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Stem Cell Reports

Roberto De Gregorio, Salvatore Pulcrano, Claudia De Sanctis, Floriana Volpicelli, Ezia Guatteo, Lars von Oerthel, Emanuele Claudio Latagliata, Roberta Esposito, Rosa Maria Piscitelli, Carla Perrone-Capano, Valerio Costa, Dario Greco, Stefano Puglisi-Allegra, Marten P Smidt, Umberto di Porzio, Massimiliano Caiazzo, Nicola Biagio Mercuri, Meng Li, Gian Carlo Bellenchi
The differentiation of dopaminergic neurons requires concerted action of morphogens and transcription factors acting in a precise and well-defined time window. Very little is known about the potential role of microRNA in these events. By performing a microRNA-mRNA paired microarray screening, we identified miR-34b/c among the most upregulated microRNAs during dopaminergic differentiation. Interestingly, miR-34b/c modulates Wnt1 expression, promotes cell cycle exit, and induces dopaminergic differentiation. When combined with transcription factors ASCL1 and NURR1, miR-34b/c doubled the yield of transdifferentiated fibroblasts into dopaminergic neurons...
March 2, 2018: Stem Cell Reports
Navroop K Dhaliwal, Kamelia Miri, Scott Davidson, Hala Tamim El Jarkass, Jennifer A Mitchell
Cooperative action of a transcription factor complex containing OCT4, SOX2, NANOG, and KLF4 maintains the naive pluripotent state; however, less is known about the mechanisms that disrupt this complex, initiating exit from pluripotency. We show that, as embryonic stem cells (ESCs) exit pluripotency, KLF4 protein is exported from the nucleus causing rapid decline in Nanog and Klf4 transcription; as a result, KLF4 is the first pluripotency transcription factor removed from transcription-associated complexes during differentiation...
March 1, 2018: Stem Cell Reports
Wen-Li Deng, Mei-Ling Gao, Xin-Lan Lei, Ji-Neng Lv, Huan Zhao, Kai-Wen He, Xi-Xi Xia, Ling-Yun Li, Yu-Chen Chen, Yan-Ping Li, Deng Pan, Tian Xue, Zi-Bing Jin
Retinitis pigmentosa (RP) is an irreversible, inherited retinopathy in which early-onset nyctalopia is observed. Despite the genetic heterogeneity of RP, RPGR mutations are the most common causes of this disease. Here, we generated induced pluripotent stem cells (iPSCs) from three RP patients with different frameshift mutations in the RPGR gene, which were then differentiated into retinal pigment epithelium (RPE) cells and well-structured retinal organoids possessing electrophysiological properties. We observed significant defects in photoreceptor in terms of morphology, localization, transcriptional profiling, and electrophysiological activity...
February 28, 2018: Stem Cell Reports
Hai-Qin Huo, Zhuang-Yin Qu, Fang Yuan, Lixiang Ma, Lin Yao, Min Xu, Yao Hu, Jing Ji, Anita Bhattacharyya, Su-Chun Zhang, Yan Liu
The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum...
February 28, 2018: Stem Cell Reports
Cathelijne W van den Berg, Laila Ritsma, M Cristina Avramut, Loes E Wiersma, Bernard M van den Berg, Daniëlle G Leuning, Ellen Lievers, Marije Koning, Jessica M Vanslambrouck, Abraham J Koster, Sara E Howden, Minoru Takasato, Melissa H Little, Ton J Rabelink
Human pluripotent stem cell (hPSC)-derived kidney organoids may facilitate disease modeling and the generation of tissue for renal replacement. Long-term application, however, will require transferability between hPSC lines and significant improvements in organ maturation. A key question is whether time or a patent vasculature is required for ongoing morphogenesis. Here, we show that hPSC-derived kidney organoids, derived in fully defined medium conditions and in the absence of any exogenous vascular endothelial growth factor, develop host-derived vascularization...
