Shuyong Wang, Xuan Wang, Yiran Shan, Zuolong Tan, Yuxin Su, Yannan Cao, Shuang Wang, Jiahong Dong, Jin Gu, Yunfang Wang
Liver injuries often occur in a zonated manner. However, detailed regenerative responses to such zonal injuries at cellular and molecular levels remain largely elusive. By using a fate-mapping strain, Cyp2e1-DreER, to elucidate liver regeneration after acute pericentral injury, we found that pericentral regeneration is primarily compensated by the expansion of remaining pericentral hepatocytes, and secondarily by expansion of periportal hepatocytes. Employing single-cell RNA sequencing, spatial transcriptomics, immunostaining, and in vivo functional assays, we demonstrated that the upregulated expression of the mTOR/4E-BP1 axis and lactate dehydrogenase A in hepatocytes contributes to pericentral regeneration, while activation of transforming growth factor β (TGF-β1) signaling in the damaged area mediates fibrotic responses and inhibits hepatocyte proliferation...
February 21, 2024: Cell Stem Cell
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
Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME...
February 20, 2024: Cell Stem Cell
Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D'Alessandro, Britta Will
Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis...
February 19, 2024: Cell Stem Cell
Peng Du, Jun Wu
Though totipotency and pluripotency are transient during early embryogenesis, they establish the foundation for the development of all mammals. Studying these in vivo has been challenging due to limited access and ethical constraints, particularly in humans. Recent progress has led to diverse culture adaptations of epiblast cells in vitro in the form of totipotent and pluripotent stem cells, which not only deepen our understanding of embryonic development but also serve as invaluable resources for animal reproduction and regenerative medicine...
February 13, 2024: Cell Stem Cell
David Shin, Chang N Kim, Jayden Ross, Kelsey M Hennick, Sih-Rong Wu, Neha Paranjape, Rachel Leonard, Jerrick C Wang, Matthew G Keefe, Bryan J Pavlovic, Kevin C Donohue, Clara Moreau, Emilie M Wigdor, H Hanh Larson, Denise E Allen, Cathryn R Cadwell, Aparna Bhaduri, Galina Popova, Carrie E Bearden, Alex A Pollen, Sebastien Jacquemont, Stephan J Sanders, David Haussler, Arun P Wiita, Nicholas A Frost, Vikaas S Sohal, Tomasz J Nowakowski
Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2...
February 13, 2024: Cell Stem Cell
Kavita Raniga, Aishah Nasir, Nguyen T N Vo, Ravi Vaidyanathan, Sarah Dickerson, Simon Hilcove, Diogo Mosqueira, Gary R Mirams, Peter Clements, Ryan Hicks, Amy Pointon, Will Stebbeds, Jo Francis, Chris Denning
Advances in hiPSC isolation and reprogramming and hPSC-CM differentiation have prompted their therapeutic application and utilization for evaluating potential cardiovascular safety liabilities. In this perspective, we showcase key efforts toward the large-scale production of hiPSC-CMs, implementation of hiPSC-CMs in industry settings, and recent clinical applications of this technology. The key observations are a need for traceable gender and ethnically diverse hiPSC lines, approaches to reduce cost of scale-up, accessible clinical trial datasets, and transparent guidelines surrounding the safety and efficacy of hiPSC-based therapies...
February 12, 2024: Cell Stem Cell
Chenxi Ye, Chuanlai Yang, Heqiang Zhang, Rui Gao, Yingnan Liao, Yali Zhang, Lingjun Jie, Yanhui Zhang, Tong Cheng, Yan Wang, Jie Ren
The creation of a functional 3D bioprinted human heart remains challenging, largely due to the lack of some crucial cardiac cell types, including the atrioventricular canal (AVC) cardiomyocytes, which are essential to slow down the electrical impulse between the atrium and ventricle. By utilizing single-cell RNA sequencing analysis and a 3D bioprinting technology, we discover that stage-specific activation of canonical Wnt signaling creates functional AVC cardiomyocytes derived from human pluripotent stem cells...
February 10, 2024: Cell Stem Cell
Xiaomeng Hu, Kathy White, Chi Young, Ari G Olroyd, Paul Kievit, Andrew J Connolly, Tobias Deuse, Sonja Schrepfer
Allogeneic transplantation of pancreatic islets for patients with difficult-to-control diabetes mellitus is severely hampered by the requirement for continuous immunosuppression and its associated morbidity. We report that allogeneic transplantation of genetically engineered (B2M-/- , CIITA-/- , CD47+ ), primary, hypoimmune, pseudo-islets (p-islets) results in their engraftment into a fully immunocompetent, diabetic non-human primate wherein they provide stable endocrine function and enable insulin independence without inducing any detectable immune response in the absence of immunosuppression...
February 8, 2024: Cell Stem Cell
Qian Li, Andrew Sharkey, Megan Sheridan, Elisa Magistrati, Anna Arutyunyan, Oisin Huhn, Carmen Sancho-Serra, Holly Anderson, Naomi McGovern, Laura Esposito, Ridma Fernando, Lucy Gardner, Roser Vento-Tormo, Margherita Yayoi Turco, Ashley Moffett
In humans, balanced invasion of trophoblast cells into the uterine mucosa, the decidua, is critical for successful pregnancy. Evidence suggests that this process is regulated by uterine natural killer (uNK) cells, but how they influence reproductive outcomes is unclear. Here, we used our trophoblast organoids and primary tissue samples to determine how uNK cells affect placentation. By locating potential interaction axes between trophoblast and uNK cells using single-cell transcriptomics and in vitro modeling of these interactions in organoids, we identify a uNK cell-derived cytokine signal that promotes trophoblast differentiation at the late stage of the invasive pathway...
January 10, 2024: Cell Stem Cell
Liuliu Yang, Tae Wan Kim, Yuling Han, Manoj S Nair, Oliver Harschnitz, Jiajun Zhu, Pengfei Wang, So Yeon Koo, Lauretta A Lacko, Vasuretha Chandar, Yaron Bram, Tuo Zhang, Wei Zhang, Feng He, Chendong Pan, Junjie Wu, Yaoxing Huang, Todd Evans, Paul van der Valk, Maarten J Titulaer, Jochem K H Spoor, Robert L Furler O'Brien, Marianna Bugiani, Wilma D J Van de Berg, Robert E Schwartz, David D Ho, Lorenz Studer, Shuibing Chen
COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection...
January 10, 2024: Cell Stem Cell
Iwo Kucinski, Joana Campos, Melania Barile, Francesco Severi, Natacha Bohin, Pedro N Moreira, Lewis Allen, Hannah Lawson, Myriam L R Haltalli, Sarah J Kinston, Dónal O'Carroll, Kamil R Kranc, Berthold Göttgens
The paradigmatic hematopoietic tree model is increasingly recognized to be limited, as it is based on heterogeneous populations largely defined by non-homeostatic assays testing cell fate potentials. Here, we combine persistent labeling with time-series single-cell RNA sequencing to build a real-time, quantitative model of in vivo tissue dynamics for murine bone marrow hematopoiesis. We couple cascading single-cell expression patterns with dynamic changes in differentiation and growth speeds. The resulting explicit linkage between molecular states and cellular behavior reveals widely varying self-renewal and differentiation properties across distinct lineages...
December 29, 2023: Cell Stem Cell
Caitlin M MacCarthy, Guangming Wu, Vikas Malik, Yotam Menuchin-Lasowski, Taras Velychko, Gal Keshet, Rui Fan, Ivan Bedzhov, George M Church, Ralf Jauch, Vlad Cojocaru, Hans R Schöler, Sergiy Velychko
Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission has only been demonstrated for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a gain of function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-quality OSKM iPSCs capable of supporting the development of healthy all-iPSC mice...
December 20, 2023: Cell Stem Cell
Sanghyun Park, Chan Wook Park, Jang Hyeon Eom, Mi-Young Jo, Hye-Jin Hur, Sung Kyoung Choi, Jae Souk Lee, Seung Taek Nam, Ki-Sang Jo, Young Woo Oh, Jungil Lee, Sieun Kim, Do-Hun Kim, Chul-Yong Park, Su Jin Kim, Ho-Young Lee, Myung Soo Cho, Dae-Sung Kim, Dong-Wook Kim
Human embryonic stem cell (hESC)-derived midbrain dopaminergic (mDA) cell transplantation is a promising therapeutic strategy for Parkinson's disease (PD). Here, we present the derivation of high-purity mDA progenitors from clinical-grade hESCs on a large scale under rigorous good manufacturing practice (GMP) conditions. We also assessed the toxicity, biodistribution, and tumorigenicity of these cells in immunodeficient rats in good laboratory practice (GLP)-compliant facilities. Various doses of mDA progenitors were transplanted into hemi-parkinsonian rats, and a significant dose-dependent behavioral improvement was observed with a minimal effective dose range of 5,000-10,000 mDA progenitor cells...
December 7, 2023: Cell Stem Cell
Sanghyun Park, Chan Wook Park, Jang Hyeon Eom, Mi-Young Jo, Hye-Jin Hur, Sung Kyoung Choi, Jae Souk Lee, Seung Taek Nam, Ki-Sang Jo, Young Woo Oh, Jungil Lee, Sieun Kim, Do-Hun Kim, Chul-Yong Park, Su Jin Kim, Ho-Young Lee, Myung Soo Cho, Dae-Sung Kim, Dong-Wook Kim
No abstract text is available yet for this article.
February 1, 2024: Cell Stem Cell
Chun-Wei Chen, Linda Zhang, Ravi Dutta, Abhishek Niroula, Peter G Miller, Christopher J Gibson, Alexander G Bick, Jaime M Reyes, Yi-Tang Lee, Ayala Tovy, Tianpeng Gu, Sarah Waldvogel, Yi-Hung Chen, Bryan J Venters, Pierre-Olivier Estève, Sriharsa Pradhan, Michael-Christopher Keogh, Pradeep Natarajan, Koichi Takahashi, Adam S Sperling, Margaret A Goodell
No abstract text is available yet for this article.
February 1, 2024: Cell Stem Cell
Yuanwei Yan, Xueyan Li, Yu Gao, Sakthikumar Mathivanan, Linghai Kong, Yunlong Tao, Yi Dong, Xiang Li, Anita Bhattacharyya, Xinyu Zhao, Su-Chun Zhang
Probing how human neural networks operate is hindered by the lack of reliable human neural tissues amenable to the dynamic functional assessment of neural circuits. We developed a 3D bioprinting platform to assemble tissues with defined human neural cell types in a desired dimension using a commercial bioprinter. The printed neuronal progenitors differentiate into neurons and form functional neural circuits within and between tissue layers with specificity within weeks, evidenced by the cortical-to-striatal projection, spontaneous synaptic currents, and synaptic response to neuronal excitation...
February 1, 2024: Cell Stem Cell
Benjamin T Jackson, Lydia W S Finley
Stem cells perform many different functions, each of which requires specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have uncovered a range of metabolic preferences and strategies that correlate with or exert control over specific cell states. This review aims to describe the common themes that emerge from the study of stem cell metabolism: (1) metabolic pathways supporting stem cell proliferation, (2) metabolic pathways maintaining stem cell quiescence, (3) metabolic control of cellular stress responses and cell death, (4) metabolic regulation of stem cell identity, and (5) metabolic requirements of the stem cell niche...
February 1, 2024: Cell Stem Cell
Viviane Tabar, Roger A Barker
Sham surgery is often required for cell therapies adopting a randomized placebo-controlled double-blinded trial design. Using the case of dopamine neuron therapy for Parkinson's disease, we argue that alternative trial designs should be considered instead, for several reasons relating to ethics, patient burden, ease of unblinding, and cost.
February 1, 2024: Cell Stem Cell
Arun Pandian Chandrasekaran, Mo Li
Despite advances in stem cell cultures, modeling early human development with stem cells in a dish remains challenging. Research by Hislop et al.,1 Okubo et al.,2 and Wei et al.3 paves the way for improved in vitro embryo models and culture conditions, offering valuable insights for regenerative medicine.
February 1, 2024: Cell Stem Cell
Ilse Eidhof, Daniel Twohig, Anna Falk
COVID-19 patients often display dysfunctions of the nervous system, indicating an effect of SARS-CoV-2 on neural cells. Yang et al. now show that human stem-cell-derived dopaminergic neurons are susceptible to SARS-CoV-2, triggering inflammation and senescence. The study further identifies three FDA-approved drugs capable of reversing these cellular phenotypes.
February 1, 2024: Cell Stem Cell
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