BACKGROUND:The management of severe diabetic foot ulcers (DFUs) remains a major clinical challenge. Tibial cortex transverse transport (TTT) has emerged as an effective surgical intervention, but its underlying mechanism, particularly concerning stem cell mobilization and signaling pathways, is largely unknown. METHODS:A diabetic DFU model was established in New Zealand White rabbits using STZ, followed by TTT surgery. Wound healing was evaluated through photography, H&E, and Masson's trichrome staining. Angiogenesis was assessed by High-resolution X-ray angiography and immunofluorescence. Bone marrow-derived mesenchymal stem cell (BMSC) mobilization was analyzed via CFU-F assays and flow cytometry. Serum levels of SDF-1α, CXCR4, VEGF, and Ang2 were measured by ELISA and qRT-PCR. The activity of the Wnt/β-catenin pathway was determined by Western blot. RESULTS:TTT significantly accelerated wound closure and enhanced tissue regeneration, with improved epidermal/dermal restoration and collagen deposition. Consistently, neovascularization in wounds was markedly promoted. Mechanistically, TTT activated the Wnt/β‑catenin signaling pathway in BMSCs, which was associated with enhanced BMSC quantity, mobilization, and migration capacity. Inhibition of this pathway attenuated the TTT‑induced pro‑healing effects. CONCLUSION:TTT promotes healing of DFUs primarily by activating the Wnt/β-catenin pathway in BMSCs, thereby enhancing their mobilization, homing, and pro-angiogenic capacity. This study reveals a key molecular mechanism underlying TTT's efficacy and supports its therapeutic potential for refractory DFU.
Cancer stem cells (CSCs) constitute a rare yet highly adaptable tumor subpopulation that drives tumor initiation, intratumorally heterogeneity, metastasis, recurrence, and therapy resistance. Emerging evidence indicates that mitochondrial dynamics and mitochondrial ion signaling form an interconnected regulatory network that enables CSCs to remodel their metabolic and signaling states in response to environmental and therapeutic stress. Mitochondrial architectural remodeling through fission, fusion, biogenesis, and mitophagy cooperates closely with mitochondrial Ca2+ signaling and ion transport systems, including the mitochondrial calcium uniporter (MCU), voltage-dependent anion channels (VDACs), and mitochondrial K+ channels, to regulate mitochondrial membrane potential, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) signaling, and bioenergetic adaptation. Selected plasma membrane and ER-associated ion channels further contribute by modulating mitochondrial signaling pathways. Together, these processes govern CSC plasticity, adaptive stress tolerance, and stemness-associated programs, facilitating survival under hypoxia, nutrient deprivation, and anticancer therapy. In this review, we explore how mitochondrial dynamics and ion signaling converge to shape CSC metabolic flexibility and therapeutic resistance. We further discuss emerging diagnostic and therapeutic opportunities targeting mitochondrial dynamics-ion signaling crosstalk, while highlighting key challenges, including CSC heterogeneity, metabolic adaptability, and the need for selective strategies capable of eliminating CSCs while sparing normal stem-cell populations.
BACKGROUND:Loss-of-function mutations in the ABCA4 gene cause Stargardt disease (STGD1), the most common inherited macular dystrophy leading to progressive central vision loss. METHODS:Here, we generated human induced pluripotent stem cell-derived retinal organoids harboring a premature stop codon in exon-24 of ABCA4 to evaluate the impact of this mutation on mRNA and protein levels in a human model. RESULTS:Immunofluorescence analysis revealed the absence of ABCA4 protein in the mutant photoreceptor outer segment discs, while single-cell RNA sequencing detected no major transcriptional alterations in rods and cones. Unexpectedly, differential gene expression and pathway enrichment analyses of Müller glial cells and astrocytes highlighted disruption of neuronal development, microenvironment of glial cells, intercellular communication, and programmed cell death pathways. CONCLUSIONS:These findings suggest that ABCA4 deficiency in photoreceptor discs may trigger early stress-associated transcriptomic responses in retinal glial cells prior to overt photoreceptor degeneration, potentially contributing to Stargardt disease pathogenesis.
