Pub Date : 2024-04-04DOI: 10.1016/j.stem.2024.03.009
Petronela Ancuta
{"title":"Genetic haute couture to block HIV-1 at front doors","authors":"Petronela Ancuta","doi":"10.1016/j.stem.2024.03.009","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.009","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1016/j.stem.2024.03.003
Kenji Namoto, Clara Baader, Vanessa Orsini, Alexandro Landshammer, Eva Breuer, Kieu Trinh Dinh, Rosemarie Ungricht, Monika Pikiolek, Stephane Laurent, Bo Lu, Alexandra Aebi, Katharina Schönberger, Eric Vangrevelinghe, Olivera Evrova, Tianliang Sun, Stefano Annunziato, Julie Lachal, Emily Redmond, Louis Wang, Kristie Wetzel, Paola Capodieci, Jonathan Turner, Gabi Schutzius, Vincent Unterreiner, Markus Trunzer, Nicole Buschmann, Dirk Behnke, Rainer Machauer, Clemens Scheufler, Christian N. Parker, Magali Ferro, Armelle Grevot, Armin Beyerbach, Wei-Yu Lu, Stuart J. Forbes, Jürgen Wagner, Tewis Bouwmeester, Jun Liu, Bindi Sohal, Sukhdeep Sahambi, Linda E. Greenbaum, Felix Lohmann, Philipp Hoppe, Feng Cong, Andreas W. Sailer, Heinz Ruffner, Ralf Glatthar, Bostjan Humar, Pierre-Alain Clavien, Michael T. Dill, Elizabeth George, Jürgen Maibaum, Prisca Liberali, Jan S. Tchorz
The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation and . NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration and , enabling future research on the regenerative potential of the YAP/Hippo pathway.
{"title":"NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo","authors":"Kenji Namoto, Clara Baader, Vanessa Orsini, Alexandro Landshammer, Eva Breuer, Kieu Trinh Dinh, Rosemarie Ungricht, Monika Pikiolek, Stephane Laurent, Bo Lu, Alexandra Aebi, Katharina Schönberger, Eric Vangrevelinghe, Olivera Evrova, Tianliang Sun, Stefano Annunziato, Julie Lachal, Emily Redmond, Louis Wang, Kristie Wetzel, Paola Capodieci, Jonathan Turner, Gabi Schutzius, Vincent Unterreiner, Markus Trunzer, Nicole Buschmann, Dirk Behnke, Rainer Machauer, Clemens Scheufler, Christian N. Parker, Magali Ferro, Armelle Grevot, Armin Beyerbach, Wei-Yu Lu, Stuart J. Forbes, Jürgen Wagner, Tewis Bouwmeester, Jun Liu, Bindi Sohal, Sukhdeep Sahambi, Linda E. Greenbaum, Felix Lohmann, Philipp Hoppe, Feng Cong, Andreas W. Sailer, Heinz Ruffner, Ralf Glatthar, Bostjan Humar, Pierre-Alain Clavien, Michael T. Dill, Elizabeth George, Jürgen Maibaum, Prisca Liberali, Jan S. Tchorz","doi":"10.1016/j.stem.2024.03.003","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.003","url":null,"abstract":"The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation and . NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration and , enabling future research on the regenerative potential of the YAP/Hippo pathway.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1016/j.stem.2024.03.005
Courtney E. Vishy, Chardai Thomas, Thomas Vincent, Daniel K. Crawford, Matthew M. Goddeeris, Benjamin S. Freedman
In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world’s most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.
{"title":"Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease","authors":"Courtney E. Vishy, Chardai Thomas, Thomas Vincent, Daniel K. Crawford, Matthew M. Goddeeris, Benjamin S. Freedman","doi":"10.1016/j.stem.2024.03.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.005","url":null,"abstract":"In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world’s most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1016/j.stem.2024.03.006
Heather M. Sosnoski, Avery D. Posey Jr.
{"title":"Therapeutic intersections: Expanding benefits of CD19 CAR T cells from cancer to autoimmunity","authors":"Heather M. Sosnoski, Avery D. Posey Jr.","doi":"10.1016/j.stem.2024.03.006","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.006","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.1016/j.stem.2024.01.012
Jenna M. Kastenschmidt, Joseph G. Schroers-Martin, Brian J. Sworder, Suhas Sureshchandra, Michael S. Khodadoust, Chih Long Liu, Mari Olsen, David M. Kurtz, Maximilian Diehn, Lisa E. Wagar, Ash A. Alizadeh
{"title":"A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment","authors":"Jenna M. Kastenschmidt, Joseph G. Schroers-Martin, Brian J. Sworder, Suhas Sureshchandra, Michael S. Khodadoust, Chih Long Liu, Mari Olsen, David M. Kurtz, Maximilian Diehn, Lisa E. Wagar, Ash A. Alizadeh","doi":"10.1016/j.stem.2024.01.012","DOIUrl":"https://doi.org/10.1016/j.stem.2024.01.012","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139937524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20DOI: 10.1016/j.stem.2024.01.009
Peng Du, Jun Wu
{"title":"Hallmarks of totipotent and pluripotent stem cell states","authors":"Peng Du, Jun Wu","doi":"10.1016/j.stem.2024.01.009","DOIUrl":"https://doi.org/10.1016/j.stem.2024.01.009","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139916133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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