Abstract P815: Decoding the Cross-Talk Between Grafted Neural Stem Cells and Host Brain to Predict the Molecular Mechanisms of Stem Cell-Induced Functional Recovery After Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Seth S Tigchelaar ◽  
Ricardo L Azevedo-Pereira ◽  
Chen Dong ◽  
xibin liang ◽  
Tonya Bliss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Neural Stem Cells ◽  
Brain Tissue ◽  
Stem Cell Therapy ◽  
Functional Recovery ◽  
The United States ◽  
Paracrine Factors ◽  
Osmotic Pumps

Stroke is a leading cause of long-term disability and death in the united states. The development of new therapies for stroke are sorely needed. There is great hope that stem cell therapy will create a paradigm shift in the treatment of stroke patients. A barrier to ensuring clinical success of stem cell therapy is the paucity of understanding of the mechanisms by which stem cells exert their beneficial effects. Using a novel mRNA purification method, we identified 50 genes encoding extracellular space proteins, expressed by human neural stem cells (hNSCs) whose expression positively correlated with functional recovery. In this study, we focus on one of the paracrine factors from grafted hNSCs that correlated best with functional recovery, to investigate its therapeutic potential in promoting recovery after stroke. Male nude rats underwent stroke using the distal middle cerebral artery occlusion (dMCAo) model. One week following stroke, osmotic pumps were prepared and loaded with recombinant MTN-2. The osmotic pumps were inserted into the peri-infarct area and infused recombinant MTN-2 for 5 days. Post-stroke, animals were assessed for functional recovery for 5 weeks using both the Montoya staircase test and the whisker-paw reflex test to assess for forelimb function, dexterity, side bias, and placing deficits. After 5 weeks, brain tissue was isolated to assess glial cell morphology. Brain sections were stained with GFAP and IBA1 to visualize astrocytes and microglia, respectively. Confocal images were processed and analyzed using the Bitplane Imaris image analysis software. Output measurements of number of cells/mm2, cell volume, cell branching, and process length and thickness were obtained to characterize the changes in astrocytic and microglial response to injury and paracrine factor treatment. By identifying paracrine factors that are responsible for the regeneration of brain tissue following implantation of hNSCs in stroke brain, this work will increase the likelihood of successful clinical translation of stem cell therapy for stroke. Moreover, elucidating these molecular pathways important for brain recovery may ultimately identify novel therapeutic targets and offer hope to millions of Americans who live with the devastating effects of stroke.

Sequential paracrine mechanisms are necessary for the therapeutic benefits of stem cell therapy

2020 ◽  
Vol 319 (6) ◽  
pp. C1141-C1150
Author(s):  
Hualing Sun ◽  
Richard E. Pratt ◽  
Conrad P. Hodgkinson ◽  
Victor J. Dzau
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Conditioned Media ◽  
Paracrine Factors ◽  
Tissue Repair And Regeneration ◽  
Therapeutic Benefits ◽  
Pai 1

Stem cell injections are an attractive therapeutic tool. It has been demonstrated that injected stem cells promote tissue repair and regeneration via paracrine mechanisms. However, the effects of injected stem cells continue for far longer than they are present. We hypothesized that the effects of injected stem cells are prolonged because of a sequential paracrine relay mechanism. Conditioned media was collected from mesenchymal stem cells (MSCs) after 24 h. This media was then added to RAW264.7. Media was collected from the macrophages after 24 h and was then added to endothelial cells (ECs). This conditioned macrophage media, but not control media, promoted wound healing and induced EC differentiation. Similar results were observed with primary macrophages. To identify the active paracrine factors released by macrophages in response to stimulation by MSC conditioned media we used an antibody array, identifying increased expression of the angiogenesis-related proteins stromal cell-derived factor 1 (SDF1) and plasminogen activator inhibitor-1 (PAI-1). Knockdown of either protein inhibited the ability of conditioned media derived from MSC paracrine factor-stimulated macrophages to induce EC differentiation both in vitro and in vivo. Conditioned media derived from postnatal day 7 (P7) mouse macrophages induced EC differentiation. Moreover, SDF1 and PAI-1 levels were >120 higher in P7 macrophages compared with adult macrophages, suggesting that MSC paracrine factors promote adult macrophages to adopt a juvenile phenotype. These results indicate that MSC paracrine factors induce macrophages to secrete SDF1 and PAI-1, in-turn inducing endothelial cells to differentiate. Identification of a sequential paracrine mechanism opens new therapeutic avenues for stem cell therapy.

scholarly journals Surfing the clinical trials of mesenchymal stem cell therapy in ischemic cardiomyopathy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Iman Razeghian-Jahromi ◽  
Anthony G. Matta ◽  
Ronan Canitrot ◽  
Mohammad Javad Zibaeenezhad ◽  
Mahboobeh Razmkhah ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Clinical Practice ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Ischemic Cardiomyopathy ◽  
Reverse Remodeling ◽  
Paracrine Factors