Organoid technology has emerged as a powerful platform for modeling human development, disease, and drug responses. Advances in stem cell biology and bioengineering have enabled the generation of increasingly sophisticated organoid systems that recapitulate key structural and cellular features of native tissues. However, despite substantial progress, the translational impact of organoids in regenerative medicine remains limited. Greater structural complexity and anatomical resemblance have not consistently translated into sustained therapeutic function or clinical applicability. Major barriers include incomplete maturation, inadequate vascular and immune integration, limited long-term functional stability, and challenges in reproducibility and scalability. These limitations reflect a conceptual mismatch between structure-driven organoid development and the functional requirements of regenerative medicine. Here, we propose a function-first framework in which regenerative organoids are engineered and evaluated according to measurable therapeutic outcomes, including tissue-specific function, vascular integration, immune compatibility, reproducibility, scalability, and long-term stability. We further discuss emerging bioengineering strategies, including vascularization, immune incorporation, organ-on-a-chip platforms, advanced biomaterials, and automated manufacturing, that may accelerate clinical translation. Reframing organoids as functionally engineered therapeutic platforms rather than increasingly complex anatomical models provides a conceptual foundation for advancing regenerative organoid therapies.
BACKGROUND:Diabetic kidney disease (DKD), the leading cause of end-stage renal disease, involves injury across multiple renal compartments. Autophagy dysregulation is a key pathogenic mechanism and may reduce Klotho, a renoprotective protein diminished in DKD. This study evaluated whether bone marrow-derived mesenchymal stem cells (MSCs), combined with empagliflozin and calorie restriction, could modulate autophagy and preserve Klotho expression in DKD. METHODS:Male BTBRob/ob mice, a leptin-deficient model that develops diabetes and DKD in a progressive manner, were assigned to experimental groups and euthanized at 14-15 or 18-20 weeks. Kidney tissues were analyzed by qPCR, Western blot, and immunohistochemistry. RESULTS:MSCs therapy improved hyperglycemia in a time-dependent manner (P < .0001), decreased albuminuria, and modestly improved eGFR, though weight gain persisted. Treatment modulated LC3 protein expression in cortical and medullary regions (P < .05), suggesting attenuation of early autophagy hyperactivation. It also helped maintain Klotho expression, correlating with reduced oxidative stress (P < .05). CONCLUSION:Overall, MSCs combined with empagliflozin and calorie restriction show promise as a translational approach for DKD, warranting further long-term preclinical studies.
Neural organoids have transformed experimental neuroscience by enabling human-specific models of brain development, function, and disease. Emerging at the intersection of stem cell biology and tissue engineering, these self-organizing systems recapitulate key aspects of neurogenesis, gliogenesis, and circuit formation within a controllable in vitro context. Advances in guided patterning, vascularization, and electrophysiological monitoring have enhanced structural and functional fidelity, enabling the study of dynamic processes previously inaccessible in human models. Beyond developmental biology, neural organoids have broad translational applications, including modeling neurodevelopmental and neurodegenerative disorders, screening pharmacological compounds, and testing regenerative strategies. Integration with microfluidics, bioelectronic interfaces, and computational modeling further expands their analytical capacity, transforming organoids into modular and quantifiable platforms for mechanistic and therapeutic discovery. Despite this progress, key challenges remain, including limited maturation, inter-organoid variability, and incomplete physiological integration. Addressing these limitations requires standardized differentiation protocols, robust functional benchmarks, and cross-disciplinary collaboration. The goal is not to replicate the brain in miniature, but to reconstruct its organizing principles in an experimentally accessible system. From this perspective, neural organoids serve as a bridge between biology and technology, offering new insights into human neural complexity while advancing neuroscience and medicine.
