlying mechanisms, preclinical and clinical evidence and future directions for regenerative interventions aimed at restoring visual function. Stem cell therapy offers a transformative approach with the potential to shift ophthalmic care from palliative management to true tissue regeneration, offering hope for patients with previously untreatable ocular disorders.

Hedgehog (HH) signaling is essential in directing the fate determination of postmigratory cranial neural crest cells (CNCCs) to ensure proper craniofacial development. Gli transcription factors (TFs) are established as primary effectors of HH signaling, yet their distinct roles and regulatory mechanisms in governing cell commitment and differentiation of postmigratory CNCCs remain poorly understood. Here, using tooth root as a model, we combined transgenic mouse models with bioinformatic analyses to interrogate the functions of Gli2 and Gli3 in CNCC-derived root progenitor cells of the mouse molar. We revealed that loss of Gli3 alone in dental mesenchymal root progenitor cells caused shortened roots and that concurrent loss of Gli2 and Gli3 exacerbated root malformations, concomitant with profound impairments in cell proliferation and multilineage differentiation, suggesting a synergistic interaction between Gli2 and Gli3 during tooth root development. Mechanistically, Gli2 and Gli3 cooperatively regulated the transcription of Acvr2b, thereby modulating the activity of TGF-β/SMAD signaling within the dental mesenchyme. This Gli2/Gli3-TGF-β signaling cascade was critical for the lineage specification of tooth root progenitor cells during molar morphogenesis. Collectively, this work uncovers synergistic interactions of Gli2 and Gli3 in orchestrating tooth root morphogenesis and provides a novel insight into HH-TGF-β crosstalk in cell fate decisions of postmigratory CNCCs.

The regeneration of bone tissue depends on the harmonious interaction between blood vessels and nerve fibers, both essential for various physiological and pathological functions in the skeletal system. The key to mimicking the structure and function of natural bone lies in integrating angiogenesis and neurogenesis processes to prepare vascular-nerve-tissue-engineered bone (TEB). Unlike traditional strategies for constructing vascular nerve TEB (such as adding growth factors or cells to scaffolds or preparing composite scaffolds), this study employs a bottom-up approach, using modular microtissue units to construct novel vascular nerve TEB. Initially, vascular-nerve-bone microtissues composed of bone marrow mesenchymal stem cells, endothelial progenitor cells (EPCs), and Schwann cells (SCs) were generated through three-dimensional coculture in microporous array plates. These vascular-neural-bone microtissues were then encapsulated as modular building blocks within gelatin methacrylate (GelMA) hydrogels to construct large-scale vascular-neural TEB. The microtissue-based vascular-neural-TEB construction protocol demonstrated feasibility at the molecular, cellular, and tissue/organ levels. Research findings indicate that the GelMA/MSC/EPC/SC vascular-neural-TEB possesses concurrent capabilities for angiogenesis, neurogenesis, and osteogenesis during bone repair. These findings provide novel insights for the construction of multifunctional bone grafts and lay the foundation for the clinical treatment of bone defects.

Mesenchymal Stromal Cells (MSCs) and pericytes, although a minor cellular component of the tumor microenvironment (TME), exert outsized control over cancer progression, metastasis, and therapeutic response across both solid and hematologic malignancies. Once separated by functional and anatomical criteria, Single-cell RNA sequencing (scRNA seq) analyses and context-dependent phenotypic transitions - pericyte-to Cancer-Associated Fibroblasts (CAFs) and MSCs-to-CAFs, now blur these classical distinctions, revealing fluid entities and substantial functional convergence. We synthesize current evidence showing that MSCs and pericytes frequently adopt overlapping pro-angiogenic, immunosuppressive, and pro-invasive states driven by PDGF-B/PDGFRβ, TGF-β, CXCL12, and Notch/ROCK signaling. Across cancers, their roles are multifaceted: in Colorectal Cancer (CRC) from neo-vascularization and Drug Resistance (DR) to blood vessel formation, invasion, and metastatic spread. Moreover, MSCs reinforce immunosuppression, whereas pericyte phenotype switching may sensitize tumors to immunotherapy, thus playing a pivotal role in fibrosis-driven cancer progression. In hematologic malignancies, particularly in the Bone Marrow (BM) niche, MSCs sustain leukemic cell survival and DR. Shared markers and transcriptomic signatures, coupled with striking plasticity, underscore their central role in shaping a pro-tumorigenic milieu. This convergence helps to explain the limits of current approaches-such as anti-VEGF monotherapy and supports new strategies. Enhancing pericyte maturity or intercepting transitions toward CAFs are promising avenues to boost treatment efficacy. We propose a practical framework for classifying "MSC-pericyte states" in the TME and emphasize rigorous, multi-marker, spatially resolved analyses to dissect their complex functions, thus opening a new scenario for targeted therapies.

