Pub Date : 2024-04-24DOI: 10.1016/j.stem.2024.03.018
Zahir Shah, Lei Tian, Zhixin Li, Lewei Jin, Jianying Zhang, Zhenlong Li, Tasha Barr, Hejun Tang, Mingye Feng, Michael A. Caligiuri, Jianhua Yu
Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.
{"title":"Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer","authors":"Zahir Shah, Lei Tian, Zhixin Li, Lewei Jin, Jianying Zhang, Zhenlong Li, Tasha Barr, Hejun Tang, Mingye Feng, Michael A. Caligiuri, Jianhua Yu","doi":"10.1016/j.stem.2024.03.018","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.018","url":null,"abstract":"<p>Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors <em>in vitro</em> and <em>in vivo</em>, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other <em>in vivo</em> toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642876","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 : 2024-04-19DOI: 10.1016/j.stem.2024.03.017
Claire L. Burgess, Jessie Huang, Pushpinder S. Bawa, Konstantinos-Dionysios Alysandratos, Kasey Minakin, Lauren J. Ayers, Michael P. Morley, Apoorva Babu, Carlos Villacorta-Martin, Maria Yampolskaya, Anne Hinds, Bibek R. Thapa, Feiya Wang, Adeline Matschulat, Pankaj Mehta, Edward E. Morrisey, Xaralabos Varelas, Darrell N. Kotton
Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s.
{"title":"Generation of human alveolar epithelial type I cells from pluripotent stem cells","authors":"Claire L. Burgess, Jessie Huang, Pushpinder S. Bawa, Konstantinos-Dionysios Alysandratos, Kasey Minakin, Lauren J. Ayers, Michael P. Morley, Apoorva Babu, Carlos Villacorta-Martin, Maria Yampolskaya, Anne Hinds, Bibek R. Thapa, Feiya Wang, Adeline Matschulat, Pankaj Mehta, Edward E. Morrisey, Xaralabos Varelas, Darrell N. Kotton","doi":"10.1016/j.stem.2024.03.017","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.017","url":null,"abstract":"<p>Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human <em>in vitro</em> AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an <em>in vitro</em> model of human alveolar epithelial differentiation and a potential source of human AT1s.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140622922","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 : 2024-04-15DOI: 10.1016/j.stem.2024.03.013
Osama Al-Dalahmah, Matti Lam, Julie J. McInvale, Wenhui Qu, Trang Nguyen, Jeong-Yeon Mun, Sam Kwon, Nkechime Ifediora, Aayushi Mahajan, Nelson Humala, Tristan Winters, Ellen Angeles, Kelly A. Jakubiak, Rebekka Kühn, Yoon A. Kim, Maria Caterina De Rosa, Claudia A. Doege, Fahad Paryani, Xena Flowers, Athanassios Dovas, Angeliki Mela, Hong Lu, Michael A. DeTure, Jean Paul Vonsattel, Zbigniew K. Wszolek, Dennis W. Dickson, Tanja Kuhlmann, Holm Zaehres, Hans R. Schöler, Andrew A. Sproul, Markus D. Siegelin, Philip L. De Jager, James E. Goldman, Vilas Menon, Peter Canoll, Gunnar Hargus
{"title":"Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons","authors":"Osama Al-Dalahmah, Matti Lam, Julie J. McInvale, Wenhui Qu, Trang Nguyen, Jeong-Yeon Mun, Sam Kwon, Nkechime Ifediora, Aayushi Mahajan, Nelson Humala, Tristan Winters, Ellen Angeles, Kelly A. Jakubiak, Rebekka Kühn, Yoon A. Kim, Maria Caterina De Rosa, Claudia A. Doege, Fahad Paryani, Xena Flowers, Athanassios Dovas, Angeliki Mela, Hong Lu, Michael A. DeTure, Jean Paul Vonsattel, Zbigniew K. Wszolek, Dennis W. Dickson, Tanja Kuhlmann, Holm Zaehres, Hans R. Schöler, Andrew A. Sproul, Markus D. Siegelin, Philip L. De Jager, James E. Goldman, Vilas Menon, Peter Canoll, Gunnar Hargus","doi":"10.1016/j.stem.2024.03.013","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.013","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557321","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 : 2024-04-11DOI: 10.1016/j.stem.2024.03.011
Hsueh-Fu Wu, Kenyi Saito-Diaz, Chia-Wei Huang, Jessica L. McAlpine, Dong Eun Seo, D. Sumner Magruder, Mohamed Ishan, Harrison C. Bergeron, William H. Delaney, Fabio R. Santori, Smita Krishnaswamy, Gerald W. Hart, Ya-Wen Chen, Robert J. Hogan, Hong-Xiang Liu, Natalia B. Ivanova, Nadja Zeltner
{"title":"Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development","authors":"Hsueh-Fu Wu, Kenyi Saito-Diaz, Chia-Wei Huang, Jessica L. McAlpine, Dong Eun Seo, D. Sumner Magruder, Mohamed Ishan, Harrison C. Bergeron, William H. Delaney, Fabio R. Santori, Smita Krishnaswamy, Gerald W. Hart, Ya-Wen Chen, Robert J. Hogan, Hong-Xiang Liu, Natalia B. Ivanova, Nadja Zeltner","doi":"10.1016/j.stem.2024.03.011","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.011","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557358","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 : 2024-04-08DOI: 10.1016/j.stem.2024.03.012
Laura N. Stankiewicz, Fabio M.V. Rossi, Peter W. Zandstra
{"title":"Rebuilding and rebooting immunity with stem cells","authors":"Laura N. Stankiewicz, Fabio M.V. Rossi, Peter W. Zandstra","doi":"10.1016/j.stem.2024.03.012","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.012","url":null,"abstract":"","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":23.9,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557338","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.2024.03.004
Jesse D. Lai, Joshua E. Berlind, Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, Violeta Yu, Zhen Zhao, Justin K. Ichida
Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes and , including in ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.
{"title":"KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury","authors":"Jesse D. Lai, Joshua E. Berlind, Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, Violeta Yu, Zhen Zhao, Justin K. Ichida","doi":"10.1016/j.stem.2024.03.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.004","url":null,"abstract":"Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes and , including in ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.","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":"140534695","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.2024.03.002
Amanda M. Dudek, William N. Feist, Elena J. Sasu, Sofia E. Luna, Kaya Ben-Efraim, Rasmus O. Bak, Alma-Martina Cepika, Matthew H. Porteus
Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of null () cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, matched bone marrow donors are rare, and transplant does not confer resistance to the CXCR4-tropic virus, it is not a viable option for most patients. We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity , and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a functional cure for both CCR5-tropic and CXCR4-tropic HIV-1 infections.
{"title":"A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection","authors":"Amanda M. Dudek, William N. Feist, Elena J. Sasu, Sofia E. Luna, Kaya Ben-Efraim, Rasmus O. Bak, Alma-Martina Cepika, Matthew H. Porteus","doi":"10.1016/j.stem.2024.03.002","DOIUrl":"https://doi.org/10.1016/j.stem.2024.03.002","url":null,"abstract":"Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of null () cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, matched bone marrow donors are rare, and transplant does not confer resistance to the CXCR4-tropic virus, it is not a viable option for most patients. We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity , and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a functional cure for both CCR5-tropic and CXCR4-tropic HIV-1 infections.","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":"140534643","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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