Pub Date : 2025-11-01DOI: 10.1016/j.diff.2025.100917
Andrew M. Vontell , Logan Willeke , Paul P.R. Iyyanar , Rolf W. Stottmann
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 dmx-like 1 (DMXL1). We used genome editing to create an allelic series of Dmxl1 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 Dmxl1 leads to very early embryonic lethality. This confirms and extends two recent findings about Dmxl1, suggesting this gene has crucial basal functions in the cell and should be further considered in human disease genetics.
{"title":"Dmxl1 is required for survival in the mouse to organogenesis stages of development","authors":"Andrew M. Vontell , Logan Willeke , Paul P.R. Iyyanar , 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}
Pub Date : 2025-11-01DOI: 10.1016/j.diff.2025.100916
Yuya Suzuki , Satoshi Takagi , Ryohei Katayama
{"title":"Response to the Letter by Aphale et al. regarding the manuscript entitled “Osteocyte-like differentiation of osteosarcoma by inorganic phosphate”","authors":"Yuya Suzuki , Satoshi Takagi , 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}
Pub Date : 2025-11-01DOI: 10.1016/j.diff.2025.100914
Elham Koosha , Qian Ma , Laura Romo Dorantes, Rayan Shafi, B. Frank Eames
The role of proteoglycans (PGs) in regulating growth factor signalling during endochondral ossification, or formation of bone around a cartilage template, is established. However, whether PGs regulate other skeletal processes, like intramembranous ossification or fin regeneration, has not been studied extensively. Given that endochondral ossification in PG-deficient fam20b mutant zebrafish is altered due to increased Bmp signalling, we hypothesized that PGs also normally inhibit Bmp signalling during intramembranous ossification and fin regeneration. To test this hypothesis, the functional relevance of Bmp signalling during craniofacial dermal bone formation and caudal fin regeneration was examined in wild type and fam20b mutant zebrafish. Bmp responsiveness of cells around wild-type dermal bones was verified by phospho-Smad1/5/9 immunoreactivity. Dermal bones in fam20b mutants were generally unaffected, apart from early formation of the dentary and quadrate, which actually initiate in the perichondrium of Meckel's cartilage and the palatoquadrate, respectively. Treatment of wild-type or fam20b−/− embryos with the Bmp inhibitor DMH1 did not yield clear differences in the size or morphology of most dermal bones, but did rescue early dentary and quadrate formation in fam20b mutants. During adult fin regeneration, Bmp signalling was confirmed by careful temporal analyses of GFP expression of Tg(5xBmpRE-Xla.Id3:GFP)ir1189 and Tg(BmpRE:EGFP)pt510 zebrafish, each expressed in different tissue compartments of the regenerating fin. fam20b−/− adults did not show fin regeneration defects. Treatment with DMH1, however, significantly reduced outgrowth of regenerating fins in distinct anatomical regions (the most dorsal and ventral principal rays) in adult zebrafish. Bony ray differentiation also was inhibited by DMH1 treatment. In total, these data do not support a major role of Bmp signalling or fam20b-dependent PGs in craniofacial intramembranous ossification, but do show that Bmp signalling is required for outgrowth of regenerating fins.