Avenanthramide C and chondroitin sulphate promote chondrogenic differentiation of adipose-derived mesenchymal stem cells.

Three-dimensional (3D) bioprinting has revolutionized tissue engineering by precisely fabricating customized scaffolds that recapitulate native tissue architectures. This study introduces a photo-crosslinkable methacrylated guar gum (GG-MA) hydrogel as a tunable monophasic bioink for cartilage tissue engineering. By adjusting methacrylation degrees, GG-MA hydrogels achieved tailored mechanical strength (Young's modulus: GG-MA2 = 0.184 MPa vs. GG-MA1 = 0.069 MPa), controlled degradation (61.41% vs. 90.71% mass loss over 60 days), and shear-thinning behavior suitable for extrusion bioprinting. Encapsulated with bone marrow mesenchymal stem cells (BMSCs), GG-MA2 scaffolds exhibited favorable biocompatibility, and promoted cell proliferation, cell migration, and chondrogenic differentiation of BMSCs, evidenced by promoting the secretion of extracellular matrix and upregulating gene expression of Collagen Type II Alpha 1 Chain (COL2A1), Aggrecan (ACAN), and SRY-box transcription factor 9 (SOX9). The novel 3D bioprinting GG-MA hydrogel scaffolds demonstrated significant potential as a versatile platform balancing biocompatibility, mechanical stability, and chondrogenic capacity for cartilage tissue engineering.

Intervertebral disk pathology, including disk herniation and degeneration, is a major contributor to chronic low back pain, and when conservative treatment fails, surgical management often involves discectomy-based procedures that leave residual annulus fibrosus (AF) defects associated with reherniation and progressive degeneration. These limitations have motivated interest in regenerative strategies using biomaterial scaffolds; however, reproducing the hierarchical, angle-ply architecture of the AF remains challenging. Here, we present a single-step extrusion-based 3D-printing approach to fabricate polycaprolactone (PCL) scaffolds with aligned microscale surface grooves that promote AF-like organization. Patterned nozzles with circumferential peaks generated uniaxial concave microgrooves (10–17 µm wide) directly during printing, enabling formation of multilamellar angle-ply constructs. Human bone marrow-derived mesenchymal stem cells cultured on patterned scaffolds aligned longitudinally within concave grooves, forming end-to-end arrays that guided extracellular matrix deposition. Gene expression analysis showed that topographical cues governed cellular organization without significantly altering gene expression profiles, while TGF-β3 supplementation upregulated outer AF-associated markers, including COL1, COL12, SFRP2, MKX, MCAM, and SCX. TAGLN expression increased specifically on patterned scaffolds in the absence of TGF-β3, indicating an association between microgroove-guided cellular organization and TAGLN expression, warranting further investigation into potential tension-related mechanisms. This novel single-step extrusion-printing approach leverages custom nozzle geometry to impart concave microgrooves, facilitating scalable fabrication of multilamellar angle-ply scaffolds that induce aligned cellular organization and support potential applications in annulus fibrosus repair, as well as mechanobiological studies of anisotropic musculoskeletal tissues.

