Differentiation Of Precursor Cells Research Articles

The differentiation of glial precursors into neuronal-like cells through the Wnt and Neurotrophin signaling pathways via Ctnnβ1

ABSTRACT Glial precursor cells are among the major types of glia in the dorsal root ganglias (DRGs) of the peripheral nervous system. Previous studies have shown that the transdifferentiation of DRGs-derived glial precursor cells contributes to peripheral neurogenesis. In the present study, we investigated the mRNA expression profiles and examined the effects of differential expression mRNAs (DEMs) during the differentiation of glial precursor cells derived from the rat DRGs. We characterized glial precursor cells derived from rat DRGs explants using immunofluorescence. Sequencing was subsequently conducted, followed by enrichment analysis utilizing gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The identified genes were subsequently subjected to protein–protein interaction (PPI) network analysis during the differentiation process of glial precursor cells derived from the rat DRGs. The establishment of a sciatic nerve injury (SNI) model was followed by the detection of the expression of key genes in the Wnt and Neurotrophin pathways in the DRGs of SNI rats via qRT–PCR. Additionally, the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was employed to assess apoptosis in the DRGs. We detected the mRNA expression profiles during the neuronal differentiation of rat DRGs-derived glial precursor cells. More DEMs and GO terms were detected on the third day of DRGs-derived glial precursor cells transdifferentiation, accompanied by morphological alterations in the cells; that is, some cells presented neuronal-like phenotypic characteristics (the early neuronal marker Tuj1 was positive). KEGG enrichment and PPI network analyses revealed that Wnt and Neurotrophin pathways play crucial roles in the process of glial precursor cell differentiation into neuronal-like cells. After knocking down cadherin-associated protein beta 1 (Ctnnβ1) in the SNI model, the number of apoptotic cells was significantly reduced, and the expression of Wnt4 and Ntrk3 was significantly increased. The Ctnnβ1 gene may be a crosstalk factor between the Wnt and Neurotrophin pathways that negatively regulates the differentiation of glial precursor cells.

Paroxetine ameliorates corticosterone-induced myelin damage by promoting the proliferation and differentiation of oligodendrocyte precursor cells.

Paroxetine ameliorates corticosterone-induced myelin damage by promoting the proliferation and differentiation of oligodendrocyte precursor cells.

Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells.

Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells.

Electroacupuncture Promotes the Proliferation and Differentiation of Enteric Neural Precursor Cells via the PTEN/PI3K/Akt/mTOR Signaling Pathway in Diabetic Mice.

Enteric neuronal loss significantly contributes to gastrointestinal (GI) motility disorders. Electroacupuncture (EA) can promote the regeneration of lost enteric neurons in diabetic mice, but its mechanisms are not fully understood. Nestin+/Ngfr+ cells can function as enteric neural precursor cells (ENPCs) to proliferate and differentiate into enteric neurons in adult mice. However, EA's effects on ENPCs remain unknown. The study aimed to investigate whether EA reversed enteric neuronal loss via regulation of ENPCs and its molecular basis. The study utilized conventional C57BL/6J mice and ENPC-tracing transgenic mice. Streptozotocin-induced type 1 diabetic mouse, PI3K inhibitor, and PTEN inhibitor models were used. GI motility was evaluated by defecation frequency, fecal water content, and whole gut transit test. The alterations of enteric neurons, ENPCs, and PTEN/PI3K/Akt/mTOR signaling were detected by Western blot and immunofluorescence. EA increased defecation frequency and fecal water content, reduced whole gut transit time, and increased the number of enteric neurons. Notably, EA inhibited ENPC apoptosis and facilitated ENPC proliferation and differentiation with a preferential into ChAT enteric neurons. Additionally, PTEN was decreased and PI3K/Akt/mTOR signaling was activated with EA. However, LY294002 (PI3K inhibitor) inhibited EA's effects on ENPCs, while BpV(HOpic) (PTEN inhibitor) partially rescued these inhibitory effects. EA alleviates diabetic enteric neuropathy by regulating ENPC dynamics through the PTEN/PI3K/Akt/mTOR signaling pathway. Notably, EA-mediated anti-apoptotic and pro-proliferative effects on ENPCs, and their preferential cholinergic differentiation establish EA as a multimodal therapy that bridges neuromodulation with precursor cell biology, offering an alternative strategy for GI motility disorders.