Diabetic enteropathy (DE) is a common complication of diabetes mellitus (DM), yet its underlying molecular mechanisms remain poorly understood. Emerging evidence suggests that abnormal differentiation of intestinal epithelial stem cells (IESCs) contributes to early intestinal dysfunction in DM. In this study, we aimed to investigate the role of CircVapa in regulating IESC differentiation and to elucidate the underlying molecular mechanism involving the miR-212-3p/Smoc2 axis. In this study, IESCs were extracted from BKS.CgDock7m+/+Lepr db/JNju (DM) mice models. A circular RNA molecule, CircVapa, was identified as being markedly enriched in IESCs. Experimental suppression of CircVapa in diabetic mice attenuated abnormal differentiation of intestinal epithelial cells (IECs). Notably, CircVapa was identified as a critical mediator of Lgr5+ stem cell functionality in hyperglycemic conditions. Mechanistically, microarray analysis, bioinformatics analysis, and luciferase reporter assays demonstrated that CircVapa serves as a competitive endogenous RNA (ceRNA) by directly binding miR-212-3p, thereby regulating Smoc2 expression. Furthermore, CircVapa regulated abnormal IESC differentiation via the miR-212-3p/Smoc2 regulatory network in diabetic mice. Collectively, this study demonstrates an important role of CircVapa in regulating IEC differentiation during DM progression.
Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness, yet its underly mechanisms remain unclear. Elevated intraocular pressure (IOP), the only modifiable risk factor for POAG, arises from increased resistance to aqueous humor outflow within the conventional outflow pathway, which comprises the trabecular meshwork (TM) and the inner wall of Schlemm's canal. Dysfunction and cellular loss within this pathway, particularly in the TM, are consistent features of the disease; however, the mechanisms responsible for impaired tissue maintenance and regenerative failure remain unclear. TM progenitor cells (TMPCs) have the capacity to replace lost TM cells, suggesting that impaired progenitor function may contribute to disease progression. Transforming growth factor beta 2 (TGFβ2), which is consistently elevated in the aqueous humor of POAG patients, plays a key role in regulating stem cell differentiation. We proposed that excess TGFβ2 disrupts TMPC function, leading to progenitor depletion and TM dysfunction. Here, we show that TGFβ2 drives TMPCs toward a differentiated, fibrotic phenotype, increasing TM and profibrotic gene expression while reducing progenitor markers. These effects are mediated through TGFβ2-SMAD2/3 signaling, as inhibition of this pathway preserves TMPC characteristics and suppresses fibrotic gene induction. Our findings identify TGFβ2-SMAD2/3 signaling as a regulator of TMPC fate in vitro and suggest a potential mechanism by which elevated TGFβ2 may influence TMPC behavior under pathological conditions.
BACKGROUND:Growth plate injuries in pediatric patients can lead to serious musculoskeletal complications, such as bony bar formation and potential growth arrest. Current clinical treatments have significant limitations, necessitating improved research models. METHODS:The present study developed a highly reproducible drill-hole injury model in the mouse distal femur and introduces a quantitative scoring system for assessing bony bar formation. Using micro-computed tomography (μCT) and histological analyses, we evaluated bone tissue formation over a 42-day period. A 5-point grading system was developed to evaluate bony bar extent, validated through radiological and histological comparisons. We further examine the utility of the model by injuring either transgenic mice with lineage tracing for platelet-derived growth factor receptor alpha (Pdgfra) or beta (Pdgfrb). RESULTS:we demonstrate a progressive increase in bone tissue formation over a 42-day period. While not present before injury, both Pdgfra and Pdgfrb reporter+ cells migrate into sites of growth plate injury and participate in bony bar formation. CONCLUSION:This model offers a standardized, reproducible, and validated approach to quantitatively study growth plate injury mechanisms, facilitating the use of transgenic animal models or the development of new therapeutic strategies in pediatric orthopedics.
