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Neural grafting for Parkinson's disease:challenges and prospects

Neural Regeneration Research 2017年第3期12卷 389-392页

作者： Thomas B.Stoker Nicholas F.Blair Roger A.Barker John van Geest Center for Brain Repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK wellcome trust-Medical Research Council stem cell institute University of CambridgeCambridgeUK

Parkinson＇s disease（PD） is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia *** motor disorder responds well to dopamine-replacement therapies,though these result in significant adverse effects due to non-physiological release of dopamine in the striatum,and off-target ***-based regenerative treatments offer a potential means for targeted replacement of dopamine,in a physiological *** neurons for cell-based therapies can be obtained from several *** ventral mesencephalon tissue contains dopaminergic neuron progenitors,and has been transplanted into the striatum of PD patients with good results in a number of ***,the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical *** pluripotent stem cells can be used to generate dopaminergic neurons for transplantation,providing a source of autologous tissue for *** approach means that challenges associated with allografts,such as the potential for immune rejection,can be ***,the associated cost and difficulty in producing a standardized product from different cell lines means that,at present,this approach is not commercially viable as a cell-based *** neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson＇s disease,with trials due to commence in the next few *** there are ethical considerations to take into account when using embryonic tissue,the possibility of producing a standardized,optimized cell product means that this approach can be both effective,and commercially viable.

关键词： Parkinson's disease neural grafting embryonic stem cells induced pluripotent stem cells induced neurons cell-based therapies

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Reprogramming mature terminally differentiated adipocytes to induced pluripotent stem cells

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Science Bulletin 2015年第20期60卷 1752-1758页

作者： Tao Nie Wei Deng Xuefei Gao Wei Sun Xiaoyan Hui Hong Song Dajiang Qin Aimin Xu Peng Li Pentao Liu Liangxue Lai Donghai Wu Key Laboratory of Regenerative Biology Guangzhou Institute of Biomedicine and Health Chinese Academy of SciencesGuangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine School of Life Sciences Anhui University Department of Pharmacology and Medicine The University of Hong Kong wellcome trust institute

Mature adipocytes are terminally differentiated somatic cells. Here, we report the successful generation of induced pluripotent stem(i PS) cells from mouse mature adipocytes by forced expression of six transcription factors(Oct4, Sox2, c-Myc, Klf4, Rarc, and Lrh1) with a piggy Bac transposon-based strategy. The resulting i PS cells were pluripotent as evidenced by the fact that they stained positive for alkaline phosphatase, expressed high levels of key pluripotency markers including Oct4, Nanog, and SSEA1,and remained pluripotent on a 2i media. In vitro differentiation of the i PS cells showed that the cell derivatives of all three germ layers could be readily obtained through formation of embryoid bodies. Most importantly, these adipocytederived i PS cells were capable of producing chimera with high frequencies when reintroduced into early-stage embryos and transmitted through the germ line. This study demonstrates that the new six-factor reprogramming technology facilitates the reset of the terminally differentiated adipocytes to the ground state of pluripotency, enabling us to fully explore the potential of mature adipocytes as a viable cell source for regenerative medicine.

关键词：多能干细胞脂肪细胞终末分化成熟诱导重编程转录因子细胞来源

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Insm1:orchestrating cellular mimicry in the thymus medulla

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cellular & Molecular Immunology 2024年第4期21卷 414-416页

作者： K.D.James J.E.Cowan UCL institute of Immunity and Transplantation The Pears BuildingRowland Hill StreetLondonNW32PPUK

The thymus is the primary production site for a functional and self-tolerant T-cell *** establishment of immune tolerance is mediated by the generation and presentation of tissue-restricted self-antigens(TRAs)by medullary thymic epithelial cells(mTECs),which screen T-cell receptors for self-reactivity to eliminate autoreactive T *** studies have extended our understanding of mTEC heterogeneity by examining the mechanisms by which mTECs mimic the peripheral self[1].

