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Stem cells for dummies
A balanced, plain-English guide to the politically charged topic of stem cell research.
Book
Induced pluripotent stem cell technology: a decade of progress
Key Points
Human induced pluripotent stem cell (iPSC) technology has evolved rapidly since its inception in 2007.
Human iPSC technology has been widely used for disease modelling; for example, for neurodegenerative and psychiatric disorders.
Human iPSC technology has yielded several drug candidates that are currently in clinical trials.
The first clinical trial using human iPSC-derived products has been initiated for age-related macular degeneration.
The combination with gene editing and 3D organoid technologies makes the iPSC platform more powerful.
The continued development of iPSC technology and its integration with other technologies has the potential to make substantial contributions to disease modelling, drug discovery and regenerative medicine.
Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.
Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, enormous progress has been made in stem cell biology and regenerative medicine. Human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. In particular, the combination of human iPSC technology with recent developments in gene editing and 3D organoids makes iPSC-based platforms even more powerful in each area of their application, including precision medicine. In this Review, we discuss the progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, and consider the remaining challenges and the emerging opportunities in the field.
Journal Article
Stem cells : a very short introduction
The topic of stem cells has a high profile in the media. We've made important advances in our scientific understanding, but despite this the clinical applications of stem cells are still in their infancy and most real stem cell therapy carried out today is some form of bone marrow transplantation. At the same time, a scandalous spread of unproven stem cell treatments by private clinics represents a serious problem, with treatments being offered which are backed by limited scientific rationale, and which are at best ineffective, and at worse harmful. This Very Short Introduction introduces stem cells, exploring what they are, and what scientists do with them. Introducing the different types of stem cells, Jonathan Slack explains how they can be used to treat diseases such as retinal degeneration, diabetes, Parkinson's disease, heart disease, and spinal trauma. He also discusses the important technique of bone marrow transplantation and some other types of current stem cell therapy, used for the treatment of blindness and of severe burns. Slack warns against fake stem cell treatments and discusses how to distinguish real from fake treatments. He also describes the latest scientific progress in the field, and looks forward to what we can expect to happen in the next few years.
Book
Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential
Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s—the long-terminal repeats of HERV type-H (HERV-H)—to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H–driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.
Journal Article
Embryonic Stem Cell‐Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic‐Ischemic Mouse Brain
Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell‐derived mesenchymal stem cells (PSC‐MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC‐MSCs (ES‐MSCs from embryonic stem cells) to fetal MSCs (AF‐MSCs from the amniotic fluid), demonstrating that ES‐MSCs have a superior neuroprotective potential over AF‐MSCs in the mouse brain following hypoxia‐ischemia. Further, we demonstrate that nuclear factor (NF)‐κB‐stimulated interleukin (IL)‐13 production contributes to an increased in vitro anti‐inflammatory potential of ES‐MSC‐conditioned medium (CM) over AF‐MSC‐CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell‐derived MSCs (iMSCs) exhibit many similarities to ES‐MSCs, including enhanced NF‐κB signaling and IL‐13 production in comparison to AF‐MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES‐MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic‐ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439–449 We hypothesize that the increased nuclear factor (NF)‐κB activation and, therefore, higher levels of interleukin (IL)‐13 production observed in pluripotent stem cell‐derived mesenchymal stem cells contributes to the increased anti‐inflammatory potential of these cells compared with other types of mesenchymal stem cells.
Journal Article
Mesenchymal and haematopoietic stem cells form a unique bone marrow niche
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin
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MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent ‘mesenspheres’ that can self-renew and expand in serial transplantations. Nestin
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MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or β3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin
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cells and favours their osteoblastic differentiation,
in vivo
nestin
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cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin
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MSCs in the bone marrow of lethally irradiated mice, whereas
in vivo
nestin
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cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
A stem-cell niche made for two
The identity of the cells that form the haematopoietic stem-cell niche in the bone marrow has been unclear. Paul Frenette and colleagues have now identified nestin-expressing mesenchymal stem cells as niche-forming cells. These cells show a close physical association with haematopoietic stem cells, express high levels of genes involved in stem-cell maintenance, and their depletion reduces bone-marrow homing of haematopoietic progenitors. This work reveals the stem-cell niche in the bone marrow as a partnership between two distinct somatic stem-cell types.
The identity of the cells that form the haematopoietic stem cell (HSC) niche in bone marrow has been unclear. These authors identify nestin-expressing mesenchymal stem cells as niche-forming cells. These nestin-expressing cells show a close physical association with HSCs and express high levels of genes involved in HSC maintenance, and their depletion reduces bone marrow homing of haematopoietic progenitors.
Journal Article
Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells
Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol’s influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders.
Journal Article