February 28, 2018: Stem Cell Reports
Xiwei Shan, Lyl Tomlinson, Qian Yang, Holly Colognato
The regulatory mechanisms that control neural stem cell (NSC) activation in the adult ventricular-subventricular zone (V-SVZ) stem cell niche have been the focus of intense investigation, yet how the niche first develops and organizes is poorly understood. Here, we examined matrix metalloproteinases (MMPs) for potential roles in V-SVZ stem cell niche development. MMP12 was found to promote appropriate niche cellular arrangements, the formation of specialized niche extracellular matrix, and the translational planar cell polarity of ependymal cells that surround and support niche NSCs...
February 28, 2018: Stem Cell Reports
Shunsuke Kuroki, Yuji Nakai, Ryo Maeda, Naoki Okashita, Mika Akiyoshi, Yutaro Yamaguchi, Satsuki Kitano, Hitoshi Miyachi, Ryuichiro Nakato, Kenji Ichiyanagi, Katsuhiko Shirahige, Hiroshi Kimura, Yoichi Shinkai, Makoto Tachibana
Histone H3 lysine 9 (H3K9) methylation is unevenly distributed in mammalian chromosomes. However, the molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here, we show that JMJD1A and JMJD1B preferentially target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing an H3K9 hypomethylation state in euchromatin. JMJD1A/JMJD1B-deficient embryos died soon after implantation accompanying epiblast cell death. Furthermore, combined loss of JMJD1A and JMJD1B caused perturbed expression of metabolic genes and rapid cell death in embryonic stem cells (ESCs)...
February 27, 2018: Stem Cell Reports
Bärbel M Ulmer, Andrea Stoehr, Mirja L Schulze, Sajni Patel, Marjan Gucek, Ingra Mannhardt, Sandra Funcke, Elizabeth Murphy, Thomas Eschenhagen, Arne Hansen
Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome)...
February 26, 2018: Stem Cell Reports
Jia Wang, Xingui Wu, Chao Wei, Xin Huang, Qian Ma, Xiaona Huang, Francesco Faiola, Diana Guallar, Miguel Fidalgo, Tingyuan Huang, Di Peng, Li Chen, Haopeng Yu, Xingyu Li, Junyi Sun, Xinyi Liu, Xiaoxia Cai, Xiao Chen, Ling Wang, Jian Ren, Jianlong Wang, Junjun Ding
Yin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG-independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency...
February 26, 2018: Stem Cell Reports
Vasco Sampaio-Pinto, Sílvia C Rodrigues, Tiago L Laundos, Elsa D Silva, Francisco Vasques-Nóvoa, Ana C Silva, Rui J Cerqueira, Tatiana P Resende, Nicola Pianca, Adelino Leite-Moreira, Gabriele D'Uva, Sólveig Thorsteinsdóttir, Perpétua Pinto-do-Ó, Diana S Nascimento
So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth...
February 26, 2018: Stem Cell Reports
Zaniar Ghazizadeh, Faranak Fattahi, Mehdi Mirzaei, Delger Bayersaikhan, Jaesuk Lee, Sehyun Chae, Daehee Hwang, Kyunghee Byun, Mehdi Sharifi Tabar, Sara Taleahmad, Shahab Mirshahvaladi, Parisa Shabani, Hananeh Fonoudi, Paul A Haynes, Hossein Baharvand, Nasser Aghdami, Todd Evans, Bonghee Lee, Ghasem Hosseini Salekdeh
The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1+ progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1+ cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1+ cells identified ALCAM (CD166) as a surface marker that enabled the isolation of ISL1+ progenitor cells...
February 23, 2018: Stem Cell Reports
Satoshi Iraha, Hung-Ya Tu, Suguru Yamasaki, Takahiro Kagawa, Motohito Goto, Riichi Takahashi, Takehito Watanabe, Sunao Sugita, Shigenobu Yonemura, Genshiro A Sunagawa, Take Matsuyama, Momo Fujii, Atsushi Kuwahara, Akiyoshi Kishino, Naoshi Koide, Mototsugu Eiraku, Hidenobu Tanihara, Masayo Takahashi, Michiko Mandai
Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis...