Repurposed Drugs to Enhance the Therapeutic Potential of Oligodendrocyte Precursor Cells Derived from Adult Rat Adipose Tissue.

Failure in the proliferation, recruitment, mobilization, and/or differentiation of oligodendrocyte precursor cells (OPCs) impedes remyelination in central nervous system (CNS) demyelinating diseases. Our group has recently achieved the generation of functional oligodendroglia through direct lineage conversion by expressing Sox10, Olig2, and Zfp536 genes in adult rat adipose tissue-derived stromal cells. The present study aimed to determine whether various repurposed drugs or molecules could enhance the myelinating capacities of these induced OPCs (iOPCs). We report that kainate, benztropine, miconazole, clobetasol, and baclofen promote in vitro iOPCs migration, differentiation, and ensheathing abilities through mechanisms similar to those observed in rat neural stem cell-derived OPCs. This research supports the potential use of iOPCs as they provide an alternative and reliable cell source for testing the effects of in vitro promyelinating repurposed drugs and for assessing the molecular and cellular mechanisms involved in therapeutic strategies for demyelinating diseases.

Impaired remyelination in late-onset multiple sclerosis

A reduced regenerative capacity may contribute to faster disease progression and poorer relapse recovery in multiple sclerosis patients with disease onset after the age of 50, a condition known as late-onset multiple sclerosis (LOMS). We hypothesized that lesions in LOMS patients show more pronounced axonal damage, less remyelination and an altered inflammatory composition, and performed a detailed histopathological analysis of MS biopsies in patients with early-stage LOMS. The number of T cells, B cells, plasma cells, microglia/macrophages, different oligodendrocyte populations as well as the axonal density and acute axonal damage were assessed in 31 LOMS and 30 normal-onset MS (NOMS, 20–40 years old) patients. No major differences in the inflammatory infiltrate or axonal damage were found. BCAS1-positive oligodendrocytes indicating early myelinating oligodendrocytes, and mature oligodendrocytes were significantly lower in the normal-appearing white matter of LOMS compared to NOMS patients (p = 0.05; p = 0.01), with a negative correlation with age (r = − 0.5, p = 0.01). In active demyelinating lesions, the number of BCAS1-positive oligodendrocytes did not differ between LOMS and NOMS, but NOMS lesions showed a higher proportion of ramified cells indicating active remyelination. In LOMS, BCAS1-positive oligodendrocytes decreased with increasing lesion age, with the lowest numbers found in inactive demyelinated lesions. In contrast, NOMS patients showed high numbers of BCAS1-positive cells with an activated morphology, even in inactive demyelinated lesions. At the last follow-up, LOMS patients had a significantly higher EDSS score (median 3.5) than NOMS patients (median 3.0, p = 0.05). A higher EDSS score correlated with fewer mature and oligodendrocyte precursor cells in active demyelinating lesions (r = − 0.4, p = 0.01 and r = − 0.6, p = 0.003). These findings suggest a clinically relevant impaired oligodendrocyte differentiation and remyelination in LOMS. Since remyelination is essential for axonal protection, it will be necessary to consider the complex and dynamic tissue environment when researching therapeutics aimed at fostering the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes.

Novel araucarene diterpenes from Agathis dammara exert hypoglycemic activity by promoting pancreatic β cell regeneration and glucose uptake.

In this study, araucarene diterpenes, characterized by a pimarene skeleton with a variably oxidized side chain at C-13, were investigated. A total of 16 araucarene diterpenoids and their derivatives were isolated from the woods of Agathis dammara, including 11 previously unreported compounds: dammaradione (1), dammarones D-G (2, 5, 14, 15), dammaric acids B-F (8-12), and dammarol (16). The structures of these new compounds were elucidated using high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and one-dimensional/two-dimensional (1D/2D) nuclear magnetic resonance (NMR), while their absolute configurations were determined through the electronic circular dichroism (ECD) exciton chirality method and Snatzke's method. The hypoglycemic activity of all isolated compounds was evaluated using a transgenic zebrafish model, and a structure-activity relationship (SAR) analysis was conducted. Araucarone (3) and dammaric acid C (9), serving as representative compounds, demonstrated significant hypoglycemic effects on zebrafish. The primary mechanism involves the promotion of pancreatic β cell regeneration and glucose uptake. Specifically, these compounds enhance the differentiation of pancreatic endocrine precursor cells (PEP cells) into β cells in zebrafish.

