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Abstract

The article provides a laconic analysis of the prospects of using cellular technologies in the therapy of brain diseases. The authors compared different technologies of implantation of stem cells into the brain. The article focuses attention on implantation methods based on the natural migration of autologous stem cells to the brain along the cranial nerves.
Positive and negative aspects of cell technologies in
cerebral diseases
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System, SpineAssist, Renaissance Robotic Systems), assimilation
of high-tech operations (microsurgical, endovascular, stereotaxic
interventions etc.), implementation of combined therapy and new
rehabilitation techniques.4–6 Opportunities of diagnostic procedures
in cerebral diseases are also increased through modern diagnostic
equipment (MRI Scan, PET scan, SPECT scan, DWI MRI etc.), that
is able to enhance early-stage diagnostics, but still has no effect on
treatment outcomes.7–9 Current situation remains the basis for constant
search of new methods of treatment of cerebral diseases. And these
methods have been developed lately in the eld of cell biology and
neurophysiology.
In particular, cell technologies have been adapted to treatment of
socially important diseases in recent years.10 There were both followers
and opponents of cell technologies’ implementation into clinical
practice at the early stage, by the way that is usual for any novelty.
We will pay attention in terms of observed problem to methods based
on stem cells (SC) use in combined treatment of cerebral diseases. SC
has been found in various organs and systems of living organism and
their role is still not investigated in detail. Three main pools of SC
were detected in brain: in the area of olfactory bulbs, in hippocampus
and walls of brain ventricles.11 Potential of endogenous brain stem
cells in health and disease is constantly studied, but oppressive
statistics of chronic brain diseases and high mortality due to TBI,
stroke, inammatory and neurodestructive processes speaks for their
low effectiveness. There were experimental attempts performed
to increase potential of endogenous SC by additional injection of
exogenous SC by different ways into the area of pathological focus.
The amount of preliminarily in vitro cultivated exogenous stem
cells reached thousands and even millions per 1 ml. Three ways of
administration of SC suspension or mesenchymal SC (MSC) are
used in order to implement new method in cerebral diseases: into
bloodstream of arterial and venous vessels, into cerebrospinal uid
via lumbar or suboccipital puncture and nally directly into the area
of pathological focus in brain after additional craniotomy.12,13 Several
lacks have been stated at the experimental stage of all these ways of
SC administration. Administration of SC into bloodstream – besides
distribution in the whole volume of circulating blood – causes problems
at the stage of SC penetration through blood-brain barrier. Necessity of
additional surgical procedure – craniotomy – also becomes a negative
approach for seriously ill patient after stroke or TBI. Administration
of SC into cerebrospinal uid requires measures in order to overcome
craniospinal liquor ow and reach destructive area in brain (change of
body position, lumbar or suboccipital punctures). First experience of
cell technologies use also revealed one more negative effect coming
from the risk of SC transformation into tumor cells.14–16 Information
about malignancy processes usually appears after surgical procedures
in cosmetology rooms. However negative response in mass media
forms awareness in future patients.
Despite of pronounced side effects, cell technologies demonstrated
high effectiveness of reparative potential in cerebral diseases along
with minimum of side effects after application of autologous MSC on
the area of cranial nerves endings.17,18 Olfactory and trigeminal nerves
are the most common targets for application in the modelling of
brain diseases.17–19 For example, intranasal injection of FITC-labeled
MSC into the area of olfactory nerve endings resulted in appearance
of uorescent MSC already in 30 minutes in olfactory bulbs and in
several hours – in trauma region, mainly in anterior cranial fossa.18,19
Somatotropic distribution of stem cells in brain was substantiated by
the fact of predominant migration of MSC to destructed brain areas
located in posterior cranial fossa after preliminary administration
into the area of trigeminal nerve endings. Therefore, the technique
of MSC administration based on perineural migration of MSC to
neurodestructive region was experimentally developed for clinical
application.17–19
The next self-evident conclusion should be mentioned: it was
experimentally and clinically proved, that autologous stem cells are
the safest biomaterial for recovery of violated brain functions. The use
J Neurol Stroke. 2018;8(2):8788.
Volume 8 Issue 2 - 2018
Vladimir Kulchitsky, 1 Alexandra
Zamaro, 1 Yuri Shanko,2 Stanislav
Koulchitsky3
1Institute of Physiology, National Academy of Sciences of
Belarus, Belarus
2Republican Centre of Neurology and Neurosurgery of
Ministry of Health, Belarus
3Liege University, Belgium
Correspondence: Vladimir Kulchitsky, Institute of Physiology,
National Academy of Sciences of Belarus, Address: 28
Akademicheskaya Street, Minsk, Belarus, Tel +375 17 2842458,
Email vladi@zio.bas-net.by
Received: February 15, 2018 | Published: March 15, 2018
© 2018 Kulchitsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and build upon your work non-commercially.