February 23, 2018: Stem Cell Reports
Jessica E Young, Lauren K Fong, Harald Frankowski, Gregory A Petsko, Scott A Small, Lawrence S B Goldstein
Developing effective therapeutics for complex diseases such as late-onset, sporadic Alzheimer's disease (SAD) is difficult due to genetic and environmental heterogeneity in the human population and the limitations of existing animal models. Here, we used hiPSC-derived neurons to test a compound that stabilizes the retromer, a highly conserved multiprotein assembly that plays a pivotal role in trafficking molecules through the endosomal network. Using this human-specific system, we have confirmed previous data generated in murine models and show that retromer stabilization has a potentially beneficial effect on amyloid beta generation from human stem cell-derived neurons...
February 23, 2018: Stem Cell Reports
Daniel H Miller, Dexter X Jin, Ethan S Sokol, Janel R Cabrera, Daphne A Superville, Rebecca A Gorelov, Charlotte Kuperwasser, Piyush B Gupta
The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification...
February 22, 2018: Stem Cell Reports
Thomas Robert, Ines De Mesmaeker, Geert M Stangé, Krista G Suenens, Zhidong Ling, Evert J Kroon, Daniel G Pipeleers
Human stem cells represent a potential source for implants that replace the depleted functional beta cell mass (FBM) in diabetes patients. Human embryonic stem cell-derived pancreatic endoderm (hES-PE) can generate implants with glucose-responsive beta cells capable of reducing hyperglycemia in mice. This study with device-encapsulated hES-PE (4 × 106 cells/mouse) determines the biologic characteristics at which implants establish metabolic control during a 50-week follow-up. A metabolically adequate FBM was achieved by (1) formation of a sufficient beta cell number (>0...
February 22, 2018: Stem Cell Reports
Dandan Wang, Huayong Zhang, Jun Liang, Hong Wang, Bingzhu Hua, Xuebing Feng, Gary S Gilkeson, Dominique Farge, Songtao Shi, Lingyun Sun
Allogeneic mesenchymal stem/stromal cells (MSCs) have been widely studied as an alternative cell source for regenerative medicine. Here, we report a long-term follow-up study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81)...
February 21, 2018: Stem Cell Reports
Antonela Bonafina, Paula Aldana Fontanet, Gustavo Paratcha, Fernanda Ledda
The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs) determines the correct cortical development. In this work, we show that GDNF and its receptor GFRα1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRα1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2), promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRα1 in glutamatergic cortical precursors enhances its proliferation...
February 19, 2018: Stem Cell Reports
Mark A Aminzadeh, Russell G Rogers, Mario Fournier, Rachel E Tobin, Xuan Guan, Martin K Childers, Allen M Andres, David J Taylor, Ahmed Ibrahim, Xiangming Ding, Angelo Torrente, Joshua M Goldhaber, Michael Lewis, Roberta A Gottlieb, Ronald A Victor, Eduardo Marbán
Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy (DMD), affecting the heart as well as skeletal muscle. Here, we report that clinical-stage cardiac progenitor cells, known as cardiosphere-derived cells (CDCs), improve cardiac and skeletal myopathy in the mdx mouse model of DMD. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity, and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human induced pluripotent stem cell-derived Duchenne cardiomyocytes...
February 17, 2018: Stem Cell Reports
Masakazu Yamamoto, Nicholas P Legendre, Arpita A Biswas, Alexander Lawton, Shoko Yamamoto, Shahragim Tajbakhsh, Gabrielle Kardon, David J Goldhamer
MyoD and Myf5 are fundamental regulators of skeletal muscle lineage determination in the embryo, and their expression is induced in satellite cells following muscle injury. MyoD and Myf5 are also expressed by satellite cell precursors developmentally, although the relative contribution of historical and injury-induced expression to satellite cell function is unknown. We show that satellite cells lacking both MyoD and Myf5 (double knockout [dKO]) are maintained with aging in uninjured muscle. However, injured muscle fails to regenerate and dKO satellite cell progeny accumulate in damaged muscle but do not undergo muscle differentiation...
February 17, 2018: Stem Cell Reports
Andrew J Crowther, Szu-Aun Lim, Brent Asrican, Blake H Albright, Josh Wooten, Chia-Yu Yeh, Hechen Bao, Domenic H Cerri, Jessica Hu, Yen-Yu Ian Shih, Aravind Asokan, Juan Song
Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need...
February 17, 2018: Stem Cell Reports
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