Differentiation最新文献

{"title":"Long non-coding RNA SNHG6 promotes odontoblastic differentiation of human dental pulp stem cells via the PI3K/Akt/mTOR pathway","authors":"Wantong Zhang ,&nbsp;Yan Zhou ,&nbsp;Lin Ye ,&nbsp;Chengsusu Huang ,&nbsp;Yao Wang","doi":"10.1016/j.diff.2025.100927","DOIUrl":"10.1016/j.diff.2025.100927","url":null,"abstract":"<div><div>Small nucleolar RNA host gene 6 (SNHG6) is a long non-coding RNA (lncRNA) that has been widely implicated in cellular processes such as proliferation, migration, and differentiation. This study investigated its role in the odontoblastic differentiation of human dental pulp stem cells (hDPSCs). qRT-PCR analysis revealed that SNHG6 expression increased during odontoblastic differentiation. In hDPSCs, SNHG6 was primarily localized in the cytoplasm. Functional studies using knockdown and overexpression demonstrated that SNHG6 positively regulates odontoblastic differentiation, as evidenced by alkaline phosphatase activity, Alizarin Red S staining, and the expression of differentiation markers DSPP and DMP-1. However, CCK-8 assays revealed SNHG6 had no significant impact on cell proliferation, and wound healing assays similarly showed it did not influence cell migration. Mechanistically, pathway inhibitors LY294002 and Rapamycin were used. Western blot analysis confirmed that SNHG6 promotes odontoblastic differentiation by activating the PI3K/Akt/mTOR signaling pathway, as shown by changes in phosphorylated Akt, mTOR, S6K1, and 4EBP1 levels. These findings highlight SNHG6 as a key regulator of hDPSC differentiation through PI3K/Akt/mTOR signaling, offering new insights into the molecular mechanisms controlling odontoblast formation.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100927"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut and oral microbiota in oral bone tissue engineering: Impact of mechanistic and molecular pathways","authors":"Khushi Gupta ,&nbsp;Jiyaur Rahaman ,&nbsp;Dhrubojyoti Mukherjee","doi":"10.1016/j.diff.2025.100919","DOIUrl":"10.1016/j.diff.2025.100919","url":null,"abstract":"<div><div>The influence of the oral-gut microbiota on craniofacial bone healing is increasingly recognised, as its interactions with host osteoimmune pathways are now understood to shape the course of regeneration. These microbiota play an important role in maintaining bone mass via immune modulation, metabolite production, and nutrient resorption. Under conditions of dysbiosis, inflammatory signalling through NF-κB, NLRP3, and the RANKL/OPG axis is amplified, while Wnt/β-catenin and BMP/Smad pathways are suppressed, resulting in heightened oxidative stress, increased osteoclast activity, and progressive alveolar bone loss. In contrast, a balanced microbial community is associated with the production of short-chain fatty acids, through which epithelial barrier stability is supported, Th17/Treg equilibrium is restored, and osteoblast differentiation and mineralisation are promoted. In this review, mechanistic, preclinical, and emerging clinical evidence are integrated to illustrate how these microbial interactions regulate bone remodelling and influence the performance of engineered scaffolds. Therapeutic opportunities involving probiotics, prebiotics, synbiotics, engineered microbial strains, and microbiome-responsive biomaterials are emphasized. Cellular and molecular pathways controlling bone homeostasis, including the composition of the oral and gut microbiota, impacting oral bone health, have been summarized. Overall, the microbiome is positioned as a central biological determinant of oral bone regeneration, and its targeted modulation in addition to microbiome-based therapeutic strategies for bone tissue regeneration is proposed as a personalized approach for improving outcomes in craniofacial tissue engineering.