BACKGROUND:Breast cancer (BC) has a high incidence and mortality rate among women. Doxorubicin (DOX) is one of the standard chemotherapeutic drugs for BC. However, chemoresistance to DOX represents a major therapeutic obstacle, and its underlying mechanisms remain elusive. CircEGFR (hsa_circ_0080222) is significantly upregulated in BC tissues and drives the malignant progression of BC. However, the role of circEGFR in DOX resistance remains unclear. METHODS:MTT and colony formation assays were used to assess cell growth. Quantitative real‑time PCR and western blot were performed to examine gene expression at the mRNA and protein levels, respectively. Spheroid formation and ALDH activity assays were employed to evaluate cell stemness. RNA immunoprecipitation was used to explore the interaction between circEGFR and IGF2BP2. RESULTS:CircEGFR expression was significantly upregulated in DOX-resistant MCF-7 (MCF-7/DOX) cells. CircEGFR overexpression attenuated DOX sensitivity in MCF-7 cells, as evidenced by increased cell viability and enhanced proliferative capacity. Notably, circEGFR also enhanced cancer stem cell (CSC) properties in BC cells. Conversely, circEGFR knockdown reduced chemoresistance and stem-like properties in both MDA-MB-231 and MCF-7/DOX cells. Mechanistically, circEGFR interacted with IGF2BP2 to enhance the stability of the stem cell marker SOX2 mRNA, resulting in elevated SOX2 expression. Rescue experiments demonstrated that silencing IGF2BP2 or SOX2 abrogated circEGFR-mediated chemoresistance and stemness properties in BC cells. CONCLUSION:Our study demonstrates for the first time that circEGFR drives DOX chemoresistance and maintains cancer stemness in BC cells via the IGF2BP2/SOX2 axis. Targeting circEGFR may be considered a promising therapeutic strategy for overcoming chemotherapy resistance in BC.
Initially regarded as insignificant cellular waste, extracellular vesicles (EVs) are now recognized as key mediators of intercellular communication, capable of transferring bioactive molecules-such as proteins, nucleic acids, and small compounds-between cells. This function has positioned EVs as promising cell-free therapeutic agents with the potential to transform modern medicine. Stem and progenitor cells naturally release EVs that can replicate many of the therapeutic effects of cell transplantation, while avoiding the challenges associated with administering living cells. EVs derived from various cell sources-including embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, stromal cells, cardiac progenitor cells, and endothelial progenitor cells-have shown therapeutic efficacy in preclinical models of ischemic heart disease. EVs' translation into human trials in cardiac therapy has lagged behind, however, largely due to challenges related to EV production standardization, regulatory frameworks, and the demonstration of reproducible efficacy in human subjects. Nevertheless, recent milestones have been achieved with the successful completion of the phase I EV-AMI trial (Safety Evaluation of Intracoronary Infusion of EVs in Patients with Acute Myocardial Infarction, NCT04327635) and the enrollment of the first patient in the phase I SECRET-HF trial (Treatment of Non-ischemic Cardiomyopathies by Intravenous Extracellular Vesicles of Cardiovascular Progenitor Cells, NCT05774509). This concise review outlines the evolution of EVs from basic biological discovery to innovative therapeutic platforms, with particular emphasis on their potential applications in acute myocardial infarction. Remaining challenges for clinical translation, including manufacturing and regulatory hurdles, will also be discussed.
