Pub Date : 2025-10-09DOI: 10.1016/j.devcel.2025.09.012
Zuoxing Wu, Na Li, Zhengqiong Luo, Zihan Chen, Xuemei He, Fan Shi, Jie Han, Haitao Huang, Baohong Shi, Long Zhang, Yu Li, Junmin Shen, Seoyeon Bok, Jun Sun, Xing Niu, Ke Mo, Pengbin Yin, Lige Leng, Xin Wang, Jie Zhang, Ren Xu
Low bone mass is frequently observed in Alzheimer’s disease (AD), yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that sensory nerves constitute a critical component of the skeletal stem cell (SSC) niche. Deletion of the neurotrophin receptor p75NTR in neurons or sensory-specific cells, but not in osteogenic or sympathetic cells, resulted in reduced sensory innervation, disrupted SSC homeostasis, and significant bone loss. Although a cell-intrinsic role of p75NTR in SSCs cannot be ruled out, further experiments involving sensory denervation or transplantation into hosts with sensory-neuron-specific p75NTR deficiency confirmed impaired SSC osteogenesis. Mechanistically, p75NTR controls the expression of neuronal osteopontin (SPP1), which in turn promotes SSC self-renewal and osteogenic differentiation. Notably, this p75NTR-SPP1 signaling axis was found to be disrupted in AD mouse models, offering a direct mechanistic explanation for AD-associated osteopenia and highlighting the therapeutic potential of targeting neural control of SSCs.
{"title":"The p75 neurotrophin receptor controls the skeletal stem cell niche through sensory innervation","authors":"Zuoxing Wu, Na Li, Zhengqiong Luo, Zihan Chen, Xuemei He, Fan Shi, Jie Han, Haitao Huang, Baohong Shi, Long Zhang, Yu Li, Junmin Shen, Seoyeon Bok, Jun Sun, Xing Niu, Ke Mo, Pengbin Yin, Lige Leng, Xin Wang, Jie Zhang, Ren Xu","doi":"10.1016/j.devcel.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.012","url":null,"abstract":"Low bone mass is frequently observed in Alzheimer’s disease (AD), yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that sensory nerves constitute a critical component of the skeletal stem cell (SSC) niche. Deletion of the neurotrophin receptor p75NTR in neurons or sensory-specific cells, but not in osteogenic or sympathetic cells, resulted in reduced sensory innervation, disrupted SSC homeostasis, and significant bone loss. Although a cell-intrinsic role of p75NTR in SSCs cannot be ruled out, further experiments involving sensory denervation or transplantation into hosts with sensory-neuron-specific p75NTR deficiency confirmed impaired SSC osteogenesis. Mechanistically, p75NTR controls the expression of neuronal osteopontin (SPP1), which in turn promotes SSC self-renewal and osteogenic differentiation. Notably, this p75NTR-SPP1 signaling axis was found to be disrupted in AD mouse models, offering a direct mechanistic explanation for AD-associated osteopenia and highlighting the therapeutic potential of targeting neural control of SSCs.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"9 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.devcel.2025.08.006
Darya Khantakova, Marco Colonna
In this issue of Developmental Cell, Ma et al. show that embryonically derived VSIG4⁺ macrophages suppress CD8⁺ T cell responses across cancers. They identify IL-11 as a key effector and MEF2C as a transcriptional regulator of VSIG4⁺ macrophages, highlighting new therapeutic avenues for targeting immunosuppressive tumor-associated macrophages to improve immunotherapy outcomes.
{"title":"Dual threat: VSIG4⁺ macrophages use IL-11 and VSIG4 to silence T cells","authors":"Darya Khantakova, Marco Colonna","doi":"10.1016/j.devcel.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.08.006","url":null,"abstract":"In this issue of <em>Developmental Cell</em>, Ma et al. show that embryonically derived VSIG4⁺ macrophages suppress CD8⁺ T cell responses across cancers. They identify IL-11 as a key effector and MEF2C as a transcriptional regulator of VSIG4⁺ macrophages, highlighting new therapeutic avenues for targeting immunosuppressive tumor-associated macrophages to improve immunotherapy outcomes.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"158 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.devcel.2025.07.009
Brigida Novello, Cédric Blanpain
In this issue of Developmental Cell, Journot et al. identify a conserved mechanism promoting the development and lineage segregation of multipotent stem cells across different glandular epithelia. p63, YAP, and Notch control symmetry breaking, cell positioning, and cell-fate decision during development and regeneration, illustrating how spatial cues orchestrate tissue self-organization.
