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Handbook of Innovations in Central
Nervous System Regenerative
Medicine
Handbook of
Innovations in Central
Nervous System
Regenerative Medicine
Edited by
Antonio J. Salgado
Life and Health Sciences Research Institute (ICVS),
School of Medicine, University of Minho,
Braga, Portugal
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
Copyright © 2020 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
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Licensing Agency, can be found at our website: www.elsevier.com/permissions.
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Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices, or
medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein.
In using such information or methods they should be mindful of their own safety and the safety
of others, including parties for whom they have a professional responsibility.
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assume any liability for any injury and/or damage to persons or property as a matter of
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products, instructions, or ideas contained in the material herein.
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-818084-6
Chapter 1
Insights on nervous system biology and anatomy 1
Madalena Esteves, Armando Almeida and Hugo Leite-Almeida
1.1 Introduction 1
1.2 Development of the vertebrate nervous system 2
1.2.1 Development of the trilaminar embryo 2
1.2.2 Neural induction 3
1.2.3 Neurulation 4
1.2.4 Development of brain vesicles 5
1.3 General organization of the nervous system 5
1.3.1 Spinal cord 6
1.3.2 Brain 7
1.3.3 Meninges and the ventricular system 12
1.4 Cells of the nervous system 13
1.4.1 Neurons 14
1.4.2 Glial cells 14
1.4.3 Ependymal cells 16
1.5 Technical approaches to study the nervous system 16
1.6 Conclusions 18
References 18
Chapter 2
Overview of Alzheimer’s and Parkinson’s diseases and the role
of protein aggregation in these neurodegenerative diseases 29
Mariah Lelos
2.1 Alzheimer’s disease 30
2.2 Prevalence of Alzheimer’s disease 30
2.3 Diagnosis of Alzheimer’s disease 30
2.4 Neurodegeneration and neurobiology of Alzheimer’s disease 31
2.5 Progression of amyloid deposition throughout the brain 32
2.6 Genetic influences 33
2.7 The amyloid cascade hypothesis 34
2.8 Parkinson’s disease 36
v
vi Contents
Chapter 3
Introduction to trauma in the central nervous system 55
Laureen D. Hachem and Michael G. Fehlings
3.1 Introduction 55
3.2 The current landscape of central nervous system trauma 56
3.3 Stages of central nervous system injury 57
3.3.1 Primary injury 57
3.3.2 Secondary injury: an overview of acute, subacute,
and chronic phases 58
3.4 Traumatic spinal cord injury pathophysiology 59
3.4.1 Acute injury 59
3.4.2 Subacute injury 65
3.4.3 Chronic injury 68
3.5 Traumatic brain injury 69
3.5.1 Classification 69
3.5.2 Cerebral perfusion and ischemia 70
3.5.3 Excitotoxicity and oxidative stress 70
3.5.4 Inflammation 70
3.5.5 Long-term sequelae 71
3.6 Guidelines for the management of neurotrauma 72
3.7 Conclusion 73
Acknowledgments 73
References 73
Chapter 4
Current clinical approaches in neurodegenerative diseases 79
Miguel Gago, Alvaro Machado and Sofia Rocha
4.1 Alzheimer’s disease and Parkinson’s disease in a clinical context 79
4.1.1 Epidemiology of Parkinson’s disease 79
4.1.2 Epidemiology of Alzheimer’s disease 79
4.1.3 Clinical diagnosis and the natural history of Parkinson’s disease 80
4.1.4 Clinical diagnosis and the natural history of Alzheimer’s disease 81
4.1.5 Neuropathology and etiopathogenesis of Parkinson’s disease 81
4.1.6 Neuropathology and etiopathogenesis of Alzheimer’s disease 83
4.1.7 Genetics of Parkinson’s disease 83
4.1.8 Genetics of Alzheimer’s disease 84
Contents vii
Chapter 5
Neuroprotection in the injured spinal cord 125
Rui Lima, Inês M. Pereira and Nuno A. Silva
5.1 Spinal cord injury in a clinical context 125