Adipose-derived mesenchymal stem cell (ADMSC) exosomes have emerged as promising therapeutic agents for degenerative joint diseases, yet their molecular actions in knee osteoarthritis (KOA) remain inadequately defined. In this study, exosomes were isolated from ADMSCs under both physiological and IL-1β-induced inflammatory conditions and comprehensively characterized by NTA, TEM, and exosome marker expression. Both types of exosomes were efficiently internalized by chondrocytes, with uptake reaching saturation after 12 hours regardless of inflammatory status. Functional assays revealed that while exosomes from healthy ADMSCs (EXOs) significantly enhanced levels of mitochondrial fusion proteins and decreased fission marker in IL-1β-induced chondrocytes after 24 hours, these beneficial effects were absent in exosomes derived from inflamed ADMSCs (IL-1β EXOs). Notably, EXO treatment reduced intracellular ROS accumulation, boosted SOD2 levels, and diminished apoptotic cell rates in chondrocytes. In vivo, administration of EXOs to rats with ACLT-induced KOA markedly alleviated cartilage degeneration, restoration of mitochondrial dynamics, and suppression of inflammatory and matrix-degrading mediators. Transcriptomic analysis showed that EXOs activated gene expression programs related to fatty acid metabolism, oxidative phosphorylation, and AMPK signaling, while IL-1β EXOs enriched inflammatory and apoptotic pathways. Importantly, both genetic knockdown and pharmacological inhibition of AMPK abolished the restorative effects of EXOs on mitochondrial dynamics and on the reduction of apoptotic markers both ex vivo and in vivo. These findings demonstrate that exosomes secreted by ADMSCs preserve cartilage integrity in KOA via AMPK-mediated mitochondrial dynamics. This work supports AMPK-targeted modulation of mitochondrial dynamics by stem cell exosomes as a promising disease-modifying strategy for KOA.
Huntington's disease (HD) is a neurodegenerative disorder caused by cytosine-adenine-guanine (CAG) triplet expansion in the HTT gene, producing a mutant Huntingtin protein that impairs mitochondrial dynamics by reducing fusion and increasing fission. Mesenchymal stem cells (MSCs) have shown potential therapeutic effects by sharing functional mitochondria and other secretomes. In this study, quinolinic acid-lesioned neuro-2a (QA-N2a) cells and glutamatergic neurons with 50 CAG repeats (HD neurons) were co-cultured with human umbilical cord-derived MSCs for 5 hours. For QA-N2a cells, immunocytochemistry (ICC) was performed to demonstrate the change in GABA and Substance P before and after co-culture. For HD neurons, ICC was conducted to identify mitochondrial proteins, while Western blot was employed to evaluate proteins related to inflammation and mitochondrial function. As a result, co-culture with MSC significantly restored the expression of GABA and Substance P, which diminished after QA exposure. In HD neurons co-cultured with MSCs, an increase in mitochondrial abundance was observed, with significantly higher intensity and dendritic distribution of mitochondria compared to control cells. Western blot analysis confirmed this increase and showed a rising trend in ATP5a levels. MSCs also promoted mitochondrial fusion, indicated by higher levels of Mitofusin 2 (MFN2) and Mitochondrial Dynamin Like GTPase (OPA1), and a trend of reduction in the fission marker Dynamin-Related Protein (DRP1). Additionally, the co-culture led to a decreased trend in neuroinflammation markers IL-6, TNF-α, MMP9, and p-NFkB. Collectively, this study demonstrates that MSCs alleviate HD pathology by restoring the mitochondria activity and potentially suppressing inflammation in two different HD in vitro models.
Therapeutic angiogenesis (TA) is a promising strategy for treating ischemic diseases, mainly by targeting the angiogenesis pathways and cells, particularly VEGF and endothelial progenitor cells. Although stem cell therapy has been extensively investigated, its clinical translation remains limited by challenges such as poor cell retention, low survival rates, and inefficient integration. In this review, we propose a mechanism-based framework of angiogenesis to discuss how biomaterials act synergistically with stem cells mainly through two distinct pathways: enhancing paracrine capacity and promoting direct differentiation of vascular lineage cells for vascular repair. Firstly, we go through the scientific literature and clinical studies, and summary the researches on biomaterials serve as artificial microenvironments to improve the retention and secretory function of mesenchymal stem cells (MSCs) and adipose-derived stem cells (ADSCs), thereby maximizing the release of angiogenic factors such as VEGF, bFGF, NGF, microRNA and so on. Secondly, we explore how functionalized biomaterials guide the in situ recruitment of endothelial progenitor cells (EPCs) and support the structural maturation of induced pluripotent stem cell (iPSC)-derived endothelial cells. By integrating these mechanism-driven approaches, we offer new perspectives on future directions for preclinical research and clinical translation of biomaterial-based therapies. Overall, this review has examined the role of individual stem cells and biomaterials, especially enhanced angiogenesis by stem cells focusing on their mechanisms of action and preclinical and clinical applications. We further discussed the challenges encountered by stem cell therapy in advancing to the stage of clinical transformation and considered future prospects.
