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 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 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 Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1933-1941 ◽  
Author(s):  
Satoru Otsuru ◽  
Patricia L. Gordon ◽  
Kengo Shimono ◽  
Reena Jethva ◽  
Roberta Marino ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Osteogenesis Imperfecta ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Bone Matrix ◽  
Underlying Mechanism ◽  
Growth Data ◽  
Marrow Cells

Abstract Transplantation of whole bone marrow (BMT) as well as ex vivo–expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non–(plastic)–adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell–depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

scholarly journals Endothelial cell fitness dictates the source of regenerating liver vasculature

2018 ◽  
Vol 215 (10) ◽  
pp. 2497-2508 ◽  
Author(s):  
Mahak Singhal ◽  
Xiaoting Liu ◽  
Donato Inverso ◽  
Kai Jiang ◽  
Jianing Dai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cell ◽  
Mononuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Cellular Source ◽  
Bone Marrow Derived Cells ◽  
Cell Mobilization ◽  
Marrow Infusion ◽  
Stimulating Factor ◽  
Bone Marrow Infusion

Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone marrow infusion or granulocyte colony–stimulating factor (G-CSF)–mediated progenitor cell mobilization, which resembles clinically relevant stem cell therapy, demonstrated that bone marrow–derived cells did not contribute to the regeneration of liver vasculature after two-thirds partial hepatectomy (PHx). Taken together, the data reconcile many of the discrepancies in the literature and highlight that the cellular source of regenerating endothelium depends on the fitness of the residual vasculature.

scholarly journals Statins for neuroprotection in spontaneous intracerebral hemorrhage

Neurology ◽  
2019 ◽  
Vol 93 (24) ◽  
pp. 1056-1066 ◽  
Author(s):  
Ching-Jen Chen ◽  
Dale Ding ◽  
Natasha Ironside ◽  
Thomas J. Buell ◽  
Lori J. Elder ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Clinical Studies ◽  
Functional Outcomes ◽  
Hemorrhagic Stroke ◽  
Reactive Oxygen Species Generation ◽  
Mortality Rates ◽  
Lower Mortality ◽  
Secondary Brain Injury ◽  
Spontaneous Intracerebral Hemorrhage ◽  
Statin Use

Statins, a common drug class for treatment of dyslipidemia, may be neuroprotective for spontaneous intracerebral hemorrhage (ICH) by targeting secondary brain injury pathways in the surrounding brain parenchyma. Statin-mediated neuroprotection may stem from downregulation of mevalonate and its derivatives, targeting key cell signaling pathways that control proliferation, adhesion, migration, cytokine production, and reactive oxygen species generation. Preclinical studies have consistently demonstrated the neuroprotective and recovery enhancement effects of statins, including improved neurologic function, reduced cerebral edema, increased angiogenesis and neurogenesis, accelerated hematoma clearance, and decreased inflammatory cell infiltration. Retrospective clinical studies have reported reduced perihematomal edema, lower mortality rates, and improved functional outcomes in patients who were taking statins before ICH. Several clinical studies have also observed lower mortality rates and improved functional outcomes in patients who were continued or initiated on statins after ICH. Subgroup analysis of a previous randomized trial has raised concerns of a potentially elevated risk of recurrent ICH in patients with previous hemorrhagic stroke who are administered statins. However, most statin trials failed to show an association between statin use and increased hemorrhagic stroke risk. Variable statin dosing, statin use in the pre-ICH setting, and selection biases have limited rigorous investigation of the effects of statins on post-ICH outcomes. Future prospective trials are needed to investigate the association between statin use and outcomes in ICH.

scholarly journals Angiogenic Potential of Bone Marrow Derived CD133+ and CD271+ Intramyocardial Stem Cell Trans- Plantation Post MI

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 78 ◽  
Author(s):  
Sarah Sasse ◽  
Anna Skorska ◽  
Cornelia Aquilina Lux ◽  
Gustav Steinhoff ◽  
Robert David ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Network Formation ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Angiogenic Potential ◽  
Lower Expression

Background: Bone marrow (BM)-derived stem cells with their various functions and characteristics have become a well-recognized source for the cell-based therapies. However, knowledge on their therapeutic potential and the shortage for a cross-link between distinct BM-derived stem cells, primed after the onset of myocardial infarction (MI), seems to be still rudimentary. Therefore, the post-examination of the therapeutic characteristics of such primed hematopoietic CD133+ and mesenchymal CD271+ stem cells was the object of the present study. Methods and Results: The effects of respective CD133+ and CD271+ mononuclear cells alone as well as in the co-culture model have been explored with focus on their angiogenic potential. The phenotypic analysis revealed a small percentage of isolated cells expressing both surface markers. Moreover, target stem cells isolated with our standardized immunomagnetic isolation procedure did not show any negative alterations following BM storage in regard to cell numbers and/or quality. In vitro network formation relied predominantly on CD271+ stem cells when compared with single CD133+ culture. Interestingly, CD133+ cells contributed in the tube formation, only if they were cultivated in combination with CD271+ cells. Additional to the in vitro examination, therapeutic effects of the primed stem cells were investigated 48 h post MI in a murine model. Hence, we have found a lower expression of transforming growth factor βeta 3 (TGFβ3) as well as an increase of the proangiogenic factors after CD133+ cell treatment in contrast to CD271+ cell treatment. On the other hand, the CD271+ cell therapy led to a lower expression of the inflammatory cytokines. Conclusion: The interactions between CD271+ and CD133+ subpopulations the extent to which the combination may enhance cardiac regeneration has still not been investigated so far. We expect that the multiple characteristics and various regenerative effects of CD271+ cells alone as well as in combination with CD133+ will result in an improved therapeutic impact on ischemic heart disease.

scholarly journals IFN-γ Licensing Does Not Enhance the Reduced Immunomodulatory Potential and Migratory Ability of Differentiation-Induced Porcine Bone Marrow-Derived Mesenchymal Stem Cells in an In Vitro Xenogeneic Application

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hyeon-Jeong Lee ◽  
Hwan-Deuk Kim ◽  
Chan-Hee Jo ◽  
Eun-Yeong Bok ◽  
Saet-Byul Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Specific Gene ◽  
Specific Cell ◽  
Ifn Γ

IFN-γ licensing to mesenchymal stem cells (MSCs) is applied to enhance the therapeutic potential of MSCs. However, although the features of MSCs are affected by several stimuli, little information is available on changes to the therapeutic potential of IFN-γ-licensed differentiated MSCs during xenogeneic applications. Therefore, the present study is aimed at clarifying the effects of adipogenic/osteogenic differentiation and IFN-γ licensing on the in vitro immunomodulatory and migratory properties of porcine bone marrow-derived MSCs in xenogeneic applications using human peripheral blood mononuclear cells (PBMCs). IFN-γ licensing in differentiated MSCs lowered lineage-specific gene expression but did not affect MSC-specific cell surface molecules. Although indoleamine 2,3 deoxygenase (IDO) activity and expression were increased after IFN-γ licensing in undifferentiated MSCs, they were reduced after differentiation. IFN-γ licensing to differentiated MSCs elevated the reduced IDO expression in differentiated MSCs; however, the increase was not sufficient to reach to the level achieved by undifferentiated MSCs. During a mixed lymphocyte reaction with quantification of TNF-α concentration, proliferation and activation of xenogeneic PBMCs were suppressed by undifferentiated MSCs but inhibited to a lesser extent by differentiated MSCs. IFN-γ licensing increasingly suppressed proliferation of PBMCs in undifferentiated MSCs but it was incapable of elevating the reduced immunosuppressive ability of differentiated MSCs. Migratory ability through a scratch assay and gene expression study was reduced in differentiated MSCs than their undifferentiated counterparts; IFN-γ licensing was unable to enhance the reduced migratory ability in differentiated MSCs. Similar results were found in a Transwell system with differentiated MSCs in the upper chamber toward xenogeneic PBMCs in the lower chamber, despite IFN-γ licensing increased the migratory ability of undifferentiated MSCs. Overall, IFN-γ licensing did not enhance the reduced immunomodulatory and migratory properties of differentiated MSCs in a xenogeneic application. This study provides a better understanding of the ways in which MSC therapy can be applied.

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