Stem cells sense biophysical cues within their extracellular microenvironment and respond via mechanotransduction signaling pathways that induce changes in gene expression and associated cell fate outcomes. Histone modifying enzymes are known to drive stem cell differentiation through changes in chromatin accessibility, but little is understood as to how extracellular matrix (ECM) mechanics regulate epigenomic remodeling. Here, we utilized alginate hydrogels with tunable mechanical properties to investigate the role of both matrix stiffness and stress relaxation on histone demethylase expression and activity during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Our results revealed that the expression of two histone demethylases, KDM4B and KDM6B, was upregulated during osteogenesis in response to stiff and fast stress-relaxing matrix conditions. Additionally, CUT&Tag profiling coupled with RNA-sequencing demonstrated that repressive histone methylation was decreased at osteogenic-specific loci in stiff, fast-relaxing matrices. Further, inhibition of mechanotransduction signaling pathways reduced expression of KDM4B and KDM6B and hindered osteogenic differentiation overall. Interestingly, phosphorylation of SMAD 1/5/8 increased in cells cultured in stiff, stress relaxing matrices, and pharmacological inhibition of SMAD 1/5/8 activation reduced expression of KDM4B and KDM6B. Together, our results establish novel impacts of stem cell mechanotransduction signaling events that promote osteogenesis through epigenetic remodeling.

Dyslipidemia and obesity are key risk factors for cardiometabolic diseases and are also linked to osteoporosis and other bone disorders. Evidence shows lipid metabolism influences bone homeostasis largely through immune regulation. This review first explains how abnormal lipid metabolism disrupts adipogenic and osteogenic differentiation in bone marrow mesenchymal stem cells and alters adipokines like leptin and adiponectin, upsetting bone formation and resorption and leading to bone loss. It then examines the lipid–immune–bone axis. In innate immunity, high lipid levels shift macrophages from M2 to pro-inflammatory M1, increase bone-resorbing cytokines such as TNF- α and IL-1 β , and trigger neutrophil senescence and lipid peroxidation with excess reactive oxygen species, all of which promote osteoclast formation and suppress bone growth. In adaptive immunity, hyperlipidemia changes T-cell metabolism, weakens Treg function, and drives Th17 differentiation; this Th17/Treg imbalance boosts osteoclasts via RANKL, IL-17, and related pathways. Meanwhile, in inflammation, B cells switch from producing OPG to releasing RANKL and G-CSF, while Breg-derived IL-10, IL-35, and TGF- β 1 protect bone. The review also highlights how M1 macrophages and Th17 cells work together to worsen bone damage. Understanding these immune mechanisms could lead to new treatments for metabolic bone diseases. Despite these advances, the translation of these preclinical findings into clinical practice remains a challenge that warrants further investigation.

This review examines the mechanisms of therapeutic action and prospects for clinical use of mesenchymal stromal cell (MSC) transplantation in dilated cardiomyopathy. The development of dilated cardiomyopathy is based on a complex interaction between multiple causes and mechanisms. It is characterized by a high prevalence, poor prognosis, and significant mortality, necessitating the need for innovative treatment methods. In this disease, MSCs are capable of exerting a complex effect on the damaged myocardium, mainly due to the paracrine production of cytoprotective, immunomodulatory, proangiogenic and antifibrotic factors, suppression of oxidative stress and restoration of cardiomyocyte energy metabolism. The results of preclinical and clinical studies confirm the ability of MSCs to improve cardiac contractile function and patient quality of life. Long-term maintenance of these improvements is noted, with allogeneic cells demonstrating greater therapeutic potential and a lower complication rate than autologous cells. To improve the efficacy of MSC transplantation and allow its widespread implementation in clinical practice, several challenges must be addressed, including optimizing cell sources, delivery methods, and improving survival in the unfavorable microenvironment. In this context, genetic modification of MSC aimed at enhancing their cardioprotective and pro-regenerative properties offers promising opportunities for improving treatment outcomes for dilated cardiomyopathy.

Atherosclerosis constitutes the primary pathological basis for cardiovascular diseases. It most commonly develops at the branching and curved regions of blood vessels. The disturbed blood flow in these regions can generate oscillatory shear stress (OSS). Endothelial cells exposed to OSS progressively undergo a transformation into mesenchymal cells, a process known as endothelial-to-mesenchymal transition (EndMT). EndMT is a critical event in the development of atherosclerosis. OSS promotes the occurrence of EndMT through multiple pathways. This paper provides a comprehensive analysis of the phenomena and mechanisms of OSS-induced EndMT, offering theoretical insights into the pathogenic mechanisms of atherosclerosis and corresponding therapeutic strategies.

The impact of mesenchymal stromal cells on the proliferation and functional maturation of liver organoids.

