Pub Date : 2025-01-03DOI: 10.1038/s41422-024-01049-5
Yang Liu, Hexi Feng, Ke Li, Ruiyi Li, Xiao-Jie Zhang, Ye Tian, Yujiang Fang, Yanjie Zhou, Ling Liu, Xiaoqing Zhang
Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%–80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a “donor MHC-specific thymus vaccination” (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.
{"title":"Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation","authors":"Yang Liu, Hexi Feng, Ke Li, Ruiyi Li, Xiao-Jie Zhang, Ye Tian, Yujiang Fang, Yanjie Zhou, Ling Liu, Xiaoqing Zhang","doi":"10.1038/s41422-024-01049-5","DOIUrl":"10.1038/s41422-024-01049-5","url":null,"abstract":"Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%–80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a “donor MHC-specific thymus vaccination” (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 2","pages":"132-144"},"PeriodicalIF":28.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01049-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s41422-024-01025-z
Fei Li, Pengfei Dai, Huili Shi, Yajuan Zhang, Juan He, Anuradha Gopalan, Dan Li, Yu Chen, Yarui Du, Guoliang Xu, Weiwei Yang, Chao Liang, Dong Gao
Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.
{"title":"LKB1 inactivation promotes epigenetic remodeling-induced lineage plasticity and antiandrogen resistance in prostate cancer","authors":"Fei Li, Pengfei Dai, Huili Shi, Yajuan Zhang, Juan He, Anuradha Gopalan, Dan Li, Yu Chen, Yarui Du, Guoliang Xu, Weiwei Yang, Chao Liang, Dong Gao","doi":"10.1038/s41422-024-01025-z","DOIUrl":"10.1038/s41422-024-01025-z","url":null,"abstract":"Epigenetic regulation profoundly influences the fate of cancer cells and their capacity to switch between lineages by modulating essential gene expression, thereby shaping tumor heterogeneity and therapy response. In castration-resistant prostate cancer (CRPC), the intricacies behind androgen receptor (AR)-independent lineage plasticity remain unclear, leading to a scarcity of effective clinical treatments. Utilizing single-cell RNA sequencing on both human and mouse prostate cancer samples, combined with whole-genome bisulfite sequencing and multiple genetically engineered mouse models, we investigated the molecular mechanism of AR-independent lineage plasticity and uncovered a potential therapeutic strategy. Single-cell transcriptomic profiling of human prostate cancers, both pre- and post-androgen deprivation therapy, revealed an association between liver kinase B1 (LKB1) pathway inactivation and AR independence. LKB1 inactivation led to AR-independent lineage plasticity and global DNA hypomethylation during prostate cancer progression. Importantly, the pharmacological inhibition of TET enzymes and supplementation with S-adenosyl methionine were found to effectively suppress AR-independent prostate cancer growth. These insights shed light on the mechanism driving AR-independent lineage plasticity and propose a potential therapeutic strategy by targeting DNA hypomethylation in AR-independent CRPC.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 1","pages":"59-71"},"PeriodicalIF":28.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01025-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s41422-024-01057-5
Yuting Wang, Wenhao Zhang, Chao Zhang, Hoang Q. Tran Van, Takashi Seino, Yi Zhang
Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit “younger” molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of “younger” HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
{"title":"Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice","authors":"Yuting Wang, Wenhao Zhang, Chao Zhang, Hoang Q. Tran Van, Takashi Seino, Yi Zhang","doi":"10.1038/s41422-024-01057-5","DOIUrl":"10.1038/s41422-024-01057-5","url":null,"abstract":"Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit “younger” molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of “younger” HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 1","pages":"45-58"},"PeriodicalIF":28.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01057-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-02DOI: 10.1038/s41422-024-01016-0
Wenyu Fu, Meng Chen, Kaidi Wang, Yujianan Chen, Yazhou Cui, Yangli Xie, Zi-Ning Lei, Wenhuo Hu, Guodong Sun, Guiwu Huang, Chaopeng He, Jackie Fretz, Aubryanna Hettinghouse, Ronghan Liu, Xianyi Cai, Mingshuang Zhang, Yuehong Chen, Nan Jiang, Minchun He, Daniel H. Wiznia, Huiyun Xu, Zhe-Sheng Chen, Lin Chen, Kanglai Tang, Hong Zhou, Chuan-Ju Liu
Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.
