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Stem cell replacement

Michael J Watts, David C Linch
Clinical practice and the technology of cell processing for autologous stem cell transplantation has continued to evolve over the last two decades and merits review of current quality control expectations. The external regulatory era has improved quality and safety standards but there is still variable practice, with specific risks illuminated by a number of clinical incidents. Viable CD34(+) cell assays may fail to indicate significant losses in progenitor function during storage, particularly after cryopreservation, and there is a need to develop an alternative, real time functional assay to replace colony assays...
October 17, 2016: British Journal of Haematology
Jianbin Wang, Michael C Holmes
The battle with human immunodeficiency virus (HIV) has been ongoing for more than 30 years, and although progress has been made, there are still significant challenges remaining. A few unique features render HIV to be one of the toughest viruses to conquer in the modern medicine era, such as the ability to target the host immune system, persist by integrating into the host genome and adapt to a hostile environment such as a single anti-HIV medication by continuously evolving. The finding of combination anti-retroviral therapy (cART) about 2 decades ago has transformed the treatment options for HIV-infected patients and significantly improved patient outcomes...
November 2016: Cytotherapy
Brigham J Hartley, Kristen J Brennand
Human induced pluripotent stem cells (hiPSCs) can theoretically yield limitless supplies of cells fated to any cell type that comprise the human organism, making them a new tool by which to potentially overcome caveats in current biomedical research. In vitro derivation of central nervous system (CNS) cell types has the potential to provide material for drug discovery and validation, safety and toxicity assays, cell replacement therapy and the elucidation of previously unknown disease mechanisms. However, current two-dimensional (2D) CNS differentiation protocols do not faithfully recapitulate the spatial organization of heterogeneous tissue, nor the cell-cell interactions, cell-extracellular matrix interactions, or specific physiological functions generated within complex tissue such as the brain...
October 12, 2016: Neurochemistry International
Maryam Kaviani, Negar Azarpira, Mohammad Hossein Karimi, Ismail Al-Abdullah
Cell-based therapies suggest novel treatments to overcome the complication of the current therapeutic approaches in diabetes mellitus type 1. Replacement of the destroyed pancreatic islet β-cells by appropriate alternative cells needs an efficient approach to differentiate the cells into viable and functional insulin producing cells. Small non-coding RNA molecules, MicroRNAs (miRNA), have critical roles in post-transcriptional regulation of gene expression. Therefore, they can direct the cells toward β-cell like cells and control islet β-cell development...
October 15, 2016: Cell Biology International
Jonathan C Niclis, Carlos W Gantner, Walaa F Alsanie, Stuart J McDougall, Chris R Bye, Andrew G Elefanty, Edouard G Stanley, John M Haynes, Colin W Pouton, Lachlan H Thompson, Clare L Parish
: : Recent studies have shown evidence for the functional integration of human pluripotent stem cell (hPSC)-derived ventral midbrain dopamine (vmDA) neurons in animal models of Parkinson's disease. Although these cells present a sustainable alternative to fetal mesencephalic grafts, a number of hurdles require attention prior to clinical translation. These include the persistent use of xenogeneic reagents and challenges associated with scalability and storage of differentiated cells. In this study, we describe the first fully defined feeder- and xenogeneic-free protocol for the generation of vmDA neurons from hPSCs and utilize two novel reporter knock-in lines (LMX1A-eGFP and PITX3-eGFP) for in-depth in vitro and in vivo tracking...
October 14, 2016: Stem Cells Translational Medicine
Bumpei Samata, Daisuke Doi, Kaneyasu Nishimura, Tetsuhiro Kikuchi, Akira Watanabe, Yoshimasa Sakamoto, Jungo Kakuta, Yuichi Ono, Jun Takahashi
Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1...
October 14, 2016: Nature Communications
Ai Hua Zhang, Rui Tan, Nan Jiang, Kaidiriye Yusupu, Gang Wang, Xin Lei Wang, Ren Xiang Tan
Owing to the negligible or acceptable immunogenicity, small molecules capable of inducing the differentiation of undifferentiated stem cells into organ-specific cell types are particularly promising in developing replacement therapy, but such compounds with undescribed architectures are extremely rare. Selesconol (1) is discovered from the culture of Daldinia eschscholzii IFB-TL01 as a skeletally unprecedented inducer for the differentiation of rat bone marrow mesenchymal stem cells into neural cells, with its unique framework clarified to derive from the intermediate tautomerization of the dalesconol A biosynthetic pathway...