87
Journal of Neurology & Stroke
Latter to Editor Open Access
Keywords: brain trauma; cell technology, diagnostic, intranasal
implantation, stem cell, stroke, therapy
Abbreviations: DWI, diffusion weighted imaging; FITC,
uorescein isothiocyanate; MRI, magnetic resonance imaging; MSC,
mesenchymal stem cells; PET, positron emission tomography; SC,
stem cells; SPECT, single photon emission computed tomography;
TBI, traumatic brain injury; WHO, world health organization
Introduction
Discouraging statistics characterizes low efciency of diagnostics
and treatment of acute and chronic cerebrospinal diseases and
initiates search of new, more effective technologies to resolve that
socially important issue.1,2 About 6 million people die due to stroke
each year according to WHO.1 Traumatic Brain Injuries (TBI)
claim about 10 million lives annually.3 Surgical intervention still
remains the key method of treatment of such fatal cerebral diseases
as stroke, TBI, cerebral aneurysms and neoplasms. Efciency of
surgery increases with the use of robotic devices (da Vinci Robotic
Citation: Kulchitsky V, Zamaro A, Shanko Y, et al. Positive and negative aspects of cell technologies in cerebral diseases. J Neurol Stroke. 2018;8(2):87–88.
DOI: 10.15406/jnsk.2018.08.00286
Positive and negative aspects of cell technologies in cerebral diseases 88
Copyright:
©2018 Kulchitsky et al.
of autologous SC minimizes risk of tumor development associated
with administration of exogenous stem cells into living organism.
Experimenter and clinician should follow unbreakable principle “rst,
do no harm” in order to constantly achieve positive effects of clinical
technologies use and level negative effects.
Acknowledgements
This pooled analysis was funded by OOO Synergy.
Conict of interest
All listed authors concur with the submission of the manuscript; all
authors have approved the nal version. The authors have no nancial
or personal conicts of interest.
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... В физиологических условиях эндогенные стволовые клетки в этих областях мозга генерируют нейробласты, которые мигрируют к тем участкам мозга, где требуется интенсивное образование новых нейронных сетей [36]. Нами в экспериментах на грызунах установлено, что интраназальное введение МСК в остром периоде ишемии мозга сопровождалось более быстрым восстановлением контроля двигательной активности [37,38]. ...
... Травматические и ишемические повреждения мозга продолжают оставаться одной из сложнейших проблем современной медицины [5,46]. Изучение механизмов репаративных процессов в нервной тка-ни и разработка новых методов восстановления нейрональных структур составляют одно из актуальных направлений в физиологии и медицине и имеют большое значение для разработок новых терапевтических и реабилитационных стратегий [7,37,[47][48][49]. Ишемия мозга, которая фатально завершается ишемическим инсультом, часто возникает при нарушениях церебрального кровотока, что сопровождается недостаточным снабжением кислородом отделов мозга и развитием гипоксии разной степени выраженности [4,47]. ...
... На основании таких данных можно предлагать протокол терапии, акцентированный на усилении антиоксидантной системы. В настоящее время актуальным направлением является применение в регенеративной медицине стволовых клеток в качестве ведущего средства клеточной терапии [37,60]. Исследователей и клиницистов привлекают терапевтические свойства МСК [35,36,61], включая МСК мозга [36,62,63]. ...
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... Authors enthusiastically began experimental analysis of MSCs functions in the recovery of impaired brain functions [6][7][8][9][10]. ...
... Direct injection of MSCs into damaged brain region followed by trepanation is frequently unreasonable due to additional surgical interventions. Authors chose technique of MSCs perineural migration in combined therapy of brain injuries and strokes with SCs [6][7][8][9][10]. Cranial nerves were chosen as the way for MSCs migration. ...
... Cranial nerves were chosen as the way for MSCs migration. Injection of MSCs into cranial nerves' endings in facial area is quite simple surgical procedure which guarantees MSCs migration to damaged brain regions [6][7][8][9][10]. ...
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The article briefly describes advantages of autologous mesenchymal stem cells (MSCs) use in clinical conditions to correct structure and function of damaged areas in organs and tissues of humans and animals. The effectiveness of MSCs migration via per-ineural nerve spaces to inner organs was confirmed. Such method of cell therapy allows avoiding major surgeries and achieving more effective result in combination of classic treatment techniques with MSCs perineural delivery to damaged organs and tissues.
... Under physiological conditions, endogenous stem cells in these areas of the brain generate neuroblasts that migrate to those parts of the brain where an intensive formation of new neural networks is required [42]. The authors of the article in experiments on rodents found that intranasal administration of MSCs in the acute period of brain ischemia was accompanied by a faster restoration of the control of motor activity [36,43]. According to this, the aim of this work was to study the intensity of NO production and the presence of copper (as an indicator of superoxide dismutase) in the olfactory bulbs of the brain of the rat by EPR spectroscopy after modeling ischemic stroke of the brain, as well as the effect of intranasal administration of MSCs in the acute period after obstruction of the common carotid arteries. ...
... There is another aspect of the problem in addition to the above. Currently, the use of stem cells in regenerative medicine as a leading technique of cell therapy is a main trend [43,63]. Researchers and clinicians are attracted by the therapeutic properties of MSCs [41,64], including brain MSCs [42,65]. ...
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A comparative experimental analysis by EPR spectroscopy of the intensity of nitric oxide (NO) production and the content of the copper in the tissues of olfactory bulb of the brain of male Wistar rats were performed after modeling of ischemic stroke and treatment with immediate intranasal injection of mesenchymal stem cells (MSCs). Brain ischemia was simulated by ligation at the level of bifurcation of the common carotid arteries. It was found a significant reduction of NO content in the olfactory bulb of the brain of rats on the 1st and 2nd days after modeling of ischemia. The level of NO production was also reduced on the 1st and 2nd days after ischemia with MSCs’ administration as compared to intact animals. It was not found the significant difference of the NO content in rats after ischemia with MSCs’ administration relative to ischemic rats. The copper content in the olfactory bulb of the rat, which corresponds to the level of superoxide dismutase 1 and 3, tended to increase after modeling ischemia and remained for 2 days. The MSCs’ administration was accompanied by a significant increase in copper content on the 1st day after modeling of ischemia and by decrease of its content on 2nd day after ischemia. The experiments showed that MSCs’ administration did not affect the intensity of NO production on the 1st and 2nd days after the modeling of brain ischemia, but was accompanied by an increase in the antioxidant protection of the nervous tissue 1 day after ischemia.
... The authors of the article focused on cellular technologies [3][4][5][6] as additional recovery measures in the early stages of the development and progression of brain diseases. In contrast to the popular systemic injections of stem cells (SCs), which are distributed via bloodstream throughout the body [3][4][5][6], emphasis is placed on the perineural migration of mesenchymal stem cells (MSCs) along the cranial nerves to the destruction site [7][8][9][10][11][12]. This tactic of targeted somatotopic distribution of autologous MSCs in those damaged areas of the brain, in which reparative processes are supposed to be activated, is aimed at improving the efficiency of classical therapy for patients with strokes and brain injuries [7,9,10,12]. ...
... In contrast to the popular systemic injections of stem cells (SCs), which are distributed via bloodstream throughout the body [3][4][5][6], emphasis is placed on the perineural migration of mesenchymal stem cells (MSCs) along the cranial nerves to the destruction site [7][8][9][10][11][12]. This tactic of targeted somatotopic distribution of autologous MSCs in those damaged areas of the brain, in which reparative processes are supposed to be activated, is aimed at improving the efficiency of classical therapy for patients with strokes and brain injuries [7,9,10,12]. It is noteworthy that the bioprinting technology pursues a similar goal when it is planned to implant a bioprinting substrate, including neural networks, into the damaged brain area [13]. ...
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... One of the main problems in the use of MSCs is the limited understanding of how these cells "target" damaged tissues [7] and what specific neurotrophic factors contained in MSCs are responsible for the therapeutic mechanisms of action of MSCs [95]. It should be noted that there is objective evidence that MSCs exhibit immunosuppressive effects in inflammatory conditions [96,97]. Given that the secondary mechanisms of brain injury in TBI involve inflammatory response [98], the use of MSCs in treatment may cause unexpected effects [99]. ...
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... The authors of the article are trying to uncover the mechanisms of the body's defense reactions against neoplasms. In this aspect, possibilities of cell therapy in the field of socially significant diseases are studied [5][6][7], including oncological pathology [8,9]. Other in vitro and in vivo experiments have also demonstrated that mesenchymal stem cells (MSCs) have reparative potential [10,11] and antitumor effects [12]. ...
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... Autologous MSCs from adipose tissue (6.0-8.010^6 cells) were used in complex postoperative treatment (submucous perineural implantation [18][19][20][21]). Migration of MSCs led to distinct progressive recovery of functions: bulbar disorders completely regressed in four months, hemiparesis disappeared, and motor coordination recovered. ...
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... Autologous MSCs from adipose tissue (6.0-8.010^6 cells) were used in complex postoperative treatment (submucous perineural implantation [18][19][20][21]). Migration of MSCs led to distinct progressive recovery of functions: bulbar disorders completely regressed in four months, hemiparesis disappeared, and motor coordination recovered. ...
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