5.1.1 Current spinal cord injury clinical management 126
5.2 Behind spinal cord injury 127
5.2.1 Permeability and vascular alterations 127
5.2.2 Metabolic alterations 127
5.2.3 Ionic disruption and excitotoxicity 128
5.2.4 Inflammatory response 128
5.2.5 Spinal cord scarring 129
5.3 Current neuroprotective therapies in spinal cord injury 130
5.3.1 Nimodipine 130
5.3.2 Glibenclamide (glyburide, DiaBeta) 131
5.3.3 Progesterone 131
5.3.4 Estrogen 132
5.3.5 Magnesium 132
5.3.6 Sygen (GM1) 132
5.3.7 Riluzole 133
5.3.8 Minocycline 134
5.3.9 IL-4 cytokine 134
5.3.10 Erythropoietin 135
5.3.11 Ibuprofen 135
5.3.12 Atorvastatin 136
5.3.13 Hypothermia 136
5.6 Final remarks 137
References 138
Chapter 6
The therapeutic potential of exogenous adult stem
cells for the injured central nervous system 147
Jayden A. Smith, Alice Braga, Regan Hamel, Carola Rutigliani,
Bryan Yu, Luca Peruzzotti-Jametti and Stefano Pluchino
6.1 Introduction 147
6.2 Adult stem cells and their sources 148
viii Contents
Chapter 7
Biomaterial-based systems as biomimetic agents in the
repair of the central nervous system 259
Jorge E. Collazos-Castro
7.1 Introduction 259
7.2 Considerations on the pathology of spinal cord trauma 260
Contents ix
Chapter 8
Tissue engineering and regenerative medicine in spinal cord
injury repair 291
Kristýna Kárová, Lucia Machova Urdzı́ková, Nataliya Romanyuk, Barbora
Svobodová, Kristýna Kekulová, Zuzana Kočı́, Pavla Jendelová and Šárka
Kubinová
8.1 Introduction 291
8.1.1 Pathophysiology of spinal cord injury 291
8.2 Experimental models of spinal cord injury: methodology,
advantages, disadvantages, and behavioral testing 293
8.2.1 Animal models of spinal cord injury 293
8.2.2 Behavioral testing of the animal spinal cord injury 295
8.3 Treatment strategies 299
8.3.1 Axon growth in spinal cord injury 300
8.4 Cell therapy: overview, comparison of various types of stem cells,
methods of application 302
8.4.1 Mesenchymal stem cells 302
8.4.2 Neural stem and progenitor cells 302
8.4.3 Oligodendrocyte precursor cells 303
8.4.4 Schwann cells 304
8.4.5 Olfactory ensheathing cells 304
8.4.6 Cell transplantation route 304
8.5 Antioxidant treatment 305
8.5.1 Epigallocatechin-3-gallate 306
8.5.2 Curcumin 307
8.6 Biomaterials in spinal cord injury 307
8.6.1 Synthetic scaffolds for spinal cord injury 308
8.6.2 Natural scaffolds 308
x Contents
Chapter 9
Toward the therapeutic application of small interfering
RNA bioconjugates in the central nervous system 333
João Cortinhas, Ana P. Pêgo and Pedro M.D. Moreno
9.1 Considerations on therapeutic drug delivery for neurological
disorders 333
9.2 Small interfering RNA 336
9.3 Barriers for siRNA delivery 338
9.4 Chemical modifications 339
9.5 Ribose modifications 340
9.5.1 Backbone modifications 342
9.6 Structural modifications 343
9.7 Bioconjugates 348
9.7.1 Lipids 349
9.7.2 Cell-penetrating peptides and polymers 350
9.7.3 Receptor-ligand conjugates 351
9.7.4 Antibodies 353
9.7.5 Aptamers 354
9.8 Dynamic polyconjugates 356
9.9 Other delivery systems: nanocarriers 357
9.10 Future perspectives 360
Acknowledgements 363
References 364
Chapter 10
Gene therapy approaches in central nervous system
regenerative medicine 375
Assumpcio Bosch and Miguel Chillon
10.1 Gene therapy 375
10.2 Gene therapy vectors 376
10.2.1 Adenovirus 376
10.2.2 Retrovirus 380
10.2.3 Lentivirus 381
10.2.4 Adenoassociated virus 381
10.2.5 Herpes simplex virus 382
10.2.6 Nonviral vectors 383
10.3 Gene therapy for nervous system 383
Contents xi
Chapter 11
Gene editing and central nervous system regeneration 399
Sara Monteiro Lopes and Luı́s Pereira de Almeida
11.1 Introduction 399
11.2 Targeted nucleases for efficient genome editing 400
11.3 Nuclease-mediated alterations: resolving double-strand breaks 403
11.4 CRISPR-Cas9 technology 405
11.4.1 From the natural bacterial system to the engineered nuclease 405
11.4.2 Dealing with challenges: Cas9 variants and orthologs 406
11.4.3 CRISPR-Cas9 as means for therapeutic genome editing:
evidence in brain disorders 408
11.4.4 Generation of cellular and animal models for brain disorders 419
11.4.5 Employing CRISPR-Cas beyond genome editing: gene
expression regulation in neurological disorders 419
11.4.6 Clinical translation 420
Acknowledgment 422
References 422
Chapter 12
Molecular therapeutic strategies in neurodegenerative
diseases and injury 435
Muhibullah S. Tora, Pavlos Texakalidis, Alex Greven, Razan Faraj,
Julian L. Gendreau, Zhijia Liang, Thais Federici and Nicholas M. Boulis
12.1 Introduction 435
12.2 Spinal cord injury 435
12.2.1 Neurotrophins and growth factors 436
12.2.2 Inflammation 438
12.2.3 Promoting axonal growth 438
12.2.4 Modulation of excitotoxicity 439
12.2.5 Future directions 439
12.3 Traumatic brain injury 439
12.3.1 Growth factors 440
12.3.2 Modulation of free radicals 443
12.3.3 Inflammation 443
12.3.4 Excitotoxicity 443
12.3.5 Mir-23b, apolipoprotein-E, and Nav1.3 in the preclinical
setting 444
12.3.6 Future directions 444
12.4 Amyotrophic lateral sclerosis 444
12.4.1 Excitotoxicity 445
xii Contents
Chapter 13
Spinal cord stimulation for the recovery of function
following spinal cord injury 487
R.W.P. Kissane and R.M. Ichiyama
13.1 Introduction 487
13.2 A brief history into electricity induced neuromodulation 488
Contents xiii
Chapter 14
Electroceutical therapies for injuries of the nervous system 511
Guillermo Garcı́a-Alı́as, Jaume del Valle, Ignacio Delgado-Martı́nez
and Xavier Navarro
14.1 Introduction 511
14.2 Effects of electrical fields on neural growth in vitro 512
14.3 Electrical stimulation for peripheral nerve injuries and regeneration 513
14.4 Electrical stimulation in spinal cord injuries 515
14.4.1 Electrical stimulation improves axonal regeneration in the
spinal cord 516
14.4.2 Spinal cord neuromodulation 518
14.5 Electrical stimulation in brain injuries 521
14.5.1 Electrical stimulation for stroke 522
14.5.2 Techniques for noninvasive brain stimulation 524
14.5.3 Effects of noninvasive brain stimulation on brain ischemic
injury 525
References 527
Chapter 15
Role of mesenchymal stem cells in central nervous system
regenerative medicine: past, present, and future 539
António J. Salgado
15.1 Mesenchymal stem cells: origins 539
15.2 The paradigm shift: from differentiation to secretome 541
15.3 In vivo veritas 545
15.3.1 Spinal cord injury 545
15.3.2 Parkinson’s disease 552
15.4 What lies ahead 555
15.4.1 Secretome-based approaches 556
15.4.2 Modulation of mesenchymal stem cells secretome profile 557
15.4.3 New sources for mesenchymal stem cells 560
xiv Contents
Chapter 16
Three-dimensional culture systems in central nervous system
research 571
Itse Onuwaje and James B. Phillips
16.1 Introduction 571
16.1.1 Traditional methods of central nervous system culture 571
16.1.2 Shifting to three-dimensional systems 572
16.1.3 Introduction to three-dimensional systems used in
central nervous system research 573
16.2 Organoids 574
16.2.1 Definition of organoids 574
16.2.2 Development of organoids 575
16.2.3 Disease-specific organoid models 576
16.2.4 Strengths and limitations of organoids 577
16.3 Spheroid systems 578
16.3.1 Definition of spheroids 578
16.3.2 Development of spheroids 579
16.3.3 Disease-specific spheroid models 580
16.3.4 Strengths and limitations of spheroids 581
16.4 Scaffold-based models 581
16.4.1 Hydrogels 582
16.4.2 Solid porous scaffolds 586
16.4.3 Fibrous scaffolds 588
16.4.4 Summary 588
16.5 Challenges and future directions 590
16.5.1 Key challenges of advanced central nervous system culture
models 590
16.6 Concluding remarks 591
Acknowledgments 591
References 593
Chapter 17
Scaffolds for spinal cord injury repair: from proof of concept to
first in-human studies and clinical trials 603
Zhifeng Xiao , Yannan Zhao , Bing Chen and Jianwu Dai
17.1 Scaffold-based strategies to facilitate spinal cord injury repair 604
17.1.1 Scaffolds combined with neurotrophic factor transplantation