Human embryonic stem cell (hESC)-derived hepatocytes (hEHs) display functional deficits, particularly impaired albumin secretion and ammonia metabolism, compared to primary human hepatocytes (PHHs). Here, we investigated the regulatory role of CCAAT/enhancer-binding protein beta (C/EBPβ) in hepatocyte maturation. Forced C/EBPβ expression enhanced hepatocyte functionality and upregulated hepatocyte-specific genes, while suppressing epithelial-mesenchymal transition (EMT) via downregulating canonical EMT markers. Mechanistically, CUT&Tag and luciferase reporter assays confirmed C/EBPβ directly bound to the promoter regions of CDH1 (E-cadherin) and CPS1 (carbamoyl phosphate synthetase 1). Co-immunoprecipitation identified an interaction between C/EBPβ and the MAPK pathway. RNA interference combined with Western blot analysis revealed that MAPK1-mediated phosphorylation of C/EBPβ at Thr-235 augmented its transactivation activity, accelerating hepatocyte maturation. Our findings establish C/EBPβ as a master regulator that coordinates transcriptional networks and post-translational modifications during hEHs maturation, providing novel insights for generating mature hepatocytes for disease modeling and regenerative medicine applications.
The sense of smell is maintained by regenerating olfactory sensory neurons (OSNs) from basal stem cells in the olfactory epithelium (OE). Acute inflammation destroys OSNs, causing hyposmia and anosmia, but activates basal cells. Manipulation of signaling pathways to promote basal cell proliferation and neuroregeneration would reveal novel therapeutic targets for smell deficits. We found that ciliary neurotrophic factor (CNTF) from horizontal basal cells (HBCs, quiescent stem cells) promotes neuroregeneration and functional recovery following methimazole-induced acute injury. Moreover, inhibition of focal adhesion kinase (FAK) upregulates CNTF in naïve OE. Here, we show that the small molecule FAK inhibitor increased CNTF expression in cultured primary HBCs isolated from methimazole-treated mice. Although methimazole-induced CNTF did not seem to be through FAK signaling, inducible cre-lox knockout of FAK in HBCs in mice further increased CNTF expression, as well as Mash1, a marker for globose basal cells (GBCs, neuronal progenitors), and GBC proliferation. Moreover, intranasal aspiration, but not systemic treatment, of a water-soluble pharmacological FAK inhibitor (FAK14) 3 days following methimazole, dose-dependently increased CNTF and Mash1 expression, and GBC proliferation. Intranasal FAK14 also enhanced methimazole-induced regeneration of new OSNs in CNTF+/+, but not in CNTF-/-, mice, demonstrating that FAK14 boosts neuroregeneration through additional CNTF following acute inflammation. Finally, intranasal FAK14 instillation following methimazole improved the functional recovery of smell. This study identifies the therapeutic potential of intranasal application of FAK inhibitors to enhance olfactory neuroregeneration and function following injury.
Postnatal skeletal growth in childhood and adolescence depends on cartilage organs called (epiphyseal) growth plates. Studies in the last decade have identified populations of skeletal stem cells within mouse growth plates' resting zones. While cellular quiescence is vital for the maintenance of many tissue-resident stem cell populations, the resting zone chondrocytes have been labeled "quiescent" for decades. However, the features of cellular quiescence that have been reported in the postnatal resting zone, how they were defined or experimentally assessed, and knowledge gaps relative to other quiescent cell types, remain to be well described. To address this, we conducted a systematic review, using the PRISMA guidelines, to identify studies of resting zone chondrocytes including the prefix "quiescen*." Definitions, keywords, chronological data and experimental findings were extracted. Our analysis demonstrated that, compared to those in other well-studied tissues, features of cellular quiescence in RZ chondrocytes remain poorly reported and underexplored, with limited molecular and functional characterization. Furthermore, while most identified studies reported changes in cell division parameters, integration between cues controlling resting zone cell quiescence is incomplete and heterogeneity among the various sub-populations of RZ cells/potential quiescent states is yet to be fully determined. This review identifies consensuses and knowledge gaps between studies and between quiescent RZ cells and those in other tissues and can act to enhance consistency and comparability in future studies of "quiescence" in the RZ chondrocytes.
Background Peripheral nerve injuries (PNIs) present a persistent clinical challenge due to the intrinsically limited regenerative capacity of peripheral nerves. While dental pulp stem cells (DPSCs) exhibit significant neuroregenerative potential, their therapeutic efficacy is constrained by hostile microenvironments and inherent functional heterogeneity. Genetic modification may offer a promising strategy to enhance their therapeutic capabilities.Methods DPSCs were induced toward neural lineage differentiation, and key gene candidates were identified through qRT-PCR. Lentiviral-mediated gene interference was performed to modulate target gene expression, followed by comprehensive analysis of differentiation outcomes using qRT-PCR, Western blotting, and immunofluorescence assays. RNA sequencing was employed to uncover associated signaling pathways, which were subsequently validated through pharmacological inhibition with specific inhibitors. The therapeutic efficacy of genetically engineered DPSCs was evaluated in a rat model of sciatic nerve crush injury, with neural regeneration quantitatively assessed via neuroelectrophysiological measurements and histological analyses.Results LARP7 positively regulated the Schwann cell-like differentiation of DPSCs, as well as their trophic and anti-inflammatory effects, thus enhancing its therapeutic effects on nerve repair and promoting functional recovery. Mechanistically, we found that LARP7 remodeled cytokine-cytokine receptor interactions, enhancing trophic support while attenuating proinflammatory responses, and activated the PI3K-Akt-mTOR signaling pathway, with ERBB4 serving as a critical downstream effector, promoting DPSCs differentiation into Schwann cell-like phenotypes.Conclusions Collectively, LARP7-mediated changes in DPSCs establish a new therapeutic paradigm that addresses the limitations of current stem cell-based interventions and enables the development of standardized biotherapeutics for peripheral nerve repair.
Muscle satellite cells are adult muscle stem cells indispensable for growth and regeneration of postnatal skeletal muscle. Notch plays a central role in maintenance of muscle satellite cells, but how Notch maintains the muscle stem cell pool is not fully understood. Previously, we reported that a prostaglandin E2 receptor, EP2, is upregulated by Notch signal and suppresses differentiation of human muscle progenitors. Here we examined the roles of EP2 in muscle satellite cells using a mouse Cre-LoxP conditional gene knockout system. Genetic inactivation of the EP2 gene (PTGER2) activated muscle satellite cells, caused their loss, and impaired muscle regeneration. These results indicate that EP2 is indispensable for maintenance of satellite cells. Ex vivo analysis using isolated myofibers showed that prostaglandin E2 (PGE2) delayed the activation of satellite cells via EP2. An extracellular signal-regulated kinase (ERK) 1/2 inhibitor blocked the activation of satellite cells on myofibers, and PGE2 attenuated the phosphorylation of ERK1/2 in muscle satellite cells. These results suggest that EP2 keeps the quiescence of satellite cells and maintains the satellite cell pool in part by inhibiting the ERK1/2 signaling pathway.