{"title":"Tau is a receptor with low affinity for glucocorticoids and is required for glucocorticoid-induced bone loss","authors":"Wenyu Fu, Meng Chen, Kaidi Wang, Yujianan Chen, Yazhou Cui, Yangli Xie, Zi-Ning Lei, Wenhuo Hu, Guodong Sun, Guiwu Huang, Chaopeng He, Jackie Fretz, Aubryanna Hettinghouse, Ronghan Liu, Xianyi Cai, Mingshuang Zhang, Yuehong Chen, Nan Jiang, Minchun He, Daniel H. Wiznia, Huiyun Xu, Zhe-Sheng Chen, Lin Chen, Kanglai Tang, Hong Zhou, Chuan-Ju Liu","doi":"10.1038/s41422-024-01016-0","DOIUrl":"10.1038/s41422-024-01016-0","url":null,"abstract":"Glucocorticoids (GCs) are the most prescribed anti-inflammatory and immunosuppressive drugs. However, their use is often limited by substantial side effects, such as GC-induced osteoporosis (GIO) with the underlying mechanisms still not fully understood. In this study, we identify Tau as a low-affinity binding receptor for GCs that plays a crucial role in GIO. Tau deficiency largely abolished bone loss induced by high-dose dexamethasone, a synthetic GC, in both inflammatory arthritis and GIO models. Furthermore, TRx0237, a Tau inhibitor identified from an FDA-approved drug library, effectively prevented GIO. Notably, combinatorial administration of TRx0237 and dexamethasone completely overcame the osteoporosis adverse effect of dexamethasone in treating inflammatory arthritis. These findings present Tau as a previously unrecognized GC receptor with low affinity, and provide potential strategies to mitigate a spectrum of GC-related adverse effects, particularly osteoporosis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 1","pages":"23-44"},"PeriodicalIF":28.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41422-024-01016-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-23DOI: 10.1038/s41422-024-01066-4
Sofiya Zbaranska, Sheena A. Josselyn
During learning experience, a subset of astrocytes in the hippocampus is activated and becomes both necessary and sufficient for subsequent memory recall. Williamson et al. discovered that these learning-associated astrocytes play an important role in memory by modulating engram neurons’ synaptic activity and facilitating the reactivation of engram neuron ensembles during memory retrieval.
{"title":"Astrocytes: emerging stars of engrams","authors":"Sofiya Zbaranska, Sheena A. Josselyn","doi":"10.1038/s41422-024-01066-4","DOIUrl":"https://doi.org/10.1038/s41422-024-01066-4","url":null,"abstract":"<p><b>During learning experience, a subset of astrocytes in the hippocampus is activated and becomes both necessary and sufficient for subsequent memory recall. Williamson et al. discovered that these learning-associated astrocytes play an important role in memory by modulating engram neurons’ synaptic activity and facilitating the reactivation of engram neuron ensembles during memory retrieval</b>.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"113 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873913","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 : 2024-12-20DOI: 10.1038/s41422-024-01065-5
Niels Niethard, Jan Born
In a recent work published inNature, Wang et al. reveal how protein kinase A and calcineurin dynamically regulate the daily duration of sleep and wake periods at excitatory post-synapses in the brain. This study uncovers key molecular mechanisms offering new insights into the enzymatic control of sleep homeostasis.
{"title":"Tug of war between phosphatase and kinase during sleep","authors":"Niels Niethard, Jan Born","doi":"10.1038/s41422-024-01065-5","DOIUrl":"https://doi.org/10.1038/s41422-024-01065-5","url":null,"abstract":"<p><b>In a recent work published in</b> <b><i>Nature</i></b><b>, Wang et al. reveal how protein kinase A and calcineurin dynamically regulate the daily duration of sleep and wake periods at excitatory post-synapses in the brain. This study uncovers key molecular mechanisms offering new insights into the enzymatic control of sleep homeostasis.</b></p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"10 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857716","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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