The functional regeneration of the dentin-pulp complex is pivotal for tooth preservation,yet the molecular mechanisms governing odontoblast differentiation remain poorly understood.In the current study,we revealed a d...The functional regeneration of the dentin-pulp complex is pivotal for tooth preservation,yet the molecular mechanisms governing odontoblast differentiation remain poorly understood.In the current study,we revealed a distinct NKD1^(+) subpopulation exhibiting secretory odontoblast characteristics,which was specifically induced in dental pulp stem cells(DPSCs) by Wnt3a,but not by Wnt5a or Wnt10a through single-cell transcriptomic profiling.We then found that the NKD1^(+) subpopulation was functional conservation,which were consistently identified in the odontoblast layers of developing tooth germs in both murine and miniature pig models,as well as within the apical open area in human molars.This conserved spatial distribution and co-localization with DSPP strongly indicates that NKD1^(+) cells were active dentin-secreting odontoblasts.Analysis of gene regulatory networks using SCENIC identified MSX1 as a key transcription factor regulating the specification of NKD1^(+) lineage.Mechanistically,Wnt3a orchestrates a tripartite cascade:upregulating NKD1/MSX1 expression,triggering NKD1 membrane detachment,and facilitating direct NKD1-MSX1interaction to promote MSX1 nuclear translocation.CUT&Tag analysis demonstrated MSX1 occupancy at promoters of odontogenic regulato rs,esta blishing its necessity for odontogenic gene activation.Murine pulp exposure models validated that Wnt3a-activated NKD1-MSX1 signaling significantly enhances reparative dentin formation.This study delineates an evolutionarily conserved Wnt3aNKD1-MSX1 axis that resolves stem cell heterogeneity into functional odontoblast commitment,providing both mechanistic insights into dentin-pulp regeneration and a foundation for targeted regenerative therapies.展开更多
目的:探讨CDX-2、NKD1、GDF11在大肠癌中的表达及其与预后的相关性分析。方法:选取2016年1月~2019年6月的大肠癌患者284例作为研究对象,采用免疫组织化学法(SP)检测大肠癌组织及其癌旁正常组织中的CDX-2、NKD1、GDF11表达,分析其在大肠...目的:探讨CDX-2、NKD1、GDF11在大肠癌中的表达及其与预后的相关性分析。方法:选取2016年1月~2019年6月的大肠癌患者284例作为研究对象,采用免疫组织化学法(SP)检测大肠癌组织及其癌旁正常组织中的CDX-2、NKD1、GDF11表达,分析其在大肠癌患者的临床病理特征及预后的相关性。结果:大肠癌组织的GDF11阳性表达率显著高于癌旁正常组织,CDX-2和NKD1阳性表达率显著低于癌旁正常组织;CDX-2、NKD1和GDF11阳性表达与肿瘤阶段、淋巴结受累、同步转移、组织学分级、CEA水平有关;CDX-2阳性表达患者3年生存率显著高于其阴性表达患者(80.23% vs 53.03%),NKD1阳性表达患者3年生存率显著高于其阴性表达患者(78.95% vs 54.81%),GDF11阳性表达患者3年生存率显著低于其阴性表达患者(57.33% vs 76.27%);CDX-2的表达和NKD1表达相关较强,GDF11与CDX-2、NKD1的表达率相关性较弱。结论:CDX-2和NKD1可能协同参与了降低肿瘤细胞的入侵和迁移、抑制癌组织的增殖过程,GDF11作为生长调节因子可调节癌细胞增殖和分化,均可作为预后的重要指示。展开更多
Aim:The convergence of tumorigenic and embryonic signaling pathways drives us to exploit the embryonic stem cell(ESC)microenvironment to restrict metastatic potential of cancer cells.We have previously demonstrated th...Aim:The convergence of tumorigenic and embryonic signaling pathways drives us to exploit the embryonic stem cell(ESC)microenvironment to restrict metastatic potential of cancer cells.We have previously demonstrated that bioengineered ESC microenvironments could restrict growth and metastatic potential of highly aggressive breast cancer cell(BCC).This study aims to further understand the regulation of convergent EGFR and canonical Wnt/β-catenin signaling pathway function in triple negative metastatic BCCs using the 3D in vitro ESC microenvironment created by encapsulating ESCs in alginate hydrogel microstrands.Methods:Co-culture with ESC-microstrands increased sensitivity to two chemotherapeutic drugs in metastatic BCCs.To test whether these changes were due to restored signaling pathway regulation in BCCs,we probed for changes in gene expression of key molecules related to the EGFR and canonical Wnt/β-catenin signaling pathways using quantitative reverse transcription polymerase chain reaction and Western blot analysis.Results:ESC-microstrands are able to alter the gene expression of highly aggressive BCCs at both mRNA and protein levels.These changes are indicative of a reversal of EGFR and canonical Wnt/β-catenin signaling pathway hyperactivation following co-culture.Increased NKD2 mRNA and protein expression coinciding with dual signaling pathway inhibition within co-cultured BCCs suggests that this reversal may be attributable to restored regulation of NKD2 within these pathways.Conclusion:ESC-microstrands are able to reverse oncogenic signaling pathway hyperactivation and restore signaling pathway regulation in metastatic BCCs.Further studies could provide insight into what role NKD2 up-regulation plays ;in BCC inhibition,leading to the development of a new targeted therapy for metastatic breast cancer.展开更多
