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Cell Stem Cell

Paul S Knoepfler
Regulators are now more often distinguishing between perceived good citizens and "bad actors" in stem cell and regenerative medicine clinical research, resulting in relatively more polar, carrot-and-stick oversight approaches. Here, I discuss why there may be too much carrot and not enough stick by regulators for effective enforcement.
June 16, 2018: Cell Stem Cell
Ting Zhao, Yao Fu, Jialiang Zhu, Yifang Liu, Qian Zhang, Zexuan Yi, Shi Chen, Zhonggang Jiao, Xiaochan Xu, Junquan Xu, Shuguang Duo, Yun Bai, Chao Tang, Cheng Li, Hongkui Deng
Chemical reprogramming provides a powerful platform for exploring the molecular dynamics that lead to pluripotency. Although previous studies have uncovered an intermediate extraembryonic endoderm (XEN)-like state during this process, the molecular underpinnings of pluripotency acquisition remain largely undefined. Here, we profile 36,199 single-cell transcriptomes at multiple time points throughout a highly efficient chemical reprogramming system using RNA-sequencing and reconstruct their progression trajectories...
June 12, 2018: Cell Stem Cell
Kenjiro Adachi, Wolfgang Kopp, Guangming Wu, Sandra Heising, Boris Greber, Martin Stehling, Marcos J Araúzo-Bravo, Stefan T Boerno, Bernd Timmermann, Martin Vingron, Hans R Schöler
Transcription factor (TF)-mediated reprogramming to pluripotency is a slow and inefficient process, because most pluripotency TFs fail to access relevant target sites in a refractory chromatin environment. It is still unclear how TFs actually orchestrate the opening of repressive chromatin during the long latency period of reprogramming. Here, we show that the orphan nuclear receptor Esrrb plays a pioneering role in recruiting the core pluripotency factors Oct4, Sox2, and Nanog to inactive enhancers in closed chromatin during the reprogramming of epiblast stem cells...
June 11, 2018: Cell Stem Cell
M Zeeshan Ozair, Christoph Kirst, Bastiaan L van den Berg, Albert Ruzo, Tiago Rito, Ali H Brivanlou
Cortical deep projection neurons (DPNs) are implicated in neurodevelopmental disorders. Although recent findings emphasize post-mitotic programs in projection neuron fate selection, the establishment of primate DPN identity during layer formation is not well understood. The subplate lies underneath the developing cortex and is a post-mitotic compartment that is transiently and disproportionately enlarged in primates in the second trimester. The evolutionary significance of subplate expansion, the molecular identity of its neurons, and its contribution to primate corticogenesis remain open questions...
June 9, 2018: Cell Stem Cell
Xing Deng, Xin Zhang, Weiping Li, Ren-Xin Feng, Lu Li, Gui-Rong Yi, Xiao-Nan Zhang, Chuan Yin, Hong-Yu Yu, Jun-Ping Zhang, Bin Lu, Lijian Hui, Wei-Fen Xie
Chronic liver injury can cause cirrhosis and impaired liver regeneration, impairing organ function. Adult livers can regenerate in response to parenchymal insults, and multiple cellular sources have been reported to contribute to this response. In this study, we modeled human chronic liver injuries, in which such responses are blunted, without genetic manipulations, and assessed potential contributions of non-parenchymal cells (NPCs) to hepatocyte regeneration. We show that NPC-derived hepatocytes replenish a large fraction of the liver parenchyma following severe injuries induced by long-term thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment...
June 7, 2018: Cell Stem Cell
Shanshan Pei, Mohammad Minhajuddin, Biniam Adane, Nabilah Khan, Brett M Stevens, Stephen C Mack, Sisi Lai, Jeremy N Rich, Anagha Inguva, Kevin M Shannon, Hyunmin Kim, Aik-Choon Tan, Jason R Myers, John M Ashton, Tobias Neff, Daniel A Pollyea, Clayton A Smith, Craig T Jordan
Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential...
June 6, 2018: Cell Stem Cell
Rebecca M Gibbs, Scott Lipnick, Joel W Bateman, Lloyd Chen, Henry C Cousins, Elizabeth G Hubbard, Geraldine Jowett, Darren S LaPointe, Maxine J McGredy, Michelle N Odonkor, Giuliana Repetti, Elizabeth Thomas, Lee L Rubin
The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.
July 5, 2018: Cell Stem Cell
Brian Lin, Priya Srikanth, Alison C Castle, Sagar Nigwekar, Rajeev Malhotra, Jenna L Galloway, David B Sykes, Jayaraj Rajagopal
In injured tissues, regeneration is often associated with cell fate plasticity, in that cells deviate from their normal lineage paths. It is becoming increasingly clear that this plasticity often creates alternative strategies to restore damaged or lost cells. Alternatively, cell fate plasticity is also part and parcel of pathologic tissue transformations that accompany disease. In this Perspective, we summarize a few illustrative examples of physiologic and aberrant cellular plasticity. Then, we speculate on how one could enhance endogenous plasticity to promote regeneration and reverse pathologic plasticity, perhaps inspiring interest in a new class of therapies targeting cell fate modulation...
May 23, 2018: Cell Stem Cell
Shiyan Yu, Kevin Tong, Yanlin Zhao, Iyshwarya Balasubramanian, George S Yap, Ronaldo P Ferraris, Edward M Bonder, Michael P Verzi, Nan Gao
Paneth cells are post-mitotic intestinal epithelial cells supporting the stem cell niche and mucosal immunity. Paneth cell pathologies are observed in various gastrointestinal diseases, but their plasticity and response to genomic and environmental challenges remain unclear. Using a knockin allele engineered at the mouse Lyz1 locus, we performed detailed Paneth cell-lineage tracing. Irradiation induced a subset of Paneth cells to proliferate and differentiate into villus epithelial cells. RNA sequencing (RNA-seq) revealed that Paneth cells sorted from irradiated mice acquired a stem cell-like transcriptome; when cultured in vitro, these individual Paneth cells formed organoids...
July 5, 2018: Cell Stem Cell
Lennart Kester, Alexander van Oudenaarden
Reconstructing lineage relationships between cells within a tissue or organism is a long-standing aim in biology. Traditionally, lineage tracing has been achieved through the (genetic) labeling of a cell followed by the tracking of its offspring. Currently, lineage trajectories can also be predicted using single-cell transcriptomics. Although single-cell transcriptomics provides detailed phenotypic information, the predicted lineage trajectories do not necessarily reflect genetic relationships. Recently, techniques have been developed that unite these strategies...
May 3, 2018: Cell Stem Cell
Stefan F Cordes, Cynthia E Dunbar
Active regulatory elements in hematopoietic stem cells (HSCs) are incompletely characterized, since extant approaches immunophenotypically define and isolate rare HSCs. In the current issue of Cell Stem Cell, Wünsche et al. (2018) use γ-retroviral insertion sites from a human gene therapy trial to identify the active enhancer landscape of functionally characterized HSCs.
July 5, 2018: Cell Stem Cell
Sunny Sun-Kin Chan, Robert W Arpke, Antonio Filareto, Ning Xie, Matthew P Pappas, Jacqueline S Penaloza, Rita C R Perlingeiro, Michael Kyba
Derivation of functional skeletal muscle stem cells from pluripotent cells without genetic modification has proven elusive. Here we show that teratomas formed in adult skeletal muscle differentiate in vivo to produce large numbers of α7-Integrin+ VCAM-1+ myogenic progenitors. When FACS-purified and transplanted into diseased muscles, mouse teratoma-derived myogenic progenitors demonstrate very high engraftment potential. As few as 40,000 cells can reconstitute ∼80% of the tibialis anterior muscle volume...
July 5, 2018: Cell Stem Cell
Mohammed A Mostajo-Radji, Alex A Pollen
How is the astonishing diversity of cortical neurons specified? In this issue of Cell Stem Cell, Ozair et al. (2018) leverage hPSC neural differentiation to show that projection neurons undergo prolonged sojourns in the subplate before migrating to deep layers, suggesting that pausing in the subplate may enable integration of intrinsic and extrinsic cues during postmitotic fate refinement.
July 5, 2018: Cell Stem Cell
Ashley C Bolte, John R Lukens
Emerging data implicate potential roles for T cells in Parkinson's disease (PD); however, direct evidence for human T cells in PD-associated neurodegeneration has been lacking. In this issue of Cell Stem Cell, Sommer et al. (2018) demonstrate that IL-17-producing T cells from sporadic PD patients promote cell death of patient iPSC-derived midbrain neurons.
July 5, 2018: Cell Stem Cell
Aaron D Schimmer
In this issue of Cell Stem Cell, Pei et al. (2018) demonstrate that leukemic stem cells (LSCs) have enhanced mitochondrial fission, which is positively regulated by FIS1. FIS1 is necessary to maintain LSC function; thus, targeting its expression and mitochondrial fission is a novel approach to decrease stemness and increase differentiation in Acute Myeloid Leukemia.
July 5, 2018: Cell Stem Cell
Hu Zhao, Jifan Feng, Kerstin Seidel, Songtao Shi, Ophir Klein, Paul Sharpe, Yang Chai
No abstract text is available yet for this article.
July 5, 2018: Cell Stem Cell
Peer Wünsche, Elias S P Eckert, Tim Holland-Letz, Anna Paruzynski, Agnes Hotz-Wagenblatt, Raffaele Fronza, Tim Rath, Irene Gil-Farina, Manfred Schmidt, Christof von Kalle, Christoph Klein, Claudia R Ball, Friederike Herbst, Hanno Glimm
Genes that regulate hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation are tightly controlled by regulatory regions. However, mapping such regions relies on surface markers and immunophenotypic definition of HSCs. Here, we use γ-retroviral integration sites (γRV ISs) from a gene therapy trial for 10 patients with Wiskott-Aldrich syndrome to mark active enhancers and promoters in functionally defined long-term repopulating HSCs. Integration site clusters showed the highest ATAC-seq signals at HSC-specific peaks and strongly correlated with hematopoietic risk variants...
July 5, 2018: Cell Stem Cell
Vania Broccoli, Mirko Luoni
In a recent issue of Nature, Tsunemoto et al. (2018) perform a systematic screening to identify several transcription factor pairs able to generate a variety of different induced neuronal cell populations that share a core neuronal signature, yet differ for specific molecular features.
July 5, 2018: Cell Stem Cell
Annika Sommer, Franz Maxreiter, Florian Krach, Tanja Fadler, Janina Grosch, Michele Maroni, Daniela Graef, Esther Eberhardt, Markus J Riemenschneider, Gene W Yeo, Zacharias Kohl, Wei Xiang, Fred H Gage, Jürgen Winkler, Iryna Prots, Beate Winner
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls...
July 5, 2018: Cell Stem Cell
George K Michalopoulos
In this issue of Cell Stem Cell and recently in Nature, Deng et al. (2018) and Schaub et al. (2018) (respectively) demonstrate that following acute liver injury, hepatocytes and cholangiocytes restore liver mass and function. When proliferative capacity of either cell type is impaired, the other cell type will transdifferentiate to restore full regeneration and hepatic histology.
July 5, 2018: Cell Stem Cell
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