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Shanko Y, Navitskaya V, Zamaro A, Krivenko S, Zafranskaya M, Pashkevich S, Koulchitsky S, Takalchik Stukach Y, Denisov A, Kulchitsky V. Prospects of Perineural Administration of Autologous Mesenchymal Stem Cells of Adipose Tissue in Patients with Cerebral Infarction. Biomed J Sci&Tech Res 10(1)-2018. BJSTR. MS.ID.001884. DOI: 10.26717/ BJSTR.2018.10.001884.
Volume 5- Issue 4: 2018
ISSN: 2574-1241
DOI: 10.26717/BJSTR.2018.10.001884
Kulchitsky Vladimir.
Biomed J Sci & Tech Res
Short Communication
Biomedical Journal of
The search for “brain infarction mesenchymal stem cell
therapy” in PubMed on October 01, 2018 showed 233 results.
Experience with MSC therapy in patients with cerebral infarction
is described in 34 articles and search for word combination “brain
infarction mesenchymal stem cell autologous therapy patient”
showed only 9 links. Authors want to pay attention that there are
no results of search for “brain infarction mesenchymal stem cell
autologous perineural therapy patient”. Therefore, there is an empty
Authors recently had only experimental skills in MSC perineural
implantation [1-3]. There are several studies in experimental and
clinical practice when relatively new techniques of SC use are
tested [3,4]. SC are accumulated around damaged brain regions
after their local implantation through trepanation hole to the area
of brain infarct and after systemic injection into bloodstream. Then
Shanko Yuri11234
 : October 08, 2018;  : October 11, 2018
 Kulchitsky Vladimir, Institute of Physiology, National Academy of Sciences, Minsk, Belarus, Europe, Tel:
375172842458; Email:
               
visceral functions is one of the negative consequences of existing therapy. Such state is developed due to persistent structural and functional lack of
central control of various body activities by brain neural networks. Finally, most of the patients have severe invalidities even in distant period after
performed treatment. Therefore, development and implementation of technologies that will allow activating reparative processes in brain after
cerebral infarction is one of prospective tasks.
development and implementation of new technique of cerebral infarctions treatment using autologous mesenchymal stem cells (MSC)
of adipose tissue.
 Authors developed unique technique aimed at formation of conditions for natural migration of stem cells (SC) to the area of cerebral
infarction after their endoscopic administration into nasal submucosa.
 Autologous mesenchymal stem cells (MSC) of 25 patients naturally migrated to the area of cerebral infarction after their administration
into nasal submucosa. The process of MSC differentiation into neuron-like elements after penetration to cranial cavity was previously shown in
               
physiological functions control in 6 months after course therapy with SC assessed by National Institutes of Health Stroke Scale (NIHSS) and Glasgow
Coma Scale (GCS), respectively. Administration of allogeneic SC to patients with cerebral infarctions (n=5) was ineffective.
 Combination of standard therapy of cerebral infarctions with endoscopic perineural implantation of autologous
MSC of adipose tissue is accompanied with activation of reparative processes leading to recovery of neurologic functions.
 Cerebral infarction, Mesenchymal stem cells, Perineural implantation, Patient, Reparative process
GCS: Glasgow Coma Scale; MSC: Mesenchymal Stem Cells; NIHSS: National Institutes of Health Stroke Scale; SC: Stem Cells
 Shanko Y, Navitskaya V, Zamaro A, Krivenko S, Zafranskaya M, Pashkevich S, Koulchitsky S, Takalchik Stukach Y, Denisov
A, Kulchitsky V. Prospects of Perineural Administration of Autologous Mesenchymal Stem Cells of Adipose Tissue in Patients with Cerebral
Infarction. Biomed J Sci&Tech Res 10(1)-2018. BJSTR. MS.ID.001884. DOI: 10.26717/ BJSTR.2018.10.001884.
Volume 10- Issue 1: 2018
SC differentiate into neuron-like elements [5]. It is obvious that
technique of MSC perineural implantation into peripheral areas of
cranial nerve endings (e.g. nasal cavity) [1-3] positively differs from
other cellular technologies such as intracerebral MSC implantation
 
Materials and Methods
Technique of perineural delivery of MSC into brain after their
endoscopic administration into nasal submucosa was developed
and implemented [1,3]. The method was used in addition to standard
therapy of acute cerebral infarction. 25 patients were examined. 12
group, 8 patients with secondary brain infarctions after intracranial
hemorrhages - into second group (aged 27-73 years, 40.25 mean).
        
perineural administration of MSC using the previously described
technique [3]. Patients with primary cerebral infarctions from
the third group (n=5) received standard therapy with allogeneic
MSC. 50ml of adipose tissue was taken from umbilical area of each
         
using previously described technique [3] and then endoscopic
threefold intranasal implantation of autologous MSC in the amount
of 5-12×106 cells was performed with the intervals of 5-9 days.
Allogeneic SC were prepared from donor material in the absence
of conditions for autologous tissues retrieval and administered
perineurally to patients from the third group.
Use of allogeneic MSC by means of their perineural delivery to
 
         
improved after combination of classic therapy of cerebral
infarctions with intranasal implantation of autologous MSC. This
outcome is a valid argument in discussion on reasonability of
autologous and allogeneic biomaterial use. Obtained data allow
recommending autologous MSC as basic cellular technology for
         
          
(within 1 point of British medical research council scale) recovery
of certain neurologic functions in 24 hours after each implantation
of autologous MSC (Figure 1).
Figure 1: Efcacy assessment of cell therapy of primary cerebral infarctions (n=12) was performed in the early period after implantation and
in 6 months. Injections were made on Day 1 (rst), Day 7 (second) and Day 13 (third).
In particular, NIHSS score changed in patients with primary
cerebral infarctions (n=12) from 14.2 at the beginning to 1.8 in 6
months; none of them had recurrent cerebral infarctions during
one year of observation. In comparison, NIHSS score changed
in patients of control group (n=20, classic therapy of cerebral
infarctions) from 14.4 at the beginning to 9.8 in 6 months; three of
them (15%) had recurrent cerebral infarctions during six months
of observation.
multiple secondary cerebral infarctions (n=8) because all of them
were in comatose state and NIHSS assessment was not applicable.
Combined therapy (classic standard of care and administration of
autologous MSC) was started at 6.2 GCS. Second group of patients
did not show rapid regress of neurologic disorders, even after
each SC implantation. These patients had GCS score 9.2 after the
end of therapy with SC and NIHSS score 12.3 in six months after
perineural implantation of MSC and standard therapy together with
rehabilitation. It was hard to compare with control group, because
one patient died there, three were in vegetative state and the last
one had GCS score 28.0. However, it is important that there were no
complications in any case.
Discussion and Conclusion
Combination of classic therapy of cerebral infarctions with
endoscopic intranasal perineural implantation of autologous MSC,
which migrate to the area of brain infarct, is accompanied with
formation of conditions for activation of reparative processes
leading to recovery of neurologic functions [3,8].
Positive results of clinical observations also led to appearance
of several conclusions and questions. No clear dependence was
established between effectiveness of reparative processes and
amount of implanted SC [8,9]. Diversity of effects determined by
 Volume 10- Issue 1: 2018
 Shanko Y, Navitskaya V, Zamaro A, Krivenko S, Zafranskaya M, Pashkevich S, Koulchitsky S, Takalchik Stukach Y, Denisov
A, Kulchitsky V. Prospects of Perineural Administration of Autologous Mesenchymal Stem Cells of Adipose Tissue in Patients with Cerebral
Infarction. Biomed J Sci&Tech Res 10(1)-2018. BJSTR. MS.ID.001884. DOI: 10.26717/ BJSTR.2018.10.001884.
individual features of patients and variety of clinical performance
of cerebral infarction was revealed. No dependence between
reparative effect and the period of cellular therapy beginning was
established. Relatively short period of observation (about one
         
of long-term effect of cellular therapy (e.g. in one-two years) after
cerebral infarction development and beginning of therapy. There
are also some questions remained unclear according effectiveness
of additional implantations of autologous MSC of adipose tissue in
distant periods after treatment beginning (after one or more years).
The mechanism of neurotrophic effects after autologous MSC use
and recovery of neural network functions in brain was supposed,
but not proved [3,10,11]. Therefore, the future task aimed at
analysis of activation of neurotrophic and other endogenous
      
This pooled analysis was funded by SSTP “New methods of
medical care”, section “Transplantation of cells, tissues and organs”
(2016-2020), and by grant OOO “Synergy”.
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ISSN: 2574-1241
DOI: 10.26717/BJSTR.2018.10.001884
Kulchitsky Vladimir. Biomed J Sci & Tech Res
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Full-text available
Abstract Background: Neurodestructive processes of any etiology are related to problematic and socially important diseases due to ineffective therapeutic strategy and need to search for new successful ways of treatment and rehabilitation of patient with cerebral infarctions and brain attacks. Aims: Authors plan to verify hypothesis on viability of additional use of perineural implantation of autologous mesenchymal stem cells (MSC) in order to optimize standard therapy of patients with brain attacks. Such combined technology is aimed at extra activation of brain plasticity mechanisms during development of neurodestructive processes. Methods: The technique of MSC perineural migration to injured brain regions was experimentally verified on rats (n=40) paying attention to somatotopic organization of cranial nerves. This technique was clinically tested in pilot project. Phenotyping of autologous MSC from adipose tissue (AT) was performed in 23 patients with brain attacks. These 23 patients received standard treatment as per international guidelines together with three perineural implantations of autologous MSC from AT with 5-9 days intervals. The other group of patients (n=7) received only standard therapy as per international guidelines. Results: Additional use of cell therapy resulted in more rapid and effective recovery of disordered neurological functions in all cases compared to those who received standard therapy. The phenomenon of abrupt recovery of neurological functions was established during first 24 hours after each injection of autologous MSC. Cumulative recovery of functions progressed after each implantation. Discussion and Conclusion: Experimentally developed technique of perineural implantation of autologous MSC was successfully verified in clinical conditions in accordance with certified cell therapy guideline (The Ministry of Health of the Republic of Belarus) in combination with standard treatment of patients with cerebral infarctions. Cell therapy with autologous MSC from AT by means of perineural delivery to injured brain regions is the basis for activation of reparative potential of nerve tissue and progressive recovery of neurological functions in patients with cerebral infarctions. Citation: Shanko Y, Navitskaya V, Zamaro A, et al. Somatotopic principle of perineural implantation of stem cells in patients with brain injuries. J Neurol Stroke. 2018;8(5):259‒261. DOI: 10.15406/jnsk.2018.08.00321
Full-text available
Recent advances in neuroscience and devices are ushering in a new generation of medical treatments. Engineered biodevices are demonstrating the potential to create long-term changes in neural circuits, termed neuroplasticity. Thus, the approach of engineering neuroplasticity is rapidly expanding, building on recent demonstrations of improved quality of life for people with movement disorders, epilepsy, and spinal cord injury. In addition, discovering the fundamental mechanisms of engineered neuroplasticity by leveraging anatomically well-documented systems like the spinal cord is likely to provide powerful insights into solutions for other neurotraumas, such as stroke and traumatic brain injury, as well as neurodegenerative disorders, such as Alzheimer’s, Parkinson disease, and multiple sclerosis. Now is the time for advancing both the experimental neuroscience, device development, and pioneering human trials to reap the benefits of engineered neuroplasticity as a therapeutic approach for improving quality of life after spinal cord injury.
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Hypothesis on migration of stem cells to injured brain region after introduction of stem cells into nasolacrimal duct has been experimentally verified on Wistar rats (n=7). Fluorescent stem cells have been detected in the injured region of frontal cerebral cortex using confocal microscopy in 20 hours after implantation of mesenchymal stem cells into nasolacrimal duct of rats. Keywords: brain trauma, cell technology, nasolacrimal implantation, stem cells
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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.
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Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the brain might be a promising, non-invasive therapeutic approach to restore the damaged brain. Therefore, our goal is to study the remyelinating potential of human Wharton's Jelly mesenchymal stem cells (hWJ-MSC) after intranasal delivery. Wistar rat pups, previously brain-damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150'000 cells in 3μl) that were intranasally delivered twice to each nostril (600'000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, as well as neurotrophic factors, was analyzed by real-time polymerase chain reaction (PCR). Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat brain. Further studies should address the dose and frequency of administration.
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In this review, we evaluated the literature reporting the use of amniotic stem cells (ASCs) in regenerative medicine for the treatment of neurological disorders. There is an increasing amount of evidence that indicates the exacerbation of the primary injury by inflammation in neurological disorders characterized by rampant inflammation, thereby increasing damage to the central nervous system (CNS). To address this, we focus on the amnion cells′ anti-inflammatory properties, which make their transplantation a promising treatment for these disorders. In addition, we offered insights into new applications of the ASC in the fields of regenerative medicine and tissue engineering.
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Intra-cerebral cell transplantation is increasingly finding a clinical translation. However, the number of cells surviving after implantation is low (5-10%) compared to the number of cells injected. Although a significant effort has investigated apoptosis of cells after implantation, very little optimization of cell preparation and administration has been undertaken. Moreover, there is a general neglect of the biophysical aspects of cell injection. Cell transplantation can only be an efficient therapeutic approach, if an optimal transfer of cells from the dish to the brain can be ensured. We therefore here focused on the in vitro aspects of cell preparation of a clinical-grade human neural stem cell (NSC) line for intracerebral cell implantation. NSCs were suspended in five different vehicles: Phosphate Buffered Saline (PBS), Dulbecco's Modified Eagle Medium (DMEM), artificial Cerebral Spinal Fluid (aCSF), Hypothermosol and Pluronic. Suspension accuracy, consistency, and cell settling were determined for different cell volume fractions in addition to cell viability, cell membrane damage and clumping. Maintenance of cells in suspension was evaluated while these were stored for 8 hours on ice, at room temperature, or physiological normothermia. Significant differences between suspension vehicles and cellular volume fractions were evident. Hypothermosol and Pluronic performed best, with PBS, aCSF and DMEM exhibiting less consistency, especially in maintaining a suspension and preserving viability under different storage conditions. These results provide the basis to further investigate these preparation parameters during the intra-cerebral delivery of NSCs to provide an optimized delivery process that can ensure an efficient clinical translation.
Stem cells of various sources have been investigated in a series of small, safety and feasibility-focused studies over the past 15 years. Understanding of mechanisms of action has evolved and the trial paradigms have become focused on two different approaches – one being an early subacute delivery of cells to reduce acute tissue injury and modify the tissue environment in a direction favourable to reparative processes (for example by being anti-inflammatory, anti-apoptotic, and encouraging endogenous stem cell mobilisation); the other exploring later delivery of cells during the recovery phase after stroke to modulate the local environment in favour of angiogenesis and neurogenesis. The former approach has generally investigated intravenous or intra-arterial delivery of cells with an expected paracrine mode of action and no expected engraftment within the brain. The latter has explored direct intracerebral implantation adjacent to the infarct. Several relevant trials have been conducted, including two controlled trials of intravenously delivered bone marrow-derived cells in the early subacute stage, and two small single-arm phase 1 trials of intracerebrally implanted cells. The findings of these studies and their implications for future trial design are considered.
Background: CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. Methods: We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2-4) 6-60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with, number NCT01151124. Findings: 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60-82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6-8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. Interpretation: Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. Funding: ReNeuron Limited.
Background and importance: Local biological drug delivery in the brain is an innovative field of medicine that developed rapidly in recent years. Our report illustrates a unique case of de novo development of a cerebral arteriovenous malformation (AVM) after implantation of genetically modified allogeneic mesenchymal stem cells in the brain. Clinical presentation: A 50-year-old man was included in a prospective clinical study (study ID number CM GLP-1/01, 2007-004516-31) investigating a novel neuroprotective approach in stroke patients to prevent perihematomal neuronal damage. In this study, alginate microcapsules containing genetically modified allogeneic mesenchymal stem cells producing the neuroprotective glucagon-like peptide-1 (GLP-1) were implanted. Three years later, the patient presented with aphasia and a focal seizure due to a new left frontal intracerebral hemorrhage. Angiography revealed a de novo left frontal AVM. Conclusion: The development of an AVM within a period of 3 years after implantation of the glucagon-like peptide-1-secreting mesenchymal stem cells suggests a possible relationship. This case exemplifies that further investigations are necessary to assess the safety of genetically modified cell lines for local biological drug delivery in the brain. Abbreviations: ALK1, activin-like kinase 1AVM, arteriovenous malformationENG, endoglin; GLP-1, glucagon-like peptide-1GLP-1R, glucagon-like peptide-1 receptorMSC, mesenchymal stem cell.