关键词： medullary eliminate restricted

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Drugging SUMOylation for neuroprotection and oncotherapy

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Neural Regeneration Research 2018年第3期13卷 415-416页

作者： Joshua D. Bernstock Daniel G. Ye Yang-ja Lee Florian Gessler Gregory K. Friedman Wei Zheng John M. Hallenbeck Stroke Branch National Institute of Neurological Disorders and Stroke National institutes of Health (NINDS/NIH) Bethesda MD USA Department of Clinical Neurosciences - Division of stem cell Neurobiology Wellcome Trust-Medical Research Council Stem Cell Institute and NIHR Biomedical Research Centre University of Cambridge UK Department of Pediatrics Division of Pediatric Hematology and Oncology University of Alabama at Birmingham Birmingham AL USA National Center for Advancing Translational Sciences National Institutes of Health (NCATS/NIH) Bethesda MD USA

Recently there have been exciting research advances in neuroprotective therapies for ischemic stroke. In the past, the search for neu- roprotective agents has been fraught with failure at the clinical trials stage due to numerous factors, including subject heterogeneity and improper therapeutic windows （Tymianski, 2017）. Moreover, it is becoming clearer that the complex and evolving pathobiology of stroke requires multimodal therapeutic approaches capable of modulating the numerous axes that contribute to ischemia/reperfusion damage, rather than targeting a single axis （Bernstock et al., 2018a）. With the success of recent endovascular thrombectomy （EVT） trials, it has been suggested that clinical trials of EVT with adjunct neuroprotection can overcome past difficulties and maximize the effect size by using imaging to reduce patient heterogeneity （i. e., selecting those with large vessel occlusions, small ischemic cores, and good collateral circulation）, restoring perfusion using better EVT devices, and enrolling patients in the correct therapeutic window （i.e., when they still have salvageable brain tissue）（Tymianski, 2017）. Considering the opportunity that this represents for new, better clinical trials of neuroprotective agents, the search is on for high-potential compounds that may be investigated in these future studies.

关键词： Drugging SUMOylation for neuroprotection and oncotherapy OGD

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Myt1L Promotes Differentiation of Oligodendrocyte Precursor cells and is Necessary for Remyelination After Lysolecithin-Induced Demyelination

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Neuroscience Bulletin 2018年第2期34卷 247-260页

作者： Yanqing Shi Qi Shao Zhenghao Li Ginez A. Gonzalez Fengfeng Lu Dan Wang Yingyan Pu Aijun Huang Chao Zhao Cheng He Li Cao institute of Neuroscience Key Laboratory of Molecular Neurobiology of The Ministry of Education and The Collaborative Innovation Center for Brain Science Second Military Medical University Shanghai 200433 China institute of Health Sciences Anhui University Hefei 230601China wellcome trust-Medical Research Council stem cell Insti-tute University of Cambridge Cambridge CB2 0AH UK

The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.

关键词： Myt1L Oligodendrocyte precursor cells Remyelination Demyelination Olig1

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Fate plasticity in the intestine: The devil is in the detail

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World Journal of Gastroenterology 2019年第25期25卷 3116-3122页

作者： Simon Buczacki Cambridge stem cell institute Jeffrey Cheah Biomedical CentreAddenbrooke’s Biomedical Campus

The intestinal epithelium possesses a remarkable ability for both proliferation and *** last two decades have generated major advances in our understanding of the stem cell populations responsible for its maintenance during homeostasis and more recently the events that occur during injury induced *** fundamental discoveries have capitalised on the use of transgenic mouse models and in vivo lineage tracing to make their *** is evident that maintenance is driven by rapidly proliferating crypt base stem cells,but complexities associated with the technicality of mouse modelling have led to several overlapping populations being held responsible for the same ***,it has been shown that essentially any population in the intestinal crypt can revert to a stem cell state given the correct stimulus during epithelial *** these observations are profound it is uncertain how relevant they are to human intestinal homeostasis and ***,these recent studies are presented,in context with technical considerations of the models used,to argue that their conclusions may indeed not be applicable in understanding“homeostatic regeneration”and experimental suggestions presented for validating their results in human tissue.