Humans encounter numerous pathogens every day and therefore rely heavily on the innate immune system that acts as the first line of defense against infectious agents. Neutrophils make up more than half of the circulating leukocytes in humans and are well equipped to neutralize invaders and thus are a crucial part of our defense system [Friedl and Weigelin (2008). Nat Immunol 9: 960; Rankin (2010). J Leukoc Biol 88: 241]. To get from the bloodstream to sites of insult, neutrophils often have to migrate through various tissues and cover distances much further than many other cells. Thus, it is not surprising that they use elements from both amoeboid and mesenchymal migration, allowing them to migrate efficiently through various environments as they navigate in the body. Here we will discuss the cellular properties of neutrophils that make them exceptional migrators in a variety of physiological contexts, along with the various signaling pathways that guide neutrophil migration.

A major challenge in bone tissue engineering is the embedding of osteocyte-like cells at high density within a mineralized matrix at the micro-scale and a trabecular-like architecture at the macro-scale. Volumetric bioprinting (VBP) enables rapid creation of complex cell-laden constructs through tomographic light projections. However, integrating both high cell densities and inorganic mineral precursors into VBP processes poses challenges due to light scattering, which can compromise print fidelity. In this study, we aim to combine bioinspired polymer-induced liquid-phase precursor (PILP) mineralization with VBP to fabricate cell-laden gelatin methacryloyl hydrogel constructs with amorphous mineral precursors. By stabilizing amorphous mineral precursors with poly-aspartic acid, light scattering is sufficiently reduced to enable printing. Tuning the refractive index of this mineralizing bioresin allows fast VBP of mineralized bone-like constructs with cell densities of up to 3 million cells/ml. The constructs display high cell viability (>90%) and enhanced mineralization when cultured in osteogenic conditions with βglycerophosphate. Encapsulated human mesenchymal stromal cells exhibit an early osteocytic phenotype after 28 days of differentiation. Collectively, this PILP-assisted VBP platform holds promise for the development of advanced in vitro bone models with more physiologically relevant architecture and cellular composition.

Senescent mesenchymal stem cells residing in an inflammatory, dysbiotic, and hypoxic microenvironment pose a barrier to periodontal regeneration. Here we introduce a hydrocaffeic acid (HCA)-mediated silk fibroin hydrogel incorporating Mn/HCA-modified calcium peroxide (Mn-hCaO₂) and HCA-modified zeolitic imidazolate framework-8 (hZIF8) to rejuvenate this environment. The strategy imbues the hydrogel with enhanced adhesion and adaptability in periodontal pockets. The Mn-HCA complex acts catalytically to reduce oxidative stress and correct hypoxia. Simultaneously, Zn²⁺ and HCA restore microbial balance and mitigate inflammation. This multifunctional hydrogel targets the senescent periodontal niche by normalizing microbiota homeostasis and promoting a regenerative immune profile. Concurrently, it directly alleviates telomere shortening, DNA damage and oxidative stress in stem cells, thereby rejuvenating cellular function. By specifically addressing hypoxia and zinc deficiency, this polyphenol-mediated synergistic strategy offers a pathway to rejuvenate the senescent periodontal microenvironment, thereby overcoming tissue regeneration barriers and offering a translatable pathway for treating periodontitis and other aging-associated inflammatory diseases.

Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disease of prematurity characterized by inflammation, necrosis, and high morbidity. Current therapies are limited, necessitating the development of novel treatments. Mesenchymal stromal cells (MSCs) have shown promise in murine NEC models. Given the anatomical and physiological similarities between premature piglets and human infants, we employed a preterm piglet model to evaluate MSC efficacy. We hypothesized that intraperitoneal MSC administration would reduce intestinal injury in NEC. Preterm piglets were delivered via cesarean section. NEC was induced on day 3 through hypertonic enteral feeding. MSCs were administered intraperitoneally at low, medium, or high doses. Piglets were monitored and euthanized based on clinical criteria. Clinical scores, weight change, gross and histologic intestinal injuries were assessed. Cytokine levels in serum and ileum were quantified via ELISA, and intestinal tissue was analyzed by RNA sequencing. Statistical significance was set at p < 0.05. Medium-dose MSCs significantly improved clinical scores and reduced both gross and histologic intestinal injury (p < 0.05). A corresponding decrease in pro-inflammatory cytokines was observed. This is the first study to demonstrate therapeutic benefit of MSCs in a preterm piglet NEC model, supporting their potential use in translational NEC therapies.