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100919"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating biochemical cues and mechanical forces in stem cell-epithelial differentiation","authors":"Siti Nurnasihah Md Hashim ,&nbsp;Sarahani Harun ,&nbsp;Ahmad Sukari Halim ,&nbsp;Suzina Sheikh Abdul Hamid ,&nbsp;Thirumulu Ponnuraj Kannan ,&nbsp;Khairul Bariah Ahmad Amin Noordin ,&nbsp;Nazia Abdul Majid ,&nbsp;Ahmad Azlina","doi":"10.1016/j.diff.2026.100931","DOIUrl":"10.1016/j.diff.2026.100931","url":null,"abstract":"<div><div>Epithelial differentiation from stem cells is fundamental to regenerative medicine, with applications ranging from skin repair to epithelial tissue engineering. While traditionally guided by biochemical regulators such as retinoic acid (RA) and growth factors, the mechanical microenvironment is a critical, yet often underrepresented regulator of epithelial fate. This review addresses the knowledge gap by examining how chemical and mechanical cues cooperate to guide epithelial commitment across both conventional two-dimensional (2D) and advanced three-dimensional (3D) culture models. We specifically focus on the mechanism of mechanotransduction, detailing how mechanical forces are converted into biochemical signals. This process relies on specialized mechanosensitive mediators such as focal adhesion, ion channels, and cell-cell adhesion molecules. These inputs converge on the central Hippo-YAP/TAZ transcriptional hub, which acts as the primary mechanical sensor to modulate lineage trajectories. This integration reshapes how cells interpret signals through the major regulatory network (WNT, Notch, and TGFβ pathways) while balancing stemness against epithelial differentiation. Addressing this integrated mechanobiological perspective is essential for improving mechanistic understanding and reproducibility in stem cell-epithelial differentiation protocols. Incorporating dynamic mechanical conditioning and scaffold design into protocols is critical to advancing translational potential for regenerative applications.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100931"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Odd-skipped family members have conserved roles in segmentation, appendage, excretory system and gut development in bilaterian animals","authors":"Vasikar Murugapoopathy ,&nbsp;Claire Ramsay ,&nbsp;Ehab Abouheif ,&nbsp;Indra R. Gupta","doi":"10.1016/j.diff.2025.100930","DOIUrl":"10.1016/j.diff.2025.100930","url":null,"abstract":"<div><div>The odd-skipped related family of proteins are evolutionarily conserved zinc finger transcription factors in bilaterian animals with essential roles in body segmentation, as well as gut, excretory system and appendage development. Although they are prognostic biomarkers in several cancers, their molecular function is poorly understood. To gain a deeper understanding of how this family of transcription factors is implicated in human disorders and cancer, we explore the functions of Odd-skipped related transcription factors as well as their invertebrate homologs during development. We found that vertebrate Osr1 binds to DNA targets within the WNT, BMP, HH, TGFβ, Notch and retinoic acid signaling pathways, suggesting that <em>Osr</em> genes coordinate and integrate multiple pathways during development, potentially by binding to heterochromatin as pioneer transcription factors. From a protein tree analysis of odd-skipped family orthologs and paralogs, it appears that vertebrate, nematode, and insect paralogues have arisen via independent gene duplication events, and that their common ancestor likely had a single odd-family gene. We hypothesize that the ancestral odd-family protein was required for gut and gut-derived structures and was subsequently co-opted to perform additional functions in other tissues as part of the evolution of organisms. These observations posit new uncharacterized functions for <em>Osr</em> genes in the development of bilaterian animals and in cancer models.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100930"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEK8/Ephrin-A4 defines the tendon field boundary through WNT–TGF-β crosstalk in the chicken embryo","authors":"Jessica Cristina Marín-Llera,&nbsp;Claudio Ivan Galván-Hernández,&nbsp;Carlos Amaury Jiménez-Cárdenas,&nbsp;Jesus Chimal-Monroy","doi":"10.1016/j.diff.2026.100932","DOIUrl":"10.1016/j.diff.2026.100932","url":null,"abstract":"<div><div>The development of tendons in vertebrate limbs occurs through the precise regulation of genes and signaling pathways between the skeletal elements and the ectoderm. Although it is known that SCX is a crucial regulator of tendon development, the establishment and maintenance of the tenogenic regions remain unclear. This study explores the role of CEK8 (Ephrin-A4) in early tendon differentiation in the chicken limb and its interaction with WNT/β-catenin and TGF-β pathways