Expression and Function of miR-144 in β-Thalassemia

Expression and Function of miR-144 in β-Thalassemia

Microglial Lcn2 knockout enhances chronic intracerebral hemorrhage recovery by restoring myelin and reducing inflammation.

Rationale: Damage to white matter and myelin poses a significant challenge to neurological recovery in the chronic phase of intracerebral hemorrhage (ICH). The repair of myelin damage post-ICH largely depends on the activation and differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes, a process that is significantly influenced by the inflammatory microenvironment. Lipocalin-2 (Lcn2) regulate phenotypic transformation of microglia and thus modulates inflammation. However, the exact role of Lcn2 in facilitating myelin recovery during the chronic phase of ICH remains to be fully understood. Methods: To create the ICH model, autologous blood from male C57BL/6 and Lcn2fl/flCx3cr1Cre mice was utilized. Behavioral tests were conducted to evaluate neurological recovery. The differentiation of OPCs and extent of myelin recovery were assessed using OPC and myelin markers. A multi-factor inflammatory chip was employed to investigate potential molecular regulatory mechanisms. Additionally, the Lcn2 inhibitor ZINC-94/89 was administered to explore its potential in targeting Lcn2 for enhancing myelin recovery during the chronic phase of ICH. Results: Knocking out Lcn2 in microglia significantly improved behavioral performance in chronic ICH mice, reduced inflammatory response, and enhanced myelin recovery. Both in vivo and in vitro experiments confirmed that Lcn2 knockout promoted microglia transformation to the M2 phenotype and enhanced OPCs differentiation. Mechanistically, Lcn2 knockout might affect Gdf-1 secretion in BV2 cells by modulating the JAK/STAT signaling pathway. Treatment with JAK inhibitors decreased Gdf-1 expression in BV2 cells, inhibiting OPCs migration and differentiation. Additionally, phosphorylation of Stat3 at Thr705 plays a critical role in enhancing Gdf-1 transcription and translation. Administration of the Lcn2 inhibitor ZINC-94/89 significantly improved behavioral performance, reduced inflammatory response, and promoted myelin recovery in chronic ICH mice. Conclusions: Lcn2 is crucial for myelin recovery in the chronic phase of ICH by modulating microglial phenotypes, thereby enhancing the migration and differentiation of OPCs. Administering an Lcn2 inhibitor early on could serve as a novel and effective strategy to boost recovery during this phase.

Enhancing myelinogenesis through LIN28A rescues impaired cognition in PWMI mice

BackgroundIn premature newborn infants, preterm white matter injury (PWMI) causes motor and cognitive disabilities. Accumulating evidence suggests that PWMI may result from defected differentiation of oligodendrocyte precursor cells (OPCs) and impaired maturation of oligodendrocytes. However, the underlying mechanisms remain unclear.MethodsUsing RNAscope, we analyzed the expression level of RNA-binding protein LIN28A in individual OPCs. Knockout of one or both alleles of Lin28a in OPCs was achieved by administrating tamoxifen to NG2CreER::Ai14::Lin28aflox/+ or NG2CreER::Ai14::Lin28aflox/flox mice. Lentivirus expressing FLEX-Lin28a was used in NG2CreER mice to overexpress LIN28A in OPCs. A series of behavioral tests were performed to assess the cognitive functions of mice. Two-tailed unpaired t-tests was carried out for statistical analysis between groups.ResultsWe found that the expression of Lin28a was decreased in OPCs in a PWMI mouse model. Knockout of one or both alleles of Lin28a in OPCs postnatally resulted in reduced OPC differentiation, decreased myelinogenesis and impaired cognitive functions. Supplementing LIN28A in OPCs postnatally was able to promote OPC differentiation and enhance myelinogenesis, thus rescuing the cognitive functions in PWMI mice.ConclusionOur study reveals that LIN28A is critical in regulating postnatal myelinogenesis. Overexpression of LIN28A in OPCs rescues cognitive deficits in PWMI mice by promoting myelinogenesis, thus providing a potential strategy for the treatment of PWMI.

Multi-modal magnetic resonance imaging assessment and mechanism exploration of preterm white matter injury in neonatal rats

To evaluate preterm white matter injury (PWMI) in neonatal rats using multimodal magnetic resonance imaging (MRI) combined with histological assessments and to explore its underlying mechanisms. Healthy 3-day-old Sprague-Dawley neonatal rats were randomly divided into a sham operation group and a PWMI group (n=12 in each group). A PWMI model was established in neonatal rats through hypoxia-ischemia. Laser speckle imaging was used to observe changes in cerebral oxygen saturation and blood flow at different time points post-modeling. Multimodal MRI was employed to assess the condition of white matter injury, while hematoxylin-eosin staining was utilized to observe morphological changes in the striatal area on the injured side. Immunofluorescence staining was performed to detect the proliferation and differentiation of oligodendrocyte precursor cells. At 0, 6, 12, 24, and 72 hours post-modeling, the relative blood flow and relative oxygen saturation on the injured side in the PWMI group were significantly lower than those in the sham operation group (P<0.05). At 24 hours post-modeling, T2-weighted imaging showed high signals in the white matter of the injured side in the PWMI group, with relative apparent diffusion coefficient values and Lorenz differential values being lower than those in the sham operation group (P<0.001); additionally, the arrangement of nerve cells in the PWMI group was disordered, and the number of EdU+PDGFR-α+ cells was higher than that in the sham operation group (P<0.001). At 28 days post-modeling, the relative fractional anisotropy values, the number of EdU+Olig2+ cells, and the fluorescence intensity of myelin basic protein and neurofilament protein 200 in the white matter region of the PWMI group were all lower than those in the sham operation group (P<0.001). Multimodal MRI can evaluate early and long-term changes in PWMI in neonatal rat models in vivo, providing both imaging and pathological evidence for the diagnosis and treatment of PWMI in neonates. Hypoxia-ischemia inhibits the proliferation and differentiation of oligodendrocyte precursor cells in neonatal rats, leading to PWMI.

MDP/NOD2 enhances RANKL-induced osteoclast differentiation of RAW264.7 cells.

MDP/NOD2 enhances RANKL-induced osteoclast differentiation of RAW264.7 cells.

Combination Therapy Dramatically Promotes Remyelination.

Multiple sclerosis (MS) is an immune-mediated disease in the central nervous system that is characterized by demyelination, axonal degeneration, and progressive neurological disability and is so far incurable. Current medications are predominantly immune-targeted but fail to prevent disease progression due to their inability to actively promote remyelination. Small molecules have been reported to promote myelin regeneration but their therapeutic efficacy is limited by insufficient immune modulation. Thus, the strategies achieving both immunomodulation and active myelin regeneration are highly desired. Here, we investigated a combination therapy (CT) for MS designed to simultaneously modulate immune responses and promote oligodendrocyte precursor cell (OPC) differentiation and in situ remyelination in an experimental autoimmune encephalomyelitis (EAE) mouse model. Remarkably, CT suppressed acute inflammatory activity, activated the signaling pathways for myelin development, induced the expression of myelin-related genes, and significantly promoted remyelination and the recovery of motor performance. Furthermore, a reduced immunomodulator dosage or shorter treatment duration with small-molecule drugs achieved comparable symptom reversal. Our findings demonstrate the potential of CT to address complex pathobiology and lay a foundation for developing novel therapeutic strategies for MS.

