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Taking central nervous system regenerative therapies to the clinic: curing rodents versus nonhuman primates versus humans

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Neural Regeneration Research 2020年第3期15卷 425-437页

作者： Magdalini Tsintou Kyriakos Dalamagkas nikos makris Departments of Psychiatry and Neurology Services Center for Neural Systems InvestigationsCenter for Morphometric AnalysisAthinoula A.Martinos Center for Biomedical ImagingMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA Department of Psychiatry Psychiatry Neuroimaging LaboratoryBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA University College of London Division of Surgery&Interventional Science Center for Nanotechnology&Regenerative MedicineUniversity College LondonLondonUK Department of Physical Medicine and Rehabilitation The University of Texas Health Science Center at HoustonHoustonTXUSA The Institute for Rehabilitation and Research Memorial Hermann Research Center The Institute for Rehabilitation and Research Memorial Hermann HospitalHoustonTXUSA Department of Anatomy&Neurobiology Boston University School of MedicineBostonMAUSA

The central nervous system is known to have limited regenerative capacity.Not only does this halt the human body’s reparative processes after central nervous system lesions,but it also impedes the establishment of effective and safe therapeutic options for such patients.Despite the high prevalence of stroke and spinal cord injury in the general population,these conditions remain incurable and place a heavy burden on patients’families and on society more broadly.Neuroregeneration and neural engineering are diverse biomedical fields that attempt reparative treatments,utilizing stem cells-based strategies,biologically active molecules,nanotechnology,exosomes and highly tunable biodegradable systems(e.g.,certain hydrogels).Although there are studies demonstrating promising preclinical results,safe clinical translation has not yet been accomplished.A key gap in clinical translation is the absence of an ideal animal or ex vivo model that can perfectly simulate the human microenvironment,and also correspond to all the complex pathophysiological and neuroanatomical factors that affect functional outcomes in humans after central nervous system injury.Such an ideal model does not currently exist,but it seems that the nonhuman primate model is uniquely qualified for this role,given its close resemblance to humans.This review considers some regenerative therapies for central nervous system repair that hold promise for future clinical translation.In addition,it attempts to uncover some of the main reasons why clinical translation might fail without the implementation of nonhuman primate models in the research pipeline.

关键词： animal models central nervous system regeneration clinical translation exosomes hydrogels neural tissue engineering nonhuman primates spinal cord injury stem cells stroke

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The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke:a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches

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Neural Regeneration Research 2021年第4期16卷 605-613页

作者： Magdalini Tsintou Kyriakos Dalamagkas Tara LMoore Yogesh Rathi Marek Kubicki Douglas LRosene nikos makris Departments of Psychiatry and Neurology Services Center for Neural Systems InvestigationsCenter for Morphometric AnalysisAthinoula A.Martinos Center for Biomedical ImagingMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA Department of Psychiatry Psychiatry Neuroimaging LaboratoryBrigham and Women’s HospitalHarvard Medical SchoolBostonMAUSA University College of London Division of Surgery&Interventional Science Center for Nanotechnology&Regenerative MedicineUniversity College LondonLondonUK Department of Physical Medicine and Rehabilitation The University of Texas Health Science Center at HoustonHoustonTXUSA The Institute for Rehabilitation and Research Memorial Hermann Research Center The Institute for Rehabilitation and Research Memorial Hermann HospitalHoustonTXUSA Department of Anatomy&Neurobiology Boston University School of MedicineBostonMAUSA

Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish no

关键词： cortical injury exosomes extracellular vesicles hydrogels neural tissue engineering neural tissue repair neuroregeneration non-human primates stroke

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Altered periaqueductal gray resting state functional connectivity in migraine and the modulation effect of treatment

Altered periaqueductal gray resting state functional connect...

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中国中西医结合学会医学影像专业委员会第十五次全国学术大...

作者：李政杰曾芳兰蕾 nikos makris 李瑛龚启勇孔健梁繁荣成都中医药大学四川大学华西医院美国哈佛医学院/麻省总医院

＜正＞The aims of this study were to 1)compare resting state functional connectivity（rs-fc）of the periaqueductal gray（PAG）,a key region in the descending pain modulatory system（DPMS）between migraine without aura（MwoA）patients and healthy controls（HC）,and 2)investigate how an effective treatment can influence the PAG rs-

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