during tendon blastema formation. Our results show that <em>Cek8</em> expression mirrors <em>Scx</em> in the developing tendon blastema but is localized at the boundary of SCX-positive cells. Inhibiting CEK8 upregulates <em>Scx</em> and other tenogenic genes; however, the effects are not sustained, indicating that CEK8 initially suppresses but later supports tenogenic differentiation. Through functional assays using protein-soaked beads in the tendon blastema, we determined that WNT signaling initially upregulates but later inhibits <em>Cek8</em> expression in a time-dependent manner. TGF-β signaling induces a wider <em>Cek8</em> expression domain compared to <em>Scx</em>, while CEK8 is necessary for the effects of TGF-β to maintain Scx induction. Inhibiting CEK8 expands the β-catenin and SMAD2/3 regions, favoring a tenogenic phenotype. These results identify CEK8 as a regulator of tendon progenitor architecture, likely involved in establishing positional information, which functions in association with WNT and TGF-β to control tenogenic differentiation both spatially and temporally. Our study provides new insights into the morphogenetic signals and cell interactions that occur during chicken tendon development.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100932"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal regulation of the Ihh-PTHrP signaling axis modulates condylar development via angiogenesis","authors":"Chuanqing Mao ,&nbsp;Yunpeng Weng ,&nbsp;Wenjie Zhou ,&nbsp;Zuhui Li ,&nbsp;Yongzhen Lai ,&nbsp;Chengyong Wang ,&nbsp;Meng Lu ,&nbsp;Weihui Chen","doi":"10.1016/j.diff.2026.100933","DOIUrl":"10.1016/j.diff.2026.100933","url":null,"abstract":"<div><div>Vismodegib, a <em>Smoothened (Smo)</em> receptor antagonist, effectively suppresses <em>Hedgehog (Hh)</em> signaling activity during embryonic development and is known to influence craniofacial morphogenesis. However, its specific role in temporomandibular joint (TMJ) development remains unclear. In this study, a single dose of vismodegib (150 mg/kg) was administered to pregnant mice at embryonic day 14.5 (E14.5) to investigate its impact on fetal TMJ morphogenesis. At postnatal day 21, offspring from the treatment group exhibited significantly reduced condylar length and bone surface area density compared to vehicle-treated controls. Despite no observable differences in cellular proliferation or apoptosis—as assessed by <em>phospho-Histone H3 (PHH3)</em> and TUNEL assays—angiogenic markers, including <em>VEGF</em>, <em>CD31</em>, and <em>CD34</em>, were markedly upregulated in the condylar region of vismodegib-treated mice. Furthermore, at E15.5, expression of key components of the <em>Ihh</em>-<em>PTHrP</em> signaling axis (<em>Gli1</em>, <em>Ptch1</em>, and <em>PTHrP)</em> was significantly downregulated in the experimental group relative to controls. These findings suggest that vismodegib disrupts TMJ development by inhibiting the <em>Ihh</em>-<em>PTHrP</em> signaling pathway, thereby altering angiogenesis in the condyle and ultimately impairing cartilage growth and structural integrity.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"147 ","pages":"Article 100933"},"PeriodicalIF":2.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dmxl1 is required for survival in the mouse to organogenesis stages of development","authors":"Andrew M. Vontell ,&nbsp;Logan Willeke ,&nbsp;Paul P.R. Iyyanar ,&nbsp;Rolf W. Stottmann","doi":"10.1016/j.diff.2025.100917","DOIUrl":"10.1016/j.diff.2025.100917","url":null,"abstract":"<div><div>Cleft lip and cleft palate are among the most common congenital anomalies and are the result of incomplete fusion of embryonic craniofacial processes or palatal shelves. Genetic factors are known to play a large role in these anomalies, but the list of known causal genes is far from complete. As part of a larger effort to sequence patients with micrognathia and cleft palate, we identified candidate pathogenic variants in <em>dmx-like 1 (DMXL1</em>). We used genome editing to create an allelic series of <em>Dmxl1</em> in the mouse: a small deletion and the two orthologous missense variants. We do not find evidence that either missense allele is pathogenic, but we do see that loss of <em>Dmxl1</em> leads to very early embryonic lethality. This confirms and extends two recent findings about <em>Dmxl1</em>, suggesting this gene has crucial basal functions in the cell and should be further considered in human disease genetics.