Healing of perforating inflammatory root resorption by allogeneic bone marrow mesenchymal stromal cells transplantation: A Case Report.

Early vascularization is one of the limitations of periodontal tissue engineering (PTE) based on mesenchymal stem cells (MSCs). Directed differentiation of endothelial progenitor cells (EPCs) into endothelial cells facilitates the osteogenic effect of MSCs. Therefore, this study constructed EPCs/peripheral blood derived-MSCs (EPCs/PBMSCs) sheets and evaluated their repair value and potential molecular mechanisms in bone regeneration. Different ratios of EPCs and PBMSCs were co-cultured to prepare EPCs/PBMSCs sheets and the osteogenic differentiation was assessed. Exploring the bone regeneration properties of EPCs/PBMSC sheets in an animal model of alveolar bone defects. The effect of the SLIT3/ROBO1 axis on angiogenic-osteogenic coupling of EPCs/PBMSCs sheets was explored using exogenous modulation by shRNA lentivirus and neutralizing antibody. EPCs/PBMSCs sheets could form angiogenic-osteogenic coupling, and different ratios of EPCs/PBMSCs sheets had higher angiogenic and osteogenic differentiation properties than EPCs or PBMSCs alone, especially the ratio 4:6. Moreover, EPCs/PBMSCs sheets accelerated bone regeneration in the alveolar bone defect model and the treatment was superior to PBMSCs alone. The expression patterns of SLIT3 and ROBO1 were consistent with the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets. Knockdown of SLIT3 in PBMSCs and/or neutralization of ROBO1 protein in EPCs effectively suppressed calcified nodule formation and markers expression of osteogenic differentiation and angiogenesis (ALP, RUNX2, OCN, Osx, EMCN, and CD31) in EPCs/PBMSCs sheets, and hindered its therapeutic effect in the alveolar bone defect model. EPCs/PBMSCs sheets ameliorate the limitations of early vascularization in PTE and the SLIT3/ROBO1 axis mediates the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets, thereby augmenting their osteogenic effects.

Cyclophosphamide (CYP) may through its toxic metabolite, acrolein, induce hemorrhagic cystitis and bladder hyperactivity. Previous studies demonstrated intra-iliac arterial administration of adipose derived mesenchymal stem cells (ADSC)-derived microvesicles with less immune response and adverse effects than ADSC itself may confer anti-oxidative stress and anti-inflammatory potential to improve bladder dysfunction. We explored whether ADSC-derived microvesicles may prevent CYP-induced bladder cystitis and overactivity. Female Wistar rats were divided into control (Con), CYP (Cy), CYP+microvesicles (CyM), and microvesicles treated control (CoM) groups. Con rats were intraperitoneally treated with saline, while the Cy rats were induced by intraperitoneally administered CYP (100 mg/kg body weight). We injected ADSC-derived microvesicles at the dosage of 15 μg/ml via intra-iliac artery to the rats with or without CYP treatment. We measured the responses of transcystometrogram, pathology, expression of muscarinic receptors (M3) and purinergic receptors (P2X7), pyroptosis related Caspase 1 and IL-1β, xCT/Gpx4 related ferroptosis by western blot in CYP-treated bladders. Wire myography of the urinary bladder was determined. ADSC-derived microvesicles effectively decreased micturition frequency (overactivity), inflammation and fibrosis in CyM rats versus Cy rats. ADSC-derived microvesicles efficiently downregulated P2X7 and M3 receptor expression, Caspase 1/IL-1β mediated pyroptosis, xCT/Gpx4 regulated ferroptosis and restored Bcl-2/HO-1 mediated antioxidant defense mechanisms in CYP-induced cystitis. The pathologic results also displayed the effective reduction of bladder immune cell infiltration (inflammation) and fibrosis, and the preservation of the integrity in the urothelium by the treatment of ADSC-derived microvesicles. ADSC-derived microvesicles can ameliorate CYP-induced bladder overactivity, inflammation, fibrosis, ferroptosis and pyroptosis.

Experimental and data modeling approaches of umbilical cord blood allogenic response identify cytokine profiles as potential biomarkers associated with the initial stages of alloreactivity and immunomodulation.