{"title":"Common mechanisms regulate stem cell self-organization and symmetry breaking across various glandular epithelia","authors":"Brigida Novello, Cédric Blanpain","doi":"10.1016/j.devcel.2025.07.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.07.009","url":null,"abstract":"In this issue of <em>Developmental Cell</em>, Journot et al. identify a conserved mechanism promoting the development and lineage segregation of multipotent stem cells across different glandular epithelia. p63, YAP, and Notch control symmetry breaking, cell positioning, and cell-fate decision during development and regeneration, illustrating how spatial cues orchestrate tissue self-organization.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"82 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.devcel.2025.06.011
Wenhui Chen, Yanjie Shen, Guangshuai Jia
Chronic inflammation shapes the tumor microenvironment and influences cancer stem cell behavior. In this issue of Developmental Cell, Gu et al. identify TNFAIP6 as a key responder to tumor necrosis factor alpha (TNF-α) that promotes self-renewal of glioblastoma stem cells and reprograms pro-inflammatory macrophages toward an immunosuppressive phenotype, identifying a therapeutic vulnerability in glioblastoma.
{"title":"How glioblastoma stem cells turn inflammatory cues into tumor growth and immune suppression","authors":"Wenhui Chen, Yanjie Shen, Guangshuai Jia","doi":"10.1016/j.devcel.2025.06.011","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.06.011","url":null,"abstract":"Chronic inflammation shapes the tumor microenvironment and influences cancer stem cell behavior. In this issue of <em>Developmental Cell</em>, Gu et al. identify TNFAIP6 as a key responder to tumor necrosis factor alpha (TNF-α) that promotes self-renewal of glioblastoma stem cells and reprograms pro-inflammatory macrophages toward an immunosuppressive phenotype, identifying a therapeutic vulnerability in glioblastoma.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"52 4 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1016/j.devcel.2025.09.006
Fangxia Wang, Yuu Kimata
Cells exiting quiescence must simultaneously prepare for DNA replication and boost metabolism. Paul et al.1 now show that mitogen-activated mTOR transiently suppresses APC/C-CDH1, unleashing the glycolytic activator PFKFB3 to provide an energetic pulse that jump-starts proliferation before APC/C is reactivated.
{"title":"Kickstart the cell cycle with a sugar boost: mTOR brake on APC/C-CDH1 triggers a glycolytic pulse","authors":"Fangxia Wang, Yuu Kimata","doi":"10.1016/j.devcel.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.006","url":null,"abstract":"Cells exiting quiescence must simultaneously prepare for DNA replication and boost metabolism. Paul et al.<span><span><sup>1</sup></span></span> now show that mitogen-activated mTOR transiently suppresses APC/C-CDH1, unleashing the glycolytic activator PFKFB3 to provide an energetic pulse that jump-starts proliferation before APC/C is reactivated.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"75 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.devcel.2025.09.009
Rongfeng Huang, Jiacheng Wang, Mingzeng Chang, Wenxin Tang, Yongqiang Yu, Yi Zhang, Yao Peng, Yanan Wang, Yihan Guo, Ting Lu, Yang Cao, Yewei Zhou, Qinglin Zhang, Yuehong Huang, Angxiao Wu, Luyan Ren, Michelle Gallei, Juan Dong, Haodong Chen, Jun He, Tongda Xu
The versatile and pivotal roles of the phytohormone auxin in regulating plant growth and development are typically linked to its directional transport, relying on the polarized PIN-FORMED (PIN) auxin exporters at the plasma membrane (PM). For decades, auxin has been proposed to promote PIN polarization, generating self-regulatory feedback mediating much of plant development, but mechanistic insight into this regulation is lacking. Here, we uncover an auxin-induced protein complex at the PM, containing auxin co-receptors transmembrane kinases (TMKs) and PIN1 auxin exporter, as the core machinery that underlies this feedback regulation. Auxin promotes PIN1 phosphorylation by TMKs, modulating PIN1 polarization and transport activity. We also provide evidence that PIN1-exported extracellular auxin is crucial for TMK activation and cell elongation, thus forming the simplest two-element self-regulatory feedback circuit. Thus, these findings offer direct mechanistic insights into a potential self-organizing circuit for auxin signaling and transport to ensure proper plant development in Arabidopsis.