October 14, 2016: Organic Letters
Yohei Kawano, Georg Petkau, Ingrid Wolf, Julia Tornack, Fritz Melchers
Long-term proliferating, DH JH -rearranged mouse precursor B-cell lines have previously been established in serum- and IL-7-containing media from fetal liver, but not from bone marrow. Serum and stromal cells expose these pre-B cells to undefined factors, hampering accurate analyses of ligand-dependent signalling, which controls pre-B cell proliferation, survival, residence and migration. Here, we describe a novel serum-free, stromal cell-free culture system, which allows to establish and maintain pre-B cells not only from fetal liver, but also from bone marrow with practically identical efficiencies in proliferation, cloning and differentiation...
October 14, 2016: European Journal of Immunology
Jacob Kjell, Lars Olson
A long-standing goal of spinal cord injury research is to develop effective spinal cord repair strategies for the clinic. Rat models of spinal cord injury provide an important mammalian model in which to evaluate treatment strategies and to understand the pathological basis of spinal cord injuries. These models have facilitated the development of robust tests for assessing the recovery of locomotor and sensory functions. Rat models have also allowed us to understand how neuronal circuitry changes following spinal cord injury and how recovery could be promoted by enhancing spontaneous regenerative mechanisms and by counteracting intrinsic inhibitory factors...
October 1, 2016: Disease Models & Mechanisms
Xiaotang Hu
Since 2012, the CRISPR-Cas9 system has been quickly and successfully tested in a broad range of organisms and cells including hematopoietic cells. The application of CRISPR-Cas9 in human hematopoietic cells mainly involves the genes responsible for HIV infection, β-thalassemia and sickle cell disease (SCD). The successful disruption of CCR5 and CXCR4 genes in T cells by CRISPR-Cas9 promotes the prospect of the technology in the functional cure of HIV. More recently, eliminating CCR5 and CXCR4 in induced pluripotent stem cells (iPSCs) derived from patients and targeting the HIV genome have been successfully carried out in several laboratories...
October 2, 2016: Blood Cells, Molecules & Diseases
Lei Hu, Ying Wen, Junji Xu, Tingting Wu, Chunmei Zhang, Jinsong Wang, Jie Du, Songlin Wang
Mesenchymal stem cell (MSC)-mediated bone regeneration is used to replace lost bone. However, methods to accelerate the process and stabilize regenerated bone remain limited. Therefore, we investigated the effect of bisphosphonates (BPs) on the function of bone marrow mesenchymal stem cells (BMMSCs) to determine if they might enhance MSC-mediated bone regeneration. We isolated and cultured BMMSCs from BALB/c mice and treated the cells with 0.1, 0.5, 1, 5, or 10 μM zoledronic acid (ZA; Zometa, a commercially available BP)...
October 13, 2016: Stem Cells and Development
Jong Seok Jeong, Mehmet Topsakal, Peng Xu, Bharat Jalan, Renata M Wentzcovitch, K Andre Mkhoyan
Perovskite oxides form an eclectic class of materials owing to their structural flexibility in accommodating cations of different sizes and valences. They host well known point and planar defects, but so far no line defect has been identified other than dislocations. Using analytical scanning transmission electron microscopy (STEM) and ab initio calculations we have detected and characterized the atomic and electronic structures of a novel line defect in NdTiO3 perovskite. It appears in STEM images as a perovskite cell rotated by 45 degrees...
October 13, 2016: Nano Letters
Mark A DeWitt, Wendy Magis, Nicolas L Bray, Tianjiao Wang, Jennifer R Berman, Fabrizia Urbinati, Seok-Jin Heo, Therese Mitros, Denise P Muñoz, Dario Boffelli, Donald B Kohn, Mark C Walters, Dana Carroll, David I K Martin, Jacob E Corn
Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34(+) hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs...