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100917"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145662645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal phenotype as a hallmark of undifferentiated states","authors":"Mirco Galiè","doi":"10.1016/j.diff.2025.100913","DOIUrl":"10.1016/j.diff.2025.100913","url":null,"abstract":"<div><div>The mesenchymal phenotype has long been related to either the structural support or the transition between two subsequent epithelial stages. Although this view is generally correct in certain contexts of embryonic development as well as of adult anatomy, it has been challenged by recent advances from convergent fields of research that showed how the presence of mesenchymal traits may hallmark states of intrinsic plasticity and stem cell identity both in physiological and pathological contexts. Following this line, the present review summarizes studies that support the hypothesis that the partially or fully mesenchymal phenotype might represent a general paradigm of stem cell plasticity underlying embryonic development, regenerative potential as well as their pathological counterparts.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100913"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145362955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to the Letter by Aphale et al. regarding the manuscript entitled “Osteocyte-like differentiation of osteosarcoma by inorganic phosphate”","authors":"Yuya Suzuki ,&nbsp;Satoshi Takagi ,&nbsp;Ryohei Katayama","doi":"10.1016/j.diff.2025.100916","DOIUrl":"10.1016/j.diff.2025.100916","url":null,"abstract":"","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100916"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EMT: from embryogenesis, through cancer progression, to the development of carcinosarcoma","authors":"Marcello Guarino","doi":"10.1016/j.diff.2025.100903","DOIUrl":"10.1016/j.diff.2025.100903","url":null,"abstract":"<div><div>Epithelial cells are tightly connected to one another by intercellular junctions which prevent much of their motility, and have distinct apical-basal cell polarity, with their basal pole facing the basement membrane; they form mono- or multilayered sheet-like structures, and establish the borders of tissues and organs. In contrast, mesenchymal cells fill the spaces delimitated by other tissues, do not form stable contacts with other cells, are embedded within the extracellular matrix with which their entire surface interacts, and have definite locomotory capabilities. Epithelial-mesenchymal transition (EMT) occurs when an epithelium loses its distinguishing characteristics, and acquires mesenchymal traits. It is recognised as an important and reversible mechanism of embryogenesis aimed at creating cells with the ability to move within the embryo, and implies the possibility of reforming new epithelia at distant sites through the reverse process, mesenchymal-epithelial transition (MET). Importantly, EMT-based phenotype changes are recapitulated in cancer progression and metastasis, thus indicating that EMT is a conserved mechanism in adult life and, furthermore, also suggesting that it may provide the possibility of expanding the differentiation potential of tumours. Indeed, in carcinomas, EMT may underlie the unexpected development of mesenchymal differentiation and give rise to tumours with mixed epithelial-mesenchymal phenotype, carcinosarcomas, malignant neoplasms known to be usually associated with high biological aggressiveness and poor response to therapy. Although these cancers have been known for a long time, the biological mechanisms underlying their histopathogenesis have not yet been definitively clarified, therefore requiring a conceptual placement in a modern framework. In this article an overview on EMT is provided, with brief presentations of single examples occurring in embryogenesis, the involvement of EMT in cancer progression is concisely illustrated and, finally, the proposition that carcinosarcoma develops through an EMT-based mechanism is discussed, refuting the two alternative mechanisms that have been proposed, the collision theory and the combination theory.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100903"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}