植物激素生长素在调节植物生长发育中的关键作用通常与其定向运输有关，这种定向运输依赖于质膜（PM）上的极化PIN- formed （PIN）生长素出口蛋白。几十年来，生长素被认为促进PIN极化，产生自我调节反馈，介导了植物的大部分发育，但缺乏对这种调节的机制认识。在这里，我们在PM发现了生长素诱导的蛋白复合物，包含生长素共受体跨膜激酶（TMKs）和生长素输出PIN1，作为这种反馈调节的核心机制。生长素通过TMKs促进PIN1磷酸化，调节PIN1的极化和运输活性。我们还提供证据表明，pin1输出的细胞外生长素对TMK激活和细胞伸长至关重要，从而形成最简单的二元自我调节反馈回路。因此，这些发现为研究生长素信号和运输的潜在自组织回路提供了直接的机制见解，以确保拟南芥植物的正常发育。
{"title":"TMK-PIN1 drives a short self-organizing circuit for auxin export and signaling in Arabidopsis","authors":"Rongfeng Huang, Jiacheng Wang, Mingzeng Chang, Wenxin Tang, Yongqiang Yu, Yi Zhang, Yao Peng, Yanan Wang, Yihan Guo, Ting Lu, Yang Cao, Yewei Zhou, Qinglin Zhang, Yuehong Huang, Angxiao Wu, Luyan Ren, Michelle Gallei, Juan Dong, Haodong Chen, Jun He, Tongda Xu","doi":"10.1016/j.devcel.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.009","url":null,"abstract":"The versatile and pivotal roles of the phytohormone auxin in regulating plant growth and development are typically linked to its directional transport, relying on the polarized PIN-FORMED (PIN) auxin exporters at the plasma membrane (PM). For decades, auxin has been proposed to promote PIN polarization, generating self-regulatory feedback mediating much of plant development, but mechanistic insight into this regulation is lacking. Here, we uncover an auxin-induced protein complex at the PM, containing auxin co-receptors transmembrane kinases (TMKs) and PIN1 auxin exporter, as the core machinery that underlies this feedback regulation. Auxin promotes PIN1 phosphorylation by TMKs, modulating PIN1 polarization and transport activity. We also provide evidence that PIN1-exported extracellular auxin is crucial for TMK activation and cell elongation, thus forming the simplest two-element self-regulatory feedback circuit. Thus, these findings offer direct mechanistic insights into a potential self-organizing circuit for auxin signaling and transport to ensure proper plant development in <em>Arabidopsis</em>.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"214 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Water uptake and redistribution represent a significant challenge for plant colonization of land. While vascular plants have evolved specialized structures for water transport, how water homeostasis is maintained in meristematic tissues remains elusive. Here, we show that the Arabidopsis shoot meristem develops within a high-humidity niche. The homeodomain leucine zipper (HD-ZIP) transcription factor ARABIDOPSIS THALIANA MERISTEM LAYER 1 (ATML1) and its regulatory target PIP2;5 establish a water conduit across L1 cells to facilitate hydraulic exchange with the surrounding microenvironment. The ATML1-PIP2;5 module regulates stem cell activity in response to humidity fluctuations and is associated with local adaptation to arid climates in natural populations. Transcriptional activation of water flux by class IV homeodomain-leucine zipper (C4HDZ) proteins predates the emergence of vascular systems, contributing to hydraulic response in the liverwort Marchantia polymorpha. Our results reveal an evolutionarily conserved epidermal hydraulic pathway that integrates developmental patterning with environmental sensing, highlighting a fundamental role for the shoot meristem in shaping plant adaptation in terrestrial habitats.
{"title":"Epidermal hydrodynamics controls water homeostasis of shoot meristems for plant adaptation to terrestrial environments","authors":"Yimin Zhu, Xianmiao Zhu, Simin Bi, Dan Teng, Muhammad Tahir, Yangxuan Liu, Long Wang, Huanhuan Liu, Tingting Wen, Leyao Zhu, Zhenquan Li, Xing Chen, Minhua Zhang, Wenjuan Cai, Zhijun Liu, Mingyue Zheng, Yu Zhang, Ji-Ming Gong, Jia-Wei Wang, Zuhua He, Weibing Yang","doi":"10.1016/j.devcel.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.007","url":null,"abstract":"Water uptake and redistribution represent a significant challenge for plant colonization of land. While vascular plants have evolved specialized structures for water transport, how water homeostasis is maintained in meristematic tissues remains elusive. Here, we show that the <em>Arabidopsis</em> shoot meristem develops within a high-humidity niche. The homeodomain leucine zipper (HD-ZIP) transcription factor ARABIDOPSIS THALIANA MERISTEM LAYER 1 (ATML1) and its regulatory target <em>PIP2;5</em> establish a water conduit across L1 cells to facilitate hydraulic exchange with the surrounding microenvironment. The ATML1-PIP2;5 module regulates stem cell activity in response to humidity fluctuations and is associated with local adaptation to arid climates in natural populations. Transcriptional activation of water flux by class IV homeodomain-leucine zipper (C4HDZ) proteins predates the emergence of vascular systems, contributing to hydraulic response in the liverwort <em>Marchantia polymorpha</em>. Our results reveal an evolutionarily conserved epidermal hydraulic pathway that integrates developmental patterning with environmental sensing, highlighting a fundamental role for the shoot meristem in shaping plant adaptation in terrestrial habitats.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"11 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1016/j.devcel.2025.09.002