{"title":"fam20b-dependent proteoglycans do not affect dermal bone formation and fin regeneration, but Bmp signalling promotes fin regenerate outgrowth","authors":"Elham Koosha , Qian Ma , Laura Romo Dorantes, Rayan Shafi, B. Frank Eames","doi":"10.1016/j.diff.2025.100914","DOIUrl":"10.1016/j.diff.2025.100914","url":null,"abstract":"<div><div>The role of proteoglycans (PGs) in regulating growth factor signalling during endochondral ossification, or formation of bone around a cartilage template, is established. However, whether PGs regulate other skeletal processes, like intramembranous ossification or fin regeneration, has not been studied extensively. Given that endochondral ossification in PG-deficient <em>fam20b</em> mutant zebrafish is altered due to increased Bmp signalling, we hypothesized that PGs also normally inhibit Bmp signalling during intramembranous ossification and fin regeneration. To test this hypothesis, the functional relevance of Bmp signalling during craniofacial dermal bone formation and caudal fin regeneration was examined in wild type and <em>fam20b</em> mutant zebrafish. Bmp responsiveness of cells around wild-type dermal bones was verified by phospho-Smad1/5/9 immunoreactivity. Dermal bones in <em>fam20b</em> mutants were generally unaffected, apart from early formation of the dentary and quadrate, which actually initiate in the perichondrium of Meckel's cartilage and the palatoquadrate, respectively. Treatment of wild-type or <em>fam20b</em><sup><em>−/−</em></sup> embryos with the Bmp inhibitor DMH1 did not yield clear differences in the size or morphology of most dermal bones, but did rescue early dentary and quadrate formation in <em>fam20b</em> mutants. During adult fin regeneration, Bmp signalling was confirmed by careful temporal analyses of GFP expression of <em>Tg(5xBmpRE-Xla.Id3:GFP)ir1189</em> and <em>Tg(BmpRE:EGFP)pt510</em> zebrafish, each expressed in different tissue compartments of the regenerating fin. <em>fam20b</em><sup><em>−/−</em></sup> adults did not show fin regeneration defects. Treatment with DMH1, however, significantly reduced outgrowth of regenerating fins in distinct anatomical regions (the most dorsal and ventral principal rays) in adult zebrafish. Bony ray differentiation also was inhibited by DMH1 treatment. In total, these data do not support a major role of Bmp signalling or <em>fam20b</em>-dependent PGs in craniofacial intramembranous ossification, but do show that Bmp signalling is required for outgrowth of regenerating fins.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100914"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465385","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}
Dental pulp stem cells (DPSCs), as a subclass of mesenchymal stem cells (MSCs), exhibit robust self-renewal capacity and the ability to differentiate into multiple cell lineages. In addition, DPSCs contribute to tissue repair and regeneration through paracrine mechanisms. They secrete cytokines, growth factors, and exosomes that enhance angiogenesis, modulate immune responses and inflammation, promote cell proliferation and migration, limit apoptosis and senescence, and support neuroprotection. Notably, DPSC-derived exosomes carry a unique profile of biomolecules, including microRNAs, which show a potentially safer approach to regeneration and tissue repair. Exosomes derived from DPSCs (DPSC-Exos) can influence the dental microenvironment and promote tissue regeneration in oral and maxillofacial regions, while eliminating the risks linked to direct stem cell transplantation, including immune rejection and unpredictable differentiation. Although there are challenges encountered, including heterogeneity in exosome isolation, culture conditions, the lack of an efficient delivery system, donor variability, and incomplete understanding of their molecular pathways, DPSC-Exos represent a novel frontier in regenerative dentistry and clinical applications in comparison to conventional treatments, such as direct stem cell transplantation. Gaining detailed insight into the miRNA expression patterns within DPSC-Exos is crucial for guiding the design of advanced regenerative therapies. Future investigations should aim to refine experimental procedures and standardize methodologies to achieve reliable outcomes in the therapeutic use of DPSC-Exos. This review highlights the key biological properties of DPSCs that govern the production and function of their exosomes, which underscore their potential applications in successful therapeutic approaches. It also addresses challenges and potential solutions to overcome them.