关键词： Intestinal stem cell Plasticity Lgr5 Regeneration

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Remyelinating Schwann cells in the CNS originate from both CNS and PNS

Remyelinating Schwann cells in the CNS originate from both C...

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中国神经科学学会第十二届全国学术会议

作者： Chao Zhao wellcome trust-Medical Council Cambridge stem cell institute and Department of Clinical Neuroscience University of Cambridge

Loss of myelin in the central nervous system（CNS） is the hall mark of demyelinating diseases such as multiple sclerosis in which, remyelination – the restoration of myelin is ultimately unsuccessful. Understanding the cell biology of CNS remyelination is central to developing effective means by which this process can be therapeutically enhanced. It is known that demyelinated CNS axons can be remyelinated not only by newly regenerated oligodendrocytes, but also by Schwann cells, the myelin forming cell type in the peripheral nerves. Although there is general consensus that the major source of remyelinating cell is oligodendrocyte progenitor cells（OPC）, which give rise to both oligodendrocytes and Schwann cells following demyelination. Other cell types, such as ependymal cells, have been suggested to have neural stem potentials but their contribution to CMS remyelination has not been entirely resolved. Using genetic fate tracing strategy to label foxj1 expressing ependymal epithelial cells, we determined that there is little involvement of ependymal cells in the central canal in the remyelination of toxin induce demyelination of spinal cord. But unexpectedly, foxj1 labelled nonmyelinating Schwann cells in the peripheral nerves. Unlike myelinating Schwann cells which hardly contribute to CNS Schwann cell remyelination, foxj1 labelled cells migrate in to adjacent CNS lesions and form remyelinating Schwann cells likely via breached glial limitans. These findings demonstrated a peripheral source of remyelinating Schwann cells and suggested non-myelinating Schwann cells can display distinct regenerative capacity comparing to myelinating Schwann cells.

关键词： CNS remyelination Schwann cells

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Using mouse models to study function of transcriptional factors in T cell development

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cell Regeneration 2012年第1期1卷 57-69页

作者： Peng Li Yiren Xiao Zhixin Liu Pentao Liu Key Laboratory of Regenerative Biology Guangzchou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina Guangdong Provincial Key Laboratory of stem cell and Regenerative Medicine GuangzhouChina wellcome trust Sanger institute HinxtonCambridge CB101HHUK.

Laboratory mice have widely been used as tools for basic biological research and models for studying human *** the advances of genetic engineering and conditional knockout(CKO)mice,we now understand hematopoiesis is a dynamic stepwise process starting from hematopoietic stem cells(HSCs)which are responsible for replenishing all blood *** factors play important role in *** this review we compile several studies on using genetic modified mice and humanized mice to study function of transcriptional factors in lymphopoiesis,including T lymphocyte and Natural killer(NK)cell ***,we focused on the key transcriptional factor Bcl11b and its function in regulating T cell specification and commitment.

关键词： Genetic modified mice Humanized mice Lymphopoiesis T cell development Bcl11b

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Collagen scaffolds functionalized with triple-helical peptides support 3D HUVEC culture

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Regenerative Biomaterials 2020年第5期7卷 471-482页

作者： Jean-Daniel Malcor Emma J.Hunter Natalia Davidenko Daniel V.Bax Ruth Cameron Serena Best Sanjay Sinha Richard W.Farndale Department of Biochemistry University of CambridgeCambridge CB21QWUK Department of Materials Science and Metallurgy University of CambridgeCambridge CB30FSUK Division of Medicine and wellcome trust Medical Research Council Cambridge Stem Cell InstituteUniversity of CambridgeCambridge CB20AWUK Present address:CambCol Laboratories Ltd Oak Lane Business ParkLittleportElyCambridgeshireCB79RPUK

Porous biomaterials which provide a structural and biological support for cells have immense potential in tissue engineering and cell-based therapies for tissue *** biomaterials that can host endothelial cells represent promising tools for the vascularization of engineered ***-dimensional collagen scaffolds possessing controlled architecture and mechanical stiffness are obtained through freeze–drying of collagen suspensions,followed by chemical cross-linking which maintains their ***,cross-linking scaffolds renders their biological activity suboptimal for many cell types,including human umbilical vein endothelial cells(HUVECs),by inhibiting cell–collagen ***,we have improved crucial HUVEC interactions with such cross-linked collagen biomaterials by covalently coupling combinations of triple-helical peptides(THPs).These are ligands for collagen-binding cell-surface receptors(integrins or discoidin domain receptors)or secreted proteins(SPARC and von Willebrand factor).THPs enhanced HUVEC adhesion,spreading and proliferation on 2D collagen *** grafted to 3D-cross-linked collagen scaffolds promoted cell survival over seven *** study demonstrates that THP-functionalized collagen scaffolds are promising candidates for hosting endothelial cells with potential for the production of vascularized engineered tissues in regenerative medicine applications.

关键词： collagen biomaterial endothelial cells 3D cell scaffold collagen-mimetic peptides

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Therapeutic effects of diosgenin in experimental autoimmune encephalomyelitis

Therapeutic effects of diosgenin in experimental autoimmune ...

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中国神经科学学会第十二届全国学术会议

作者： Weili Liu Mei Zhu Zhongwang Yu Dou Yin Fengfeng Lu Yingyan Pu Chao Zhao Cheng He Li Cao institute of Neuroscience Key Laboratory of Molecular Neurobiology of the Ministry of Education Second Military Medical University wellcome trust-Medical Research Council stem cell institute University of Cambridge

Objective Multiple sclerosis(MS) is a chronic autoimmune demyelinating disease of the central nervous system. Currently, there is no drug available to cure this kind of disease. Diosgenin(DG) is a plant derived steroid saponin. Previous study in our lab revealed that DG can promote oligodendrocyte progenitor cell differentiation and accelerate remyelination. In this study, we explored the therapeutic effects of DG in experimental autoimmune encephalomyelitis(EAE).Methods To evaluate different doses of DG(10 mg/kg, 20 mg/kg, 40 mg/kg) on EAE disease progression, MOG-induced EAE mice were intraperitoneally injected at D15 post immunization. On D22 the spinal cords from EAE mice were isolated to examine the demyelination area and the number of infiltrating cells in the white matter with Luxol fast blue staining and H&E staining. As activation of microglia/macrophages can cause cytotoxic damage of neuron, recruitment and activation of T lymphocytes to aggravate EAE disease, while inhibition of microglia/macrophage function can effectively reduce the incidence of EAE, we explored the effect of DG on microglia/macrophage activation in the CNS of EAE by flow cytometry analysis. Since CD4 T cells are a subtype of auto-reactive and myelin-specific cells and involved in the pathogenesis of EAE disease and the proportions of Th1 cells and Th17 cells in CD4+T cells are usually regarded as indicators of the severity of the CNS inflammation in EAE mice, we explored the effects of DG on the proliferation of CD4 T cells and the differentiation of Th1 and Th17 cells in lymphocytes of EAE mice with flow cytometry analysis, as well. Results Our study here confirmed that DG can significantly alleviate the EAE disease in a dose dependent manner and markedly inhibit the pathological inflammation and demyelination in the spinal *** treatment dramatically suppressed the activation of microglia/macrophages in the CNS of EAE mice. And DG can significantly reduce the proliferation of CD4

关键词： Diosgenin EAE MS microglia/macrophages Th1/Th17 demyelination

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