to facilitate spinal cord injury repair 604
17.1.2 Transplantation of stem cells combined with scaffolds
to facilitate spinal cord injury repair 606
Contents xv
Chapter 18
Animal models of central nervous system disorders 621
Eduardo D. Gomes, Sandra Barata-Antunes, Andreia Teixeira-Castro,
Rita C. Assunção-Silva, Cláudia R. Marques, Susana Monteiro,
Fábio G. Teixeira, Aline M. Fernandes and Nuno A. Silva
18.1 Introduction 621
18.1.1 Caenorhabditis elegans as a model system of central nervous
system disorders 621
18.1.2 Caenorhabditis elegans as a model for spinal cord injury 622
18.1.3 C. elegans as a model for Parkinson’s disease 624
18.2 Naturally regenerating animal models 627
18.2.1 Xenopus laevis 628
18.2.2 Salamander 629
18.2.3 Zebrafish 629
18.3 Rodents as a model of central nervous system disorders 630
18.4 Rodents as a model for spinal cord injury 631
18.4.1 Types of injury in rodent models 632
18.5 Rodents as a model for Parkinson’s disease 634
Acknowledgments 638
References 638
Chapter 19
Bioethics in translation research and clinical trials 651
Nadine Correia Santos
19.1 Introduction 651
19.1.1 Core ethical principles for guiding both basic and clinical
(stem cell) research 653
19.1.2 The need for regulations and ethical guidelines 656
19.1.3 The need for prioritizing rigorous and safe clinical trials 660
19.2 The role of research ethics committees 663
19.3 Conclusion 665
References 666
List of Contributors
Armando Almeida Life and Health Sciences Research Institute (ICVS), School of
Medicine, University of Minho, Braga, Portugal; ICVS/3B’s—PT Government
Associate Laboratory, Guimarães, Portugal
Rita C. Assunção-Silva Life and Health Sciences Research Institute (ICVS), School
of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal; ICVS/
3B’s PT Government Associate Laboratory, Braga/Guimarães, Portugal
Sandra Barata-Antunes Life and Health Sciences Research Institute (ICVS), School
of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal; ICVS/
3B’s PT Government Associate Laboratory, Braga/Guimarães, Portugal
Assumpcio Bosch Institut de Neurociènces (INc), Department of Biochemistry and
Molecular Biology, Universitat Autònoma Barcelona, Bellaterra, Spain; Centro de
Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED), Centro de Biologı́a Molecular SEVERO OCHOA, Universidad
Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain; Vall d’Hebron
Institut de Recerca (VHIR), Research Group on Gene Therapy at Nervous
System, Barcelona, Spain
Nicholas M. Boulis Department of Neurosurgery, Emory University School of
Medicine, Atlanta, GA, United States
Alice Braga Department of Clinical Neurosciences, University of Cambridge,
Cambridge, United Kingdom
Bing Chen State Key Laboratory of Molecular Developmental Biology, Institute of
Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing,
China
Miguel Chillon Institut de Neurociènces (INc), Department of Biochemistry and
Molecular Biology, Universitat Autònoma Barcelona, Bellaterra, Spain; Vall
d’Hebron Institut de Recerca (VHIR), Research Group on Gene Therapy at
Nervous System, Barcelona, Spain; Institució Catalana de Recerca i Estudis
Avançats (ICREA), Barcelona, Spain
Jorge E. Collazos-Castro Neural Repair and Biomaterials, National Hospital for
Paraplegics, Toledo, Spain
João Cortinhas i3S—Institute for Research and Innovation in Health, University of
Porto, Porto, Portugal; INEB—Biomedical Engineering Institute, University of
Porto, Porto, Portugal; Faculty of Engineering of the University of Porto (FEUP),
Porto, Portugal; Abel Salazar Institute of Biomedical Sciences (ICBAS),
University of Porto, Porto, Portugal
xvii
xviii List of Contributors
columns and respective nuclei are present: (3) general afferent column/tri-
geminal (V) and (5) somatic efferent column neurons/oculomotor (III). The
motor nucleus of trochlear (IV) nerve has a metencephalic origin and then
migrates to the mesencephalon (references earlier).