{"title":"Clinical applications of dental pulp stem cells-derived exosomes in oral and maxillofacial tissue regeneration and repair","authors":"Mahtab Mottaghi , Camellia Kianbakht , Shahrzad Samadian , Alieh Farshbaf , Majid Mirhashemi , Farzaneh Ahrari","doi":"10.1016/j.diff.2025.100918","DOIUrl":"10.1016/j.diff.2025.100918","url":null,"abstract":"<div><div>Dental pulp stem cells (DPSCs), as a subclass of mesenchymal stem cells (MSCs), exhibit robust self-renewal capacity and the ability to differentiate into multiple cell lineages. In addition, DPSCs contribute to tissue repair and regeneration through paracrine mechanisms. They secrete cytokines, growth factors, and exosomes that enhance angiogenesis, modulate immune responses and inflammation, promote cell proliferation and migration, limit apoptosis and senescence, and support neuroprotection. Notably, DPSC-derived exosomes carry a unique profile of biomolecules, including microRNAs, which show a potentially safer approach to regeneration and tissue repair. Exosomes derived from DPSCs (DPSC-Exos) can influence the dental microenvironment and promote tissue regeneration in oral and maxillofacial regions, while eliminating the risks linked to direct stem cell transplantation, including immune rejection and unpredictable differentiation. Although there are challenges encountered, including heterogeneity in exosome isolation, culture conditions, the lack of an efficient delivery system, donor variability, and incomplete understanding of their molecular pathways, DPSC-Exos represent a novel frontier in regenerative dentistry and clinical applications in comparison to conventional treatments, such as direct stem cell transplantation. Gaining detailed insight into the miRNA expression patterns within DPSC-Exos is crucial for guiding the design of advanced regenerative therapies. Future investigations should aim to refine experimental procedures and standardize methodologies to achieve reliable outcomes in the therapeutic use of DPSC-Exos. This review highlights the key biological properties of DPSCs that govern the production and function of their exosomes, which underscore their potential applications in successful therapeutic approaches. It also addresses challenges and potential solutions to overcome them.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100918"},"PeriodicalIF":2.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623335","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}
Pub Date : 2025-10-22DOI: 10.1016/j.diff.2025.100913
Mirco Galiè
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.
{"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":"2025-10-22","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}
Osteosarcoma (OS) cells that deviate from the normal osteogenic differentiation pathway from mesenchymal stem cells (MSCs) to less migratory osteocytes are in an undifferentiated and highly malignant state. β-glycerophosphate (β-gp) is commonly used to induce the osteogenic differentiation of MSCs, inorganic phosphate (Pi) is also widely used to promote MSC differentiation into osteocytes. Recently, OS cells were found to differentiate into an osteocyte-like state by culturing in osteocyte differentiation medium containing β-gp, dexamethasone, and ascorbate. However, whether Pi can induce the osteogenic differentiation of OS cells and its underlying mechanisms remain unclear. In this study, we evaluated the ability of two types of Pi (i.e., disodium phosphate [Na2HPO4] and monosodium phosphate [NaH2PO4]) to promote the osteogenic differentiation of OS cells. Culturing OS cells in Pi-supplemented medium resulted in increased osteogenic marker gene expression and calcium deposition and reduced cell motility. Notably, Na2HPO4 exhibited particularly strong differentiation-inducing effects. Furthermore, our data suggest that WNT5b, a key factor of the noncanonical Wnt signaling pathway, is involved in the Na2HPO4-induced osteogenic differentiation of OS cells. These findings suggest that above 3 mM of Na2HPO4 function as an inducer of osteocyte-like differentiation in OS cells and that targeting this pathway may offer new therapeutic strategies to suppress OS metastasis.
{"title":"Osteocyte-like differentiation of osteosarcoma by inorganic phosphate","authors":"Yuya Suzuki , Makoto Takeuchi , Sumie Koike , Satoshi Takagi , Ryohei Katayama","doi":"10.1016/j.diff.2025.100912","DOIUrl":"10.1016/j.diff.2025.100912","url":null,"abstract":"<div><div>Osteosarcoma (OS) cells that deviate from the normal osteogenic differentiation pathway from mesenchymal stem cells (MSCs) to less migratory osteocytes are in an undifferentiated and highly malignant state. β-glycerophosphate (β-gp) is commonly used to induce the osteogenic differentiation of MSCs, inorganic phosphate (Pi) is also widely used to promote MSC differentiation into osteocytes. Recently, OS cells were found to differentiate into an osteocyte-like state by culturing in osteocyte differentiation medium containing β-gp, dexamethasone, and ascorbate. However, whether Pi can induce the osteogenic differentiation of OS cells and its underlying mechanisms remain unclear. In this study, we evaluated the ability of two types of Pi (i.e., disodium phosphate [Na<sub>2</sub>HPO<sub>4</sub>] and monosodium phosphate [NaH<sub>2</sub>PO<sub>4</sub>]) to promote the osteogenic differentiation of OS cells. Culturing OS cells in Pi-supplemented medium resulted in increased osteogenic marker gene expression and calcium deposition and reduced cell motility. Notably, Na<sub>2</sub>HPO<sub>4</sub> exhibited particularly strong differentiation-inducing effects. Furthermore, our data suggest that WNT5b, a key factor of the noncanonical Wnt signaling pathway, is involved in the Na<sub>2</sub>HPO<sub>4</sub>-induced osteogenic differentiation of OS cells. These findings suggest that above 3 mM of Na<sub>2</sub>HPO<sub>4</sub> function as an inducer of osteocyte-like differentiation in OS cells and that targeting this pathway may offer new therapeutic strategies to suppress OS metastasis.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100912"},"PeriodicalIF":2.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057165","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}
Mesenchymal stem cells (MSCs) have been revealed as an appropriate candidate for cell-based therapies by isolation from a different range of sources such as bone marrow, umbilical cord, adipose, liver, and orofacial tissues. MSCs showed low immunogenicity, which is considered as a potential alternative therapy for autoimmune and inflammatory diseases. Transplantation of MSCs in different research studies showed that it improves the repairment and regeneration of injured and impaired tissues. MSCs release biologically active molecules, such as extracellular vehicles (EVs) and exosomes (EXOs). EXOs participate in different physiological processes, including immune response, wound healing, bone repair, stem cell maintenance, interaction between the central nervous system (CNS), and pathological impacts in tumorigenesis, inflammation, and heart diseases. Across the tissues, MSCs release exosomes and regenerative molecules and transfer proteins, mRNAs and microRNAs. MicroRNAs (miRNAs) are small noncoding RNAs (21–23 nt) in length that bind to the 3′ untranslated region (3′UTR) of target mRNA and post-transcriptionally regulate gene expression that affects different cellular pathways. More studies are needed relating to the exosome's biogenesis, cellular uptake, trafficking, isolation, qualification, purity, optimization, standardization, and molecular mechanisms of exosome connection with target cells. Recent studies reported promising applications of exosomes derived from various sources in regenerative medicine and tissue engineering approaches. Herein, we are more focused on studies with different approaches in regenerative medicine for tissue repair and healing related to bone, cartilage, tendon-bone, heart, nerves, wounds, skin, and tooth regeneration.
{"title":"Regenerative medicine and tissue engineering potential of mesenchymal stem cells exosomes-derived microRNAs","authors":"Navidreza Shayan , Negin Ghiyasimoghaddam , Nima Ameli , Mohammadhasan Baghbani , Hanieh Alsadat Mirkatuli , Amir Attaran Khorasani , Nooshin Mohtasham","doi":"10.1016/j.diff.2025.100911","DOIUrl":"10.1016/j.diff.2025.100911","url":null,"abstract":"<div><div>Mesenchymal stem cells (MSCs) have been revealed as an appropriate candidate for cell-based therapies by isolation from a different range of sources such as bone marrow, umbilical cord, adipose, liver, and orofacial tissues. MSCs showed low immunogenicity, which is considered as a potential alternative therapy for autoimmune and inflammatory diseases. Transplantation of MSCs in different research studies showed that it improves the repairment and regeneration of injured and impaired tissues. MSCs release biologically active molecules, such as extracellular vehicles (EVs) and exosomes (EXOs). EXOs participate in different physiological processes, including immune response, wound healing, bone repair, stem cell maintenance, interaction between the central nervous system (CNS), and pathological impacts in tumorigenesis, inflammation, and heart diseases. Across the tissues, MSCs release exosomes and regenerative molecules and transfer proteins, mRNAs and microRNAs. MicroRNAs (miRNAs) are small noncoding RNAs (21–23 nt) in length that bind to the 3′ untranslated region (3′UTR) of target mRNA and post-transcriptionally regulate gene expression that affects different cellular pathways. More studies are needed relating to the exosome's biogenesis, cellular uptake, trafficking, isolation, qualification, purity, optimization, standardization, and molecular mechanisms of exosome connection with target cells. Recent studies reported promising applications of exosomes derived from various sources in regenerative medicine and tissue engineering approaches. Herein, we are more focused on studies with different approaches in regenerative medicine for tissue repair and healing related to bone, cartilage, tendon-bone, heart, nerves, wounds, skin, and tooth regeneration.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"146 ","pages":"Article 100911"},"PeriodicalIF":2.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145049187","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}
Pub Date : 2025-08-29DOI: 10.1016/j.diff.2025.100903
Marcello Guarino
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.
{"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":"2025-08-29","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}
Pub Date : 2025-08-23DOI: 10.1016/j.diff.2025.100902
Tingwei Gao , Jiankun Wang , Jiajia Wang , Xi Li , Zhanhao Xiao
Sirolimus can inhibit osteoclastogenesis. But sirolimus-activated autophagy is a favorable factor for osteoclastogenesis. This study aimed to explore the significance of autophagy in sirolimus-regulated osteoclastogenesis. Our results confirmed that sirolimus inhibited osteoclastic differentiation (including the number and size of osteoclasts as well as the expression of osteoclastic genes) and promotes osteoclast precursor (OCP) autophagy (including LC3 conversion and autophagosome/autolysosome formation). As expected, OCP autophagy (including LC3 conversion and LC3-puncta formation) promoted by sirolimus was reversed by autophagy inactivation with 3-MA or Atg13 silencing. Importantly, compared with single intervention of sirolimus, the combination of sirolimus and 3-MA or Atg13 silencing more effectively inhibited osteoclastic differentiation and OCP proliferation. In vivo experiments also demonstrated that the combination of sirolimus and Atg13-silencing adeno-associated viruses (AAVs) was more effective than sirolimus alone in improving decreased bone density and damaged bone microstructure (including Micro-CT imaging results, bone tissue parameters and trabecular area), and attenuating osteoclastic activity (including the abundance of osteoclasts in trabecular bones and the production of osteoclastic markers in serum) in ovariectomized (OVX) mice. In conclusion, repressing Atg13-related autophagy can effectively enhance the function of sirolimus in inhibiting osteoclastogenesis by counteracting its pro-autophagic activity. Therefore, the combination of sirolimus and Atg13-targeting therapy is expected to enhance the efficacy of sirolimus in ameliorating osteoclastic osteoporosis.
{"title":"Inhibition of Atg13-mediated autophagy enhances the anti-osteoclastogenic effect of sirolimus by counteracting its pro-autophagic activity","authors":"Tingwei Gao , Jiankun Wang , Jiajia Wang , Xi Li , Zhanhao Xiao","doi":"10.1016/j.diff.2025.100902","DOIUrl":"10.1016/j.diff.2025.100902","url":null,"abstract":"<div><div>Sirolimus can inhibit osteoclastogenesis. But sirolimus-activated autophagy is a favorable factor for osteoclastogenesis. This study aimed to explore the significance of autophagy in sirolimus-regulated osteoclastogenesis. Our results confirmed that sirolimus inhibited osteoclastic differentiation (including the number and size of osteoclasts as well as the expression of osteoclastic genes) and promotes osteoclast precursor (OCP) autophagy (including LC3 conversion and autophagosome/autolysosome formation). As expected, OCP autophagy (including LC3 conversion and LC3-puncta formation) promoted by sirolimus was reversed by autophagy inactivation with 3-MA or Atg13 silencing. Importantly, compared with single intervention of sirolimus, the combination of sirolimus and 3-MA or Atg13 silencing more effectively inhibited osteoclastic differentiation and OCP proliferation. <em>In vivo</em> experiments also demonstrated that the combination of sirolimus and Atg13-silencing adeno-associated viruses (AAVs) was more effective than sirolimus alone in improving decreased bone density and damaged bone microstructure (including Micro-CT imaging results, bone tissue parameters and trabecular area), and attenuating osteoclastic activity (including the abundance of osteoclasts in trabecular bones and the production of osteoclastic markers in serum) in ovariectomized (OVX) mice. In conclusion, repressing Atg13-related autophagy can effectively enhance the function of sirolimus in inhibiting osteoclastogenesis by counteracting its pro-autophagic activity. Therefore, the combination of sirolimus and Atg13-targeting therapy is expected to enhance the efficacy of sirolimus in ameliorating osteoclastic osteoporosis.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"145 ","pages":"Article 100902"},"PeriodicalIF":2.6,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903192","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}
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