基金supported by the National Natural Science Foundation of China(82170951,82470961)the Beijing Natural Science Foundation (7222079)+4 种基金the Beijing Hospital Authority"Dengfeng"Talent Training Plan (DFL 20221301)the Beijing Stomatological HospitalCapital Medical University Young Scientist Program (No.YSP202401)the Laboratory for Clinical Medicine and the Central Laboratory of Capital Medical University for their technical support and fundingthe Japan China Sasakawa Medical Fellowship for their generous support and funding。
文摘The functional regeneration of the dentin-pulp complex is pivotal for tooth preservation,yet the molecular mechanisms governing odontoblast differentiation remain poorly understood.In the current study,we revealed a distinct NKD1^(+) subpopulation exhibiting secretory odontoblast characteristics,which was specifically induced in dental pulp stem cells(DPSCs) by Wnt3a,but not by Wnt5a or Wnt10a through single-cell transcriptomic profiling.We then found that the NKD1^(+) subpopulation was functional conservation,which were consistently identified in the odontoblast layers of developing tooth germs in both murine and miniature pig models,as well as within the apical open area in human molars.This conserved spatial distribution and co-localization with DSPP strongly indicates that NKD1^(+) cells were active dentin-secreting odontoblasts.Analysis of gene regulatory networks using SCENIC identified MSX1 as a key transcription factor regulating the specification of NKD1^(+) lineage.Mechanistically,Wnt3a orchestrates a tripartite cascade:upregulating NKD1/MSX1 expression,triggering NKD1 membrane detachment,and facilitating direct NKD1-MSX1interaction to promote MSX1 nuclear translocation.CUT&Tag analysis demonstrated MSX1 occupancy at promoters of odontogenic regulato rs,esta blishing its necessity for odontogenic gene activation.Murine pulp exposure models validated that Wnt3a-activated NKD1-MSX1 signaling significantly enhances reparative dentin formation.This study delineates an evolutionarily conserved Wnt3aNKD1-MSX1 axis that resolves stem cell heterogeneity into functional odontoblast commitment,providing both mechanistic insights into dentin-pulp regeneration and a foundation for targeted regenerative therapies.
文摘目的:探讨CDX-2、NKD1、GDF11在大肠癌中的表达及其与预后的相关性分析。方法:选取2016年1月~2019年6月的大肠癌患者284例作为研究对象,采用免疫组织化学法(SP)检测大肠癌组织及其癌旁正常组织中的CDX-2、NKD1、GDF11表达,分析其在大肠癌患者的临床病理特征及预后的相关性。结果:大肠癌组织的GDF11阳性表达率显著高于癌旁正常组织,CDX-2和NKD1阳性表达率显著低于癌旁正常组织;CDX-2、NKD1和GDF11阳性表达与肿瘤阶段、淋巴结受累、同步转移、组织学分级、CEA水平有关;CDX-2阳性表达患者3年生存率显著高于其阴性表达患者(80.23% vs 53.03%),NKD1阳性表达患者3年生存率显著高于其阴性表达患者(78.95% vs 54.81%),GDF11阳性表达患者3年生存率显著低于其阴性表达患者(57.33% vs 76.27%);CDX-2的表达和NKD1表达相关较强,GDF11与CDX-2、NKD1的表达率相关性较弱。结论:CDX-2和NKD1可能协同参与了降低肿瘤细胞的入侵和迁移、抑制癌组织的增殖过程,GDF11作为生长调节因子可调节癌细胞增殖和分化,均可作为预后的重要指示。
文摘Aim:The convergence of tumorigenic and embryonic signaling pathways drives us to exploit the embryonic stem cell(ESC)microenvironment to restrict metastatic potential of cancer cells.We have previously demonstrated that bioengineered ESC microenvironments could restrict growth and metastatic potential of highly aggressive breast cancer cell(BCC).This study aims to further understand the regulation of convergent EGFR and canonical Wnt/β-catenin signaling pathway function in triple negative metastatic BCCs using the 3D in vitro ESC microenvironment created by encapsulating ESCs in alginate hydrogel microstrands.Methods:Co-culture with ESC-microstrands increased sensitivity to two chemotherapeutic drugs in metastatic BCCs.To test whether these changes were due to restored signaling pathway regulation in BCCs,we probed for changes in gene expression of key molecules related to the EGFR and canonical Wnt/β-catenin signaling pathways using quantitative reverse transcription polymerase chain reaction and Western blot analysis.Results:ESC-microstrands are able to alter the gene expression of highly aggressive BCCs at both mRNA and protein levels.These changes are indicative of a reversal of EGFR and canonical Wnt/β-catenin signaling pathway hyperactivation following co-culture.Increased NKD2 mRNA and protein expression coinciding with dual signaling pathway inhibition within co-cultured BCCs suggests that this reversal may be attributable to restored regulation of NKD2 within these pathways.Conclusion:ESC-microstrands are able to reverse oncogenic signaling pathway hyperactivation and restore signaling pathway regulation in metastatic BCCs.Further studies could provide insight into what role NKD2 up-regulation plays ;in BCC inhibition,leading to the development of a new targeted therapy for metastatic breast cancer.