1.3.2.2 Cerebellum
The cerebellum has been classically associated with motor function and bal-
ance. This resonates from the early works of Luigi Rolando (1773 1831)
and others, particularly the seminal “Saggio Sopra le Vera Struttura del
Cervello Dell’uomo e Degli Animali e Sopra le Funzioni del Sistema
Nervoso” [54], where the motor impact of ablation and stimulation of the
cerebellum is described (see also [55]). Cerebellar function is, however,
much more complex and heterogenous, and it is now consensual that it plays
an important role in cognitive and emotional processes (see [56 58] for
review). It consists of two hemispheres, joined in the midline by the vermis.
Each of these hemispheres can then be divided into three lobes: anterior, pos-
terior, and flocculonodular. Connection to the brainstem is achieved via the
inferior, middle, and superior cerebellar peduncles, which respectively reach
the medulla oblongata, pons, and mesencephalon. The organization of the
cerebellum consists of an outer layer of gray matter, the cerebellar cortex,
and an internal region of white matter, which consists of fibers that run to,
and from, the brainstem [59]. The cerebellar cortex itself has a consistent
layered organization: molecular, Purkinje cells, and granule cells layers (out-
ermost to innermost). The cerebellar circuitry is relatively simple. Cerebellar
afferents are constituted by climbing fibers projecting from the inferior olive
in the pons and synapsing on Purkinje cells, and by mossy fibers with origin
in precerebellar nuclei other than the inferior olive, synapsing predominantly
on granule cells dendrites. The information on this pathway is then conveyed
to Purkinje cells by granule cells’ axons via the so-called parallel fibers on
the molecular layer. Purkinje cells then project to deep cerebellar nuclei neu-
rons, which in turn project back to other CNS areas [60].
1.3.2.3 Diencephalon
The diencephalon is located between the brainstem and the cortex. It is con-
stituted by the thalamus, subthalamus, hypothalamus, and epithalamus [61].
It receives all the pathways that ascend from the spinal cord and brainstem,
thus having a core role in sensory information awareness. The thalamus is a
heterogenous assembly of nuclei whose main function is to relay sensory and
motor information from subcortical structures to the cortex [62]. Its role in
tactile discrimination and pain [63 65], visual [66 68], and auditory
[69,70] processing is well documented, but it also plays a role in higher cog-
nitive functions [71], mood [72], arousal [73], or addiction [74,75].
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Les villes, qui avaient été autrefois des centres de la vie politique,
cessèrent de jouer un rôle. Le droit allemand les isolait de
l’administration générale du pays, en faisait, en principe, de petites
républiques autonomes, mais nullement rattachées entre elles, pas
plus qu’aux organes centraux. En pratique cela les livrait sans
défense à l’arbitraire de l’administration ou des seigneurs fonciers.
Comme elles n’avaient aucune part à la confection des lois, qui se
trouvait entre les mains de ces derniers, il en résulta pour elles une
exploitation systématique, qui les conduisit à la ruine. Bientôt tout le
commerce et l’industrie fut en la possession des israélites, qui
avaient su le mieux s’accommoder à ces conditions défavorables.
Quant à l’élément ukrainien, il passa au second rang dans les villes ;
il formait la population des faubourgs, dépourvue du droit urbain. Le
plus souvent, en effet, l’Ukrainien, en tant qu’orthodoxe, était privé
du droit d’entrer en apprentissage et de faire partie des corporations
de métiers. Pour cette même raison, il était à peu près exclu des
emplois municipaux administratifs.
Ainsi l’élément ukrainien se trouvait relégué dans la classe
paysanne, qui avait le plus à souffrir du régime polonais. Le droit
polonais avait dans la forme aboli l’esclavage, mais la grande masse
des paysans était pratiquement réduite à un état voisin du servage.
Ils avaient perdu le droit de propriété sur le sol. La terre était
considérée comme appartenant au seigneur foncier ou au roi et,
dans ce dernier cas, elle se trouvait en la possession viagère soit
d’un fonctionnaire, soit d’un noble, à qui elle avait été allouée en
raison de ses services. Le paysan était attaché au domaine
seigneurial sur lequel il était né et ni lui, ni ses enfants ne pouvaient
le quitter sans autorisation. Le seigneur avait droit de vie et de mort
sur ses sujets, il pouvait leur enlever leurs biens, les rouer de coups,
sans qu’ils pussent se plaindre. Le roi lui-même ne pouvait pas
s’immiscer dans les affaires des seigneurs avec leurs sujets. Seuls
les paysans des domaines de la couronne dont l’usufruit avait été
concédé aux familles nobles, pouvaient porter plainte devant le
tribunal du roi. Encore était-ce une procédure si difficile que, dans
les pays ukrainiens, c’était seulement les paysans de Galicie qui
essayaient de s’en servir, et bientôt en usèrent-ils de moins en
moins, car, même si le tribunal rendait un jugement en leur faveur, le
seigneur n’en tenait généralement aucun compte.
Ainsi le paysan était dépourvu non seulement de tous droits
politiques, mais aussi de tous droits civils et même naturels. On en
était déjà arrivé là dans la première moitié du XVIe siècle. Il vint s’y
ajouter, dans la seconde moitié du siècle, une extrême oppression
économique et une exploitation éhontée de l’énergie productive des
travailleurs des champs. Ce fut la conséquence de profonds
changements économiques.
Jusqu’alors on n’avait exporté de l’Ukraine que du bétail, du
poisson et des produits provenant des animaux, comme les
fourrures, le cuir, la cire, le miel. Plus tard on avait transporté à
l’étranger du bois et des produits dérivés, comme le goudron et la
potasse, par les rivières flottables de la région baltique. Surtout la
potasse, article très convoité et aisément transportable, avait attiré
les agents des seigneurs de toutes les parties de l’Ukraine. Vers le
milieu du XVIe siècle, on commença à envoyer du blé des pays
ukrainiens en Angleterre, aux Pays-Bas, en France et en Espagne,
par les ports de la Baltique. Le nombre des demandes pour cette
denrée sur le marché européen causa un changement radical dans
l’exploitation agricole des grands propriétaires fonciers.
Avant cet afflux de demandes, il n’y avait pas de raison pour se
livrer à une culture très intensive, aussi n’exigeait-on pas des
paysans de lourdes corvées : ils payaient leurs redevances soit en
argent, soit en nature. On avait fixé comme base de cet impôt,
souvent établi par le titre de fondation du village, le « lan » ou
« voloka », qui équivalait environ à 20 hectares, de sorte que son
taux était à peu près invariable. Si la terre du paysan se divisait, la
redevance était aussi divisée, et les seigneurs, n’ayant aucun intérêt
à les morceler, les lots concédés conservaient une certaine étendue
et maintenaient des familles nombreuses dans un bien-être relatif.
Les demandes de blé pour l’extérieur poussèrent à
l’augmentation de la production sur les grandes propriétés. On étend
les surfaces ensemencées, on reprend des terres aux paysans, on
leur assigne des lots plus petits, dont on favorise encore le
morcellement pour grossir la classe de ceux qui, n’ayant pas de
terres ou n’en ayant que très peu, ne peuvent payer de redevance et
sont obligés de travailler chez les propriétaires. Dès que la corvée
devint due par les détenteurs de terres sans qu’on tînt compte de
l’étendue des lots, il y eut là un moyen de multiplier les têtes
corvéables. Du reste les seigneurs ne se font pas faute d’aggraver
les obligations des gens de la glèbe. Si, au XVe siècle, une tenure
d’un « lan » est forcée de fournir à la corvée un homme pour
quelques jours par an, ou tout au plus un jour sur huit, au XVIe siècle,
dans l’Ukraine occidentale, qui était la plus grande productrice de
blé, le paysan est forcé de fournir son travail souvent pendant six
jours de la semaine.
La législation en vigueur ne laissait aucun remède à cette
situation insupportable ; il ne restait plus que de s’insurger ou de
prendre la fuite. Les temps n’étaient point propices au premier
moyen : les insurrections n’éclatent qu’assez rarement. En revanche
les évasions se multiplient de plus en plus. Certes le fugitif risque sa
peau, puisqu’on le traquera comme une bête fauve, mais il peut
atteindre la Podolie, où déjà la condition des paysans est moins
précaire, ou même plus loin à l’est, « l’Ukraine », où les grands
domaines commencent à peine de s’établir ; là la terre appartient
« seulement à Dieu ». C’était le refuge espéré contre tous les abus
de la noblesse.
XVI.
Antagonisme des nationalités.