October 12, 2016: Science Translational Medicine
Miguel López-Lázaro
Epidemiological data indicate that 5.8% of cancer deaths world-wide are attributable to alcohol consumption. The risk of cancer is higher in tissues in closest contact on ingestion of alcohol, such as the oral cavity, pharynx and esophagus. However, since ethanol is not mutagenic and the carcinogenic metabolite of ethanol (acetaldehyde) is mostly produced in the liver, it is not clear why alcohol use preferentially exerts a local carcinogenic effect. It is well known that ethanol causes cell death at the concentrations present in alcoholic beverages; however, this effect may have been overlooked because dead cells cannot give rise to cancer...
October 5, 2016: Oral Oncology
Gioele La Manno, Daniel Gyllborg, Simone Codeluppi, Kaneyasu Nishimura, Carmen Salto, Amit Zeisel, Lars E Borm, Simon R W Stott, Enrique M Toledo, J Carlos Villaescusa, Peter Lönnerberg, Jesper Ryge, Roger A Barker, Ernest Arenas, Sten Linnarsson
Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development...
October 6, 2016: Cell
Harun Najib Noristani, Jean Charles Sabourin, Hassan Boukhaddaoui, Emilie Chan-Seng, Yannick Nicolas Gerber, Florence Evelyne Perrin
BACKGROUND: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. METHODS: We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses...
October 6, 2016: Molecular Neurodegeneration
Francesco Lodola, Diego Morone, Marco Denegri, Rossana Bongianino, Hiroko Nakahama, Lucia Rutigliano, Rosanna Gosetti, Giulia Rizzo, Alessandra Vollero, Michelangelo Buonocore, Carlo Napolitano, Gianluigi Condorelli, Silvia G Priori, Elisa Di Pasquale
Catecholaminergic Polymorphic Ventricular Tachycardia type 2 (CPVT2) is a highly lethal recessive arrhythmogenic disease caused by mutations in the calsequestrin-2 (CASQ2) gene. We have previously demonstrated that viral transfer of the wild-type (WT) CASQ2 gene prevents the development of CPVT2 in a genetically induced mouse model of the disease homozygous carrier of the R33Q mutation. In the present study, we investigated the efficacy of the virally mediated gene therapy in cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs) obtained from a patient carrying the homozygous CASQ2-G112+5X mutation...
October 6, 2016: Cell Death & Disease
Pooja Teotia, Divyan A Chopra, Shashank Manohar Dravid, Matthew J Van Hook, Fang Qiu, John Morrison, Angie Rizzino, Iqbal Ahmad
Glaucoma is a complex group of diseases wherein a selective degeneration of retinal ganglion cells (RGCs) leads to irreversible loss of vision. A comprehensive approach to glaucomatous RGC degeneration may include stem cells to functionally replace dead neurons through transplantation and understand RGCs vulnerability using a disease in a dish stem cell model. Both approaches require the directed generation of stable, functional, and target-specific RGCs from renewable sources of cells, i.e., the embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)...
October 6, 2016: Stem Cells
Chew-Li Soh, Danwei Huangfu
The recent advent of engineered nucleases including the CRISPR/Cas9 system has greatly facilitated genome manipulation in human pluripotent stem cells (hPSCs). In addition to facilitating hPSC-based disease studies, the application of genome engineering in hPSCs has also opened up new avenues for cell replacement therapy. To improve consistency and reproducibility of hPSC-based studies, and to meet the safety and regulatory requirements for clinical translation, it is necessary to use a defined, xeno-free cell culture system...
2017: Methods in Molecular Biology
Anne Tscherter, Martina Heidemann, Sonja Kleinlogel, Jürg Streit
Presently there exists no cure for spinal cord injury (SCI). However, transplantation of embryonic tissue into spinal cord (SC) lesions resulted in axon outgrowth across the lesion site and some functional recovery, fostering hope for future stem cell therapies. Although in vivo evidence for functional recovery is given, the exact cellular mechanism of the graft support remains elusive: either the grafted cells provide a permissive environment for the host tissue to regenerate itself or the grafts actually integrate functionally into the host neuronal network reconnecting the separated SC circuits...
2016: Frontiers in Cellular Neuroscience
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