AbstractWhile existing remedies failed to fully address the consequences of heart failure, stem cell therapy has been introduced as a promising approach. The present review is a comprehensive appraisal of the impacts of using mesenchymal stem cells (MSCs) in clinical trials mainly conducted on ischemic cardiomyopathy. The benefits of MSC therapy for dysfunctional myocardium are likely attributed to numerous secreted paracrine factors and immunomodulatory effects. The positive outcomes associated with MSC therapy are scar size reduction, reverse remodeling, and angiogenesis. Also, a decreasing in the level of chronic inflammatory markers of heart failure progression like TNF-α is observed. The intense inflammatory reaction in the injured myocardial micro-environment predicts a poor response of scar tissue to MSC therapy. Subsequently, the interval delay between myocardial injury and MSC therapy is not yet determined. The optimal requested dose of cells ranges between 100 to 150 million cells. Allogenic MSCs have different advantages compared to autogenic cells and intra-myocardial injection is the preferred delivery route. The safety and efficacy of MSCs-based therapy have been confirmed in numerous studies, however several undefined parameters like route of administration, optimal timing, source of stem cells, and necessary dose are limiting the routine use of MSCs therapeutic approach in clinical practice. Lastly, pre-conditioning of MSCs and using of exosomes mediated MSCs or genetically modified MSCs may improve the overall therapeutic effect. Future prospective studies establishing a constant procedure for MSCs transplantation are required in order to apply MSC therapy in our daily clinical practice and subsequently improving the overall prognosis of ischemic heart failure patients.

scholarly journals Traditional Chinese Medicine Monomers: Novel Strategy for Endogenous Neural Stem Cells Activation After Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Ju Wang ◽  
Jun Hu ◽  
Xuezhu Chen ◽  
Xuejiao Lei ◽  
Hua Feng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Cell Therapy ◽  
Neural Stem Cells ◽  
Signaling Pathway ◽  
Stem Cell Therapy ◽  
Cns Injury ◽  
Endogenous Neural Stem Cells

Stem cell therapy, which has become a potential regenerative medical treatment and a promising approach for treating brain injuries induced by different types of cerebrovascular disease, has various application methods. Activation of endogenous neural stem cells (NSCs) can enable infarcted neuron replacement and promote neural networks’ regeneration without the technical and ethical issues associated with the transplantation of exogenous stem cells. Thus, NSC activation can be a feasible strategy to treat central nervous system (CNS) injury. The potential molecular mechanisms of drug therapy for the activation of endogenous NSCs have gradually been revealed by researchers. Traditional Chinese medicine monomers (TCMs) are active components extracted from Chinese herbs, and some of them have demonstrated the potential to activate proliferation and neurogenesis of NSCs in CNS diseases. Ginsenoside Rg1, astragaloside IV (AST), icariin (ICA), salvianolic acid B (Sal B), resveratrol (RES), curcumin, artesunate (ART), and ginkgolide B (GB) have positive effects on NSCs via different signaling pathways and molecules, such as the Wingless/integrated/β-catenin (Wnt/β-catenin) signaling pathway, the sonic hedgehog (Shh) signaling pathway, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). This article may provide further motivation for researchers to take advantage of TCMs in studies on CNS injury and stem cell therapy.

Abstract 14: Synaptic Remodeling after Stroke Enhanced by Transplanted Human Neural Stem Cells is Coincident with Functional Recovery

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Takeshi Hiu ◽  
Tonya Bliss ◽  
Nathan Manley ◽  
Eric Wang ◽  
Yasuhiro Nishiyama ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Functional Recovery ◽  
Cortical Layer ◽  
Synaptic Remodeling ◽  
Array Tomography ◽  
Layer 2 ◽  
Glutamate Synapses

Background: Stem cell transplantation (Tx) has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. The ultimate change in brain plasticity is manifested at the synaptic level, however, the synaptic remodeling after stem cell therapy remains unknown. Here we evaluate the effect of transplanted human neural progenitor cells (hNPCs) on the peri-infarct synaptic remodeling in the post-ischemic brain. Materials and Methods: We use array tomography, a high-resolution proteomic imaging method, to determine how hNPCs affect the number and subtype of glutamate and GABA synapses after stroke. Vehicle or hNPCs were transplanted into the ischemic cortex of Nude rats 7 days after distal middle cerebral artery occlusion. Neurological recovery was assessed weekly using a battery of behavioral tests. The arrays of serial ultrathin sections (70 nm), removed from the peri-infarct cortex at 1 and 4 weeks post-Tx, were stained using multiple synaptic markers and imaged in cortical layer 2/3 and 5. Computational analysis of the resultant staining pattern was used to identify and quantify subtypes of glutamate and GABA synapses. Results: Tx of hNPCs significantly improved behavioral recovery after stroke compared to vehicle-treated rats (4 weeks post-transplantation; p<0.01) without altering the infarct size. hNPC-treated rats had a higher density of VGluT1-containing glutamate synapses (0.223 vs 0.185 synapses/μm3, p<0.05), and GluA2-containing glutamate synapses (0.091 vs 0.069 synapses/μm3, p<0.05) in layer 5 at 4 weeks post-Tx, compared to vehicle-treated rats. However, hNPCs had did not alter total number of glutamate synapses. This synaptic increase was cortical layer-specific observed in layer 5 but not .in layer 2/3. hNPCs had no detectable effect on the density of GABA synapses in either layer 5 or 2/3 at 1 week or 4 weeks post-Tx. Conclusions: These results provide novel new information about the organization of synaptic circuitry and its plasticity after stem cell therapy. These data suggest that stem cells alter the subunit composition of glutamate synapses after stroke and this is coincident with stem cell-induced functional recovery.

