scholarly journals Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6194 ◽  
Author(s):  
Masahiro Hatakeyama ◽  
Itaru Ninomiya ◽  
Yutaka Otsu ◽  
Kaoru Omae ◽  
Yasuko Kimura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Ischemic Stroke ◽  
Clinical Studies ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Functional Independence ◽  
Therapeutic Effects ◽  
Cell Therapies ◽  
Neuronal Stem Cells

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

scholarly journals Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke

Stroke ◽  
2019 ◽  
Vol 50 (10) ◽  
pp. 2883-2891 ◽  
Author(s):  
Yuka Okinaka ◽  
Akie Kikuchi-Taura ◽  
Yukiko Takeuchi ◽  
Yuko Ogawa ◽  
Johannes Boltze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Mononuclear Cells ◽  
Blood Clot ◽  
Experimental Stroke ◽  
Bone Marrow Mononuclear Cell ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Preclinical And Clinical Studies ◽  
Possible Cause

Background and Purpose— The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies. Methods— To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used. Results— We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation. Conclusions— Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants. Visual Overview— An online visual overview is available for this article.

scholarly journals Autologous Bone Marrow Mononuclear Cells in Ischemic Cerebrovascular Accident Paves Way for Neurorestoration: A Case Report

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Alok Sharma ◽  
Hemangi Sane ◽  
Anjana Nagrajan ◽  
Nandini Gokulchandran ◽  
Prerna Badhe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Ischemic Stroke ◽  
Mononuclear Cells ◽  
Cellular Therapy ◽  
Functional Independence Measure ◽  
Autologous Bone Marrow ◽  
Functional Independence ◽  
Bone Marrow Mononuclear Cells ◽  
Autologous Bone

In response to acute ischemic stroke, large numbers of bone marrow stem cells mobilize spontaneously in peripheral blood that home onto the site of ischemia activating the penumbra. But with chronicity, the numbers of mobilized cells decrease, reducing the degree and rate of recovery. Cellular therapy has been explored as a new avenue to restore the repair process in the chronic stage. A 67-year-old Indian male with a chronic right middle cerebral artery ischemic stroke had residual left hemiparesis despite standard management. Recovery was slow and partial resulting in dependence to carry out activities of daily living. Our aim was to enhance the speed of recovery process by providing an increased number of stem cells to the site of injury. We administered autologous bone marrow mononuclear cells intrathecally alongwith rehabilitation and regular follow up. The striking fact was that the hand functions, which are the most challenging deficits, showed significant recovery. Functional Independence Measure scores and quality of life improved. This could be attributed to the neural tissue restoration. We hypothesize that cell therapy may be safe, novel and appealing treatment for chronic ischemic stroke. Further controlled trials are indicated to advance the concept of Neurorestoration.

Abstract 118: Intravenous versus Intra-arterial Autologous Bone Marrow Mononuclear cells for Acute Ischemic Stroke

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Bing Yang ◽  
Ramy El Khoury ◽  
Krystal Schaar ◽  
Xiaopei Xi ◽  
Sean.I Savitz
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Ischemic Stroke ◽  
Mononuclear Cells ◽  
Autologous Bone Marrow ◽  
Serum Levels ◽  
Bone Marrow Mononuclear Cells ◽  
Stroke Model ◽  
Tnf Α ◽  
Autologous Bone

Background: Bone marrow mononuclear cells (MNCs) are under investigation as an autologous cell-based therapy for acute ischemic stroke. Both intravenous (IV) and intra-arterial (IA) delivery of MNCs have been brought forward to clinical trials. However, the optimal route of administration for these cells is still unknown and debated. In the present study, we performed a direct comparison of IV vs IA administration of MNCs in a rodent stroke model. Methods: Long Evans adult male rats were subjected to middle cerebral artery occlusion (MCAo) for 90 minutes. At 24 hrs after stroke, animals were randomly assigned to either receive saline IV (N=5) or autologous bone marrow derived MNCs 30 million cells/kg via IV (N= 9) injection or an IA (N=8) administration of autologous MNCs 30 million cells/kg. IA infusion was performed over 5 minutes with an infusion pump. Contralateral forepaw use was evaluated by an investigator blinded to treatment groups up to 28 days after stroke. Stroke lesion volume was also measured at 28 days after stroke. Serum cytokines were analyzed from 4 to 28 days after stroke. Results: MNCs improved functional recovery and reduced lesion size compared with saline treatment at 28 days after stroke ( Fig A & Fig B, p<0.05). However, there was no significant difference between IV and IA MNC treated groups in either histological or functional outcomes. Serum levels of IL-10 were elevated in animals that received either IV or IA MNCs from 4 to 28 days after stroke, compared with saline controls (Fig C, p<0.05). In addition, serum levels of TNF-α were significantly reduced (Fig D, p<0.05) in both IV and IA MNC treated groups compared to saline controls. We did not observe differences in cytokine levels between IA and IV MNC treated groups for IL-10 and TNF-α. Furthermore, only intravenously administered MNCs led to a significant reduction in serum IL-1β levels, at 4 days after stroke, compared to saline treated controls (p<0.05). Conclusion: This is the first study to directly compare delivery routes of bone marrow derived MNCs in a rodent stroke model and assess long term outcomes. MNCs improved neurological recovery and reduced infarction sizes after stroke but we found no differences in outcome based on route of administration. We also found no evidence that either delivery route is superior in modulating the systemic inflammatory response after stroke. These findings have direct clinical implications for the design of clinical trials testing MNCs in patients with ischemic stroke.

scholarly journals Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Paulo Henrique Rosado-de-Castro ◽  
Felipe Gonçalves de Carvalho ◽  
Gabriel Rodriguez de Freitas ◽  
Rosalia Mendez-Otero ◽  
Pedro Moreno Pimentel-Coelho
Keyword(s):  
Bone Marrow ◽  
Intracerebral Hemorrhage ◽  
Clinical Studies ◽  
Hemorrhagic Stroke ◽  
Mononuclear Cells ◽  
Time Window ◽  
Therapeutic Potential ◽  
Cell Therapies ◽  
Life Years ◽  
Bone Marrow Derived Cells

Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

scholarly journals Clinical Trials of Stem Cell Therapy for Cerebral Ischemic Stroke

2020 ◽  
Vol 21 (19) ◽  
pp. 7380 ◽  
Author(s):  
Masahito Kawabori ◽  
Hideo Shichinohe ◽  
Satoshi Kuroda ◽  
Kiyohiro Houkin
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Therapeutic Effects ◽  
Stroke Patients

Despite recent developments in innovative treatment strategies, stroke remains one of the leading causes of death and disability worldwide. Stem cell therapy is currently attracting much attention due to its potential for exerting significant therapeutic effects on stroke patients. Various types of cells, including bone marrow mononuclear cells, bone marrow/adipose-derived stem/stromal cells, umbilical cord blood cells, neural stem cells, and olfactory ensheathing cells have enhanced neurological outcomes in animal stroke models. These stem cells have also been tested via clinical trials involving stroke patients. In this article, the authors review potential molecular mechanisms underlying neural recovery associated with stem cell treatment, as well as recent advances in stem cell therapy, with particular reference to clinical trials and future prospects for such therapy in treating stroke.

scholarly journals Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Louise A. Mesentier-Louro ◽  
Camila Zaverucha-do-Valle ◽  
Paulo H. Rosado-de-Castro ◽  
Almir J. Silva-Junior ◽  
Pedro M. Pimentel-Coelho ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Optic Nerve ◽  
Mononuclear Cells ◽  
Ganglion Cells ◽  
Therapeutic Effects ◽  
Cell Therapies ◽  
Routes Of Administration ◽  
Optic Nerve Diseases ◽  
The Central Nervous System ◽  
Bone Marrow Derived Cells

Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

scholarly journals Progenitor Cell Therapy for the Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Peter A. Walker ◽  
Matthew T. Harting ◽  
Shinil K. Shah ◽  
Mary-Clare Day ◽  
Ramy El Khoury ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Progenitor Cell ◽  
Neurological Injury ◽  
Cell Therapies ◽  
Potential Efficacy ◽  
Cord Injury

Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials.

scholarly journals Comparative Dose of Intracarotid Autologous Bone Marrow Mononuclear Therapy in Chronic Ischemic Stroke in Rats

2021 ◽  
Vol 9 (A) ◽  
pp. 233-243
Author(s):  
Feda Makkiyah ◽  
Wismaji Sadewo ◽  
Rahmah Nurrizka
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Ischemic Stroke ◽  
Test Scores ◽  
Mononuclear Cells ◽  
Marrow Cell ◽  
Optimum Dose ◽  
Infarct Zone ◽  
Positive Effects ◽  
Cylinder Test

Research on chronic ischemic stroke is limited. One of the more promising approaches showing positive effects in the acute stage is mononuclear bone marrow cell therapy. This research may be the first which presents data about the optimum dose of bone marrow mononuclear cells (BM-MNCs) for chronic ischemic stroke in rats and discusses factors influencing recovery in the chronic stage. We performed temporary middle cerebral artery occlusion (MCAO)  procedures on the rats which were then randomly assigned to one of two experimental groups in which they were given either low or high doses of autologous BM-MNCs  (5 million or 10 million cells per kg body weight). Rat brains were fixed for HE, CD31, and doublecortin staining for analysis of the effects. Rat behavior was assessed weekly using the cylinder test and a modified neurological severity score (NSS) test. In the four weeks prior to administration of BM-MNC, cylinder test scores improved to near normal, and NSS test scores improved moderately. The infarct zone decreased significantly (p <0,01),  there was an improvement in angiogenesis (p = 0.1590) and a significant improvement in neurogenesis (p <0,01). Reduction of the infarct zone was associated with a higher dose whereas both higher and lower doses were found to have a similar effect on improving angiogenesis, and neurogenesis. Recovery was superior after twelve weeks compared with the recovery assessment at eight weeks. In conclusion, a dose of 10 million cells was more effective than a dose of 5 million cells per kg body weight for reducing the infarct zone and ameliorating neurogenesis. There was an improvement of histopathological parameters associated with the longer infarct period.

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