Xia Yang, Yun-Zhong Nie, Chun Lu, Yang Li, Yoshihito Hayashi, Riana Plummer, Na Luo, Qinglin Li, Toshiharu Kasai, Takashi Okumura, Yumiko Isobe, Kiyoshi Yamaguchi, Yoichi Furukawa, Yan Li, Hideki Taniguchi
Human-induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) are valuable for studying human liver organogenesis but face challenges in faithfully recapitulating certain processes, like vasculogenesis, due to the lack of specific cell components. Hepatic stellate cells (HSCs), which are liver-specific pericytes and might be crucial for liver vasculogenesis, remain underutilized in developmental studies because of their disease-related status and inefficient generation process. Here, we present an efficient method for generating hiPSC-derived HSCs (hiPSC-HSCs) resembling the transcriptomic profiles of fetal human HSCs. These hiPSC-HSCs exhibit exceptional expandability (>105-fold) while maintaining essential cellular features. Additionally, in entirely hiPSC-derived LOs consisting of HSCs, hepatic endoderm, and endothelial cells, hiPSC-HSCs play a vital role in LO maturation and vascularization, both in vitro and in vivo. This work represents a significant advancement in understanding HSC roles in human liver development, and LOs containing hiPSC-HSCs hold potential in modeling congenital human liver diseases.
{"title":"Human pluripotent stem cell-derived fetal hepatic stellate cells promote vascularization and maturation in liver organoids","authors":"Xia Yang, Yun-Zhong Nie, Chun Lu, Yang Li, Yoshihito Hayashi, Riana Plummer, Na Luo, Qinglin Li, Toshiharu Kasai, Takashi Okumura, Yumiko Isobe, Kiyoshi Yamaguchi, Yoichi Furukawa, Yan Li, Hideki Taniguchi","doi":"10.1016/j.devcel.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.002","url":null,"abstract":"Human-induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) are valuable for studying human liver organogenesis but face challenges in faithfully recapitulating certain processes, like vasculogenesis, due to the lack of specific cell components. Hepatic stellate cells (HSCs), which are liver-specific pericytes and might be crucial for liver vasculogenesis, remain underutilized in developmental studies because of their disease-related status and inefficient generation process. Here, we present an efficient method for generating hiPSC-derived HSCs (hiPSC-HSCs) resembling the transcriptomic profiles of fetal human HSCs. These hiPSC-HSCs exhibit exceptional expandability (>10<sup>5</sup>-fold) while maintaining essential cellular features. Additionally, in entirely hiPSC-derived LOs consisting of HSCs, hepatic endoderm, and endothelial cells, hiPSC-HSCs play a vital role in LO maturation and vascularization, both <em>in vitro</em> and <em>in vivo</em>. This work represents a significant advancement in understanding HSC roles in human liver development, and LOs containing hiPSC-HSCs hold potential in modeling congenital human liver diseases.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"4 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-29DOI: 10.1016/j.devcel.2025.09.001
Randolph K. Larsen, Jason A. Hanna, Hongjian Jin, Kristin B. Reed, Darden W. Kimbrough, Kyna Vuong, Jongchan Hwang, Grace E. Adkins, Jack D. Hopkins, Bradley T. Stevens, Myron K. Evans, Casey G. Langdon, Catherine J. Drummond, Matthew R. Garcia, Kristin B. Wiggins, Amy R. Iverson, David Finkelstein, Patrick A. Schreiner, Jason W. Rosch, Jerold E. Rehg, Mark E. Hatley
DICER1-related tumors are characterized by germline loss-of-function mutations in one DICER1 allele (DICER1+/−) and a somatic “second hit” mutation in the remaining DICER1 allele. Whether the germline DICER1+/− mutation participates in tumorigenesis is unknown. We show that germline heterozygous loss of Dicer1 promotes tumor formation via aberrant neutrophil function in spontaneous and allograft mouse models of rhabdomyosarcoma. Germline heterozygous deletion of Dicer1 decreased tumor latency and increased tumor penetrance, while conditional heterozygous deletion in tumor cells did not, illustrating that non-cell-autonomous contributions were required for tumor promotion. We show that Dicer1+/− murine and human tumors were enriched for neutrophils and that tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically and pharmacologically preventing NET release reduced tumor promotion in Dicer1+/− mice, suggesting NETs promote tumor growth. These findings demonstrate that germline DICER1+/− mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in DICER1+/− individuals.
{"title":"Non-cell-autonomous tumor promotion in DICER1 cancer predisposition","authors":"Randolph K. Larsen, Jason A. Hanna, Hongjian Jin, Kristin B. Reed, Darden W. Kimbrough, Kyna Vuong, Jongchan Hwang, Grace E. Adkins, Jack D. Hopkins, Bradley T. Stevens, Myron K. Evans, Casey G. Langdon, Catherine J. Drummond, Matthew R. Garcia, Kristin B. Wiggins, Amy R. Iverson, David Finkelstein, Patrick A. Schreiner, Jason W. Rosch, Jerold E. Rehg, Mark E. Hatley","doi":"10.1016/j.devcel.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.001","url":null,"abstract":"DICER1-related tumors are characterized by germline loss-of-function mutations in one <em>DICER1</em> allele (<em>DICER1</em><sup><em>+/−</em></sup>) and a somatic “second hit” mutation in the remaining <em>DICER1</em> allele. Whether the germline <em>DICER1</em><sup><em>+/−</em></sup> mutation participates in tumorigenesis is unknown. We show that germline heterozygous loss of <em>Dicer1</em> promotes tumor formation via aberrant neutrophil function in spontaneous and allograft mouse models of rhabdomyosarcoma. Germline heterozygous deletion of <em>Dicer1</em> decreased tumor latency and increased tumor penetrance, while conditional heterozygous deletion in tumor cells did not, illustrating that non-cell-autonomous contributions were required for tumor promotion. We show that <em>Dicer1</em><sup><em>+/−</em></sup> murine and human tumors were enriched for neutrophils and that tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically and pharmacologically preventing NET release reduced tumor promotion in <em>Dicer1</em><sup><em>+/−</em></sup> mice, suggesting NETs promote tumor growth. These findings demonstrate that germline <em>DICER1</em><sup><em>+/−</em></sup> mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in <em>DICER1</em><sup><em>+/−</em></sup> individuals.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"118 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145183195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intestinal telocytes that reside immediately beneath the intestinal epithelium exert niche-supporting roles for intestinal stem cells and their progenies. They are heterogeneous cells compartmentalized along the crypt-villus axis, but the mechanisms governing the maintenance of this telocyte population remain unclear. Here, we identify a distinct population of subepithelial mesenchymal cells in the developing mouse embryo, marked by LIM Domain Only 3 (Lmo3), as the cellular origin of post-natal intestinal telocytes. The Lmo3+ cells emerge prior to villus formation at embryonic day 13.5, and after birth, they progressively acquire a spatial confinement to the intestinal isthmus region, where they persist as long-lived, slow-cycling cells, supplying both peri-villus and peri-crypt telocytes. Further, we show that Lmo3+ cells respond rapidly to tissue damage, becoming activated to promote repair of the telocyte niche. Therefore, a quiescent and damage-responsive progenitor cell population marked by Lmo3 maintains the intestinal telocyte niche.
{"title":"Lmo3-expressing peri-isthmus progenitor cells sustain renewal and repair of the mammalian intestinal telocyte niche","authors":"Daxin Jiang, Guoli Zhu, Yongchao Zhang, Jiawen Wang, Nannan Qian, Zhen Jin, Qingyu Sun, Haimeng Yu, Kebei Tang, Tao Cai, Fengchao Wang, Rongwen Xi","doi":"10.1016/j.devcel.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.devcel.2025.09.004","url":null,"abstract":"Intestinal telocytes that reside immediately beneath the intestinal epithelium exert niche-supporting roles for intestinal stem cells and their progenies. They are heterogeneous cells compartmentalized along the crypt-villus axis, but the mechanisms governing the maintenance of this telocyte population remain unclear. Here, we identify a distinct population of subepithelial mesenchymal cells in the developing mouse embryo, marked by <em>LIM Domain Only 3</em> (<em>Lmo3</em>), as the cellular origin of post-natal intestinal telocytes. The <em>Lmo3</em><sup><em>+</em></sup> cells emerge prior to villus formation at embryonic day 13.5, and after birth, they progressively acquire a spatial confinement to the intestinal isthmus region, where they persist as long-lived, slow-cycling cells, supplying both peri-villus and peri-crypt telocytes. Further, we show that <em>Lmo3</em><sup>+</sup> cells respond rapidly to tissue damage, becoming activated to promote repair of the telocyte niche. Therefore, a quiescent and damage-responsive progenitor cell population marked by <em>Lmo3</em> maintains the intestinal telocyte niche.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"94 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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