Electrospun scaffolds for heart valve tissue engineering

A potential solution for prosthetic heart valves is tissue-engineered heart valves. Tissue-engineered heart valves (TEHVs) are designed to replicate the complex properties found in natural tissues, such as stiffness, anisotropy, and composition and organization of cells and extracellular matrix (ECM). Electrospinning is regarded as a highly versatile and innovative approach for fabricating numerous fibrous designs. In this review, we discuss recent developments in electrospun heart valve scaffolds, including scaffold materials, cell types, and electrospinning setups used to prepare aligned nanofibers. Despite the fact that natural biomaterials provided excellent biocompatibility, nanofibers from synthetic materials provided the required mechanical compatibility. Accordingly, most studies highlighted the benefits of designing composite heart valves using biological and synthetic polymers. Various strategies, such as the application of motorized mandrel and micropatterned collector in electrospinning were effective in controlling nanofiber alignment. Studies also showed that aligned nanofiber’s mechanical strength and anisotropic structure promote cell proliferation, and differentiation, and promote attachment. Numerous studies have reported that multiple cell sources are suitable for producing heart valves. Successful results were obtained with human umbilical vein endothelial cells (HUVECs), since they provide a convenient cell source for cellularization of valve leaflets. A higher conductivity of scaffolds was achieved by using biomaterials that conduct electricity, such as polyaniline, polypyrrole, and carbon nanotubes, which resulted in better differentiation of precursor cells to cardiomyocytes and higher cell beating rates. In light of these attributes, nanofibrous scaffolds produced through electrospinning are expected to offer numerous advantages for tissue engineering and medical applications in the near future. However, multiple challenges were identified as cell infiltration and 2D nature of nanofiber mats necessitate further engineering approaches in electrospinning procedure leaflet production.

Gastrodin promotes CNS myelinogenesis and alleviates demyelinating injury by activating the PI3K/AKT/mTOR signaling.

Demyelination is a common feature of numerous neurological disorders including multiple sclerosis and leukodystrophies. Although myelin can be regenerated spontaneously following injury, this process is often inadequate, potentially resulting in neurodegeneration and exacerbating neurological dysfunction. Several drugs aimed at promoting the differentiation of oligodendrocyte precursor cells (OPCs) have yielded unsatisfactory clinical effects. A recent study has shifted the strategy of pro-OPC differentiation towards enhancing myelinogenesis. In this study we identified the pro-myelinating drug using a zebrafish model. Five traditional Chinese medicine monomers including gastrodin, paeoniflorin, puerarin, salidroside and scutellarin were assessed by bath-application in Tg(MBP:eGFP-CAAX) transgenic line at 1-5 dpf. Among the 5 monomers, only gastrodin exhibited significant pro-myelination activity. We showed that gastrodin (10 µM) enhanced myelin sheath formation and oligodendrocyte (OL) maturation without affecting the number of OLs. Gastrodin markedly increased the phosphorylation levels of PI3K, AKT, and mTOR in primary cultured OLs via direct interaction with PI3K. Co-treatment with the PI3K inhibitor LY294002 (5 µM) mitigated gastrodin-induced OL maturation. Furthermore, injection of gastrodin (100 mg·kg-1·d-1, i.p.) effectively facilitated remyelination in a lysophosphatidylcholine-induced demyelinating mouse model and alleviated demyelination in the experimental autoimmune encephalomyelitis mice. These results identify gastrodin as a promising therapeutic agent for demyelinating diseases and highlight the potential of the zebrafish model for screening pro-myelinogenic pharmacotherapy.

Intrinsic retinoic acid synthesis is required for oligodendrocyte progenitor expansion during CNS remyelination.

Myelin regeneration (remyelination) in the CNS depends on the recruitment, proliferation and differentiation of oligodendrocyte precursor cells (OPCs) at demyelinated lesions. However, despite the presence of OPCs, very few oligodendrocytes and myelin are regenerated in chronic multiple sclerosis (MS) lesions for reasons that remain poorly understood. Here, using a spontaneous remyelination model in mice, we found that retinaldehyde dehydrogenase 2 (Raldh2), a rate-limiting enzyme for retinoic acid (RA) synthesis, is upregulated in OPCs and in a subpopulation of microglia/macrophages during remyelination. Tamoxifen induced deletion of Raldh2 globally, or conditionally in OPCs, resulted in significantly fewer proliferating OPCs in lesions, leading to decreased oligodendrocyte numbers and myelin density. Moreover, induced deletion of Raldh2 globally also resulted in increased microglia/macrophage density in lesions. Further, exogenous RA delivery into lesions significantly increased oligodendrocyte lineage cells, while also decreasing proinflammatory microglia/macrophages, with no significant effect on anti-inflammatory microglia/macrophages. Postmortem MS brain sections revealed Raldh2 was absent in the majority of OPCs in chronic inactive lesions compared to the other lesion types. These results suggest that Raldh2 upregulation in lesions is critical for OPC proliferation during remyelination, and reveal that the failure to regenerate sufficient oligodendrocytes and myelin in chronic MS lesions may arise from impaired OPC expansion due to the failure to intrinsically synthesize RA.

Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a−/− OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a−/− OPCs in vitro and myelination in Tmem63a−/− mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca2+ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.

Targeting Oligodendrocyte Dynamics and Remyelination: Emerging Therapies and Personalized Approaches in Multiple Sclerosis Management.

Multiple sclerosis (MS) is a progressive autoimmune condition that primarily affects young people and is characterized by demyelination and neurodegeneration of the central nervous system (CNS). This in-depth review explores the complex involvement of oligodendrocytes, the primary myelin- producing cells in the CNS, in the pathophysiology of MS. It discusses the biochemical processes and signalling pathways required for oligodendrocytes to function and remain alive, as well as how they might fail and cause demyelination to occur. We investigate developing therapeutic options that target remyelination, a fundamental component of MS treatment. Remyelination approaches promote the survival and differentiation of oligodendrocyte precursor cells (OPCs), restoring myelin sheaths. This improves nerve fibre function and may prevent MS from worsening. We examine crucial parameters influencing remyelination success, such as OPC density, ageing, and signalling pathway regulation (e.g., Retinoid X receptor, LINGO-1, Notch). The review also examines existing neuroprotective and antiinflammatory medications being studied to see if they can assist oligodendrocytes in surviving and reducing the severity of MS symptoms. The review focuses on medicines that target the myelin metabolism in oligodendrocytes. Altering oligodendrocyte metabolism has been linked to reversing demyelination and improving MS patient outcomes through various mechanisms. We also explore potential breakthroughs, including innovative antisense technologies, deep brain stimulation, and the impact of gut health and exercise on MS development. The article discusses the possibility of personalized medicine in MS therapy, emphasizing the importance of specific medicines based on individual molecular profiles. The study emphasizes the need for reliable biomarkers and improved imaging tools for monitoring disease progression and therapy response. Finally, this review focuses on the importance of oligodendrocytes in MS and the potential for remyelination therapy. It also underlines the importance of continued research to develop more effective treatment regimens, taking into account the complexities of MS pathology and the different factors that influence disease progression and treatment.

STING1 targets MYH9 to drive adipogenesis through the AKT/GSK3β/β-catenin pathway.

STING1 targets MYH9 to drive adipogenesis through the AKT/GSK3β/β-catenin pathway.

Epiregulin ameliorates ovariectomy-induced bone loss through orchestrating the differentiation of osteoblasts and osteoclasts.

Epiregulin plays a role in a range of biological activities including malignancies. This study aims to investigate the potential contribution of epiregulin to bone cell differentiation and bone homeostasis. The data showed that epiregulin expression was upregulated during osteogenesis but downregulated during adipogenesis. Functionally, epiregulin promoted osteoblast differentiation while inhibiting adipocyte differentiation from mesenchymal progenitor cells. Epidermal growth factor receptor (EGFR), one of the two known receptors for epiregulin, exerted opposing effects compared to epiregulin. Intriguingly, silencing EGFR almost completely abolished the dysregulation of osteoblast and adipocyte differentiation induced by epiregulin, suggesting that EGFR is indispensable for mediating epiregulin function. Further mechanistic exploration indicated that epiregulin/EGFR signaled via the inactivation of mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, epiregulin downregulated RANKL expression in bone marrow stromal cells (BMSCs) and inhibited the differentiation of bone marrow osteoclast precursor cells into osteoclasts. Treatment of ovariectomized female mice with recombinant epiregulin increased osteoblasts and bone formation, decreased osteoclasts and bone resorption, and ameliorated cancellous bone loss. Consistently, epiregulin treatment improved the potential of BMSCs to differentiate into osteoblasts. Collectively, this study has identified a critical role of epiregulin in regulating osteoblast differentiation through EGFR-mediated inactivation of the mTORC1 pathway, as well as osteoclast differentiation via a mechanism associated with RANKL signaling. Additionally, it highlights the potential of epiregulin as a strategy for combating osteoporosis.