The 100 Most Cited Articles on the Applications of Stem Cells in Osteoarthritis: A Bibliometric Analysis

2020 ◽  
Author(s):  
Keda Yang ◽  
Siming Zhou ◽  
Lin Tao
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Bibliometric Analysis ◽  
Stem Cell Therapy ◽  
Molecular Mechanisms ◽  
The United States ◽  
Research Area ◽  
General Information ◽  
Publication Number

Abstract Background: Stem cells have been applied in the treatment of OA, which had attracted wide attention. However, the research area is relatively extensive, and the research level is variable. In this study, we reviewed the mechanisms and clinical applications of stem cells in OA by using bibliometric analysis for the first time. We also revealed the characteristics, superior results and developmental trends in this field.Methods: The Web of Science core collection database was used to search articles related to the application of stem cells in OA. We collected the general information from the top 100 cited articles. We analyzed and evaluated the articles according to publication number, journals, institutions, countries, keywords and extended keywords.Results: The 100 most cited articles were cited from 129 to 1353 times mainly reviews and original articles. These articles were published from 2001 to 2017 and distributed evenly in America, East Asia and European countries. The United States contributed most in published number and international cooperation. The top ten institutions are mainly major universities and Duke University published a maximum of 10 articles. In terms of journals ,57 articles were published in the top ten journals. The keywords were divided into 8 categories from molecular mechanisms to clinical application.Conclusions: In our study, we found that mesenchymal stem cells (MSCs) which could repair articular cartilage and inhibit local inflammation, are the most widely applied in research and treatment of OA. TGF-βwas crucial during the process. Exosomes are regarded as the active ingredients in stem cell therapy for OA. Microtissue engineering will contribute to accurate and effective stem cell therapy. The findings of our study will contribute to the continuous development of research and direct the research of stem cells in OA.

Stem Cell Therapy For The Treatment Of Crohn's Disease; Current Obstacles And Future Hopes. (Mini-Review)

2021 ◽  
Vol 16 ◽  
Author(s):  
Sarah El-Nakeep
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Perianal Fistula ◽  
The United States

Background: Crohn's disease (CD) is an autoimmune disease of the gastrointestinal tract, characterized by relapsing and remitting courses. The disease is debilitating in nature with three prominent phenotypic clinical presentations; fistulizing, stenosing, and inflammatory. Stem cells offer a new hope for CD patients with modifying the immune response and progression of the healing process. Aim: This mini-review discusses the role of stem cells in treating CD, their effectiveness as a new therapy and their current limitations faced. Methods: The author conducted a literature review on recent randomized controlled trials and cohort studies concerned with the topic in question using the following keywords (Crohn's Disease, perianal fistula, Stem cell therapy, mesenchymal stem cells, remission). Results: Clinical trials show that the stem cells are more effective in the CD associated complex perianal fistula than the CD enteritis. Till the time being, there are no standardized guidelines regarding; dose of stem cells used, number of doses administered, route of administration, type of stem cells used. Only one group of researchers proposed a standardized procedure for injecting mesenchymal stem cells in complex perianal fistula, according to their own experience in clinical trials. Moreover, mesenchymal stem cells and their related types (placental, adipose tissue, umbilical tissue, etc.) are the most safe and effective in clinical trials. Currently; the commercially available mesenchymal stem cells preparation (Darvadstrocel (Cx601)) is the only one approved by The United States Food and Drug Administration (FDA) for clinical use in refractory CD associated complex perianal fistula. Conclusions: Stem cell therapy (SCT) shows promise in; inducing remission in refractory Crohn's colitis, and perianal fistula, but further research is required before SCT could be applied to clinical practice guidelines

FEATURES

2012 ◽  
Vol 16 (03) ◽  
pp. 20-46
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Cell Therapy ◽  
Peripheral Nerve ◽  
Neural Stem Cells ◽  
Stem Cell Therapy ◽  
Cardiac Diseases ◽  
Peripheral Nerve Injuries ◽  
Nerve Injuries

Expatriate Researcher Returns to Roost. Past, Present and Future of Stem Cells in Regenerative Medicine. Learning Human Cardiac Diseases through Stem Cells. Bioprocessing for Stem Cell Therapy: From the Lab into the Log Phase. Neural Stem Cells and Cell-based Approaches in Neurodegeneration and Peripheral Nerve Injuries. The Marketing of Unapproved Stem Cell Products: An Industry-wide Challenge.

Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes

2009 ◽  
Vol 35 (2) ◽  
pp. 85-93 ◽  
Author(s):  
L. Vija ◽  
D. Farge ◽  
J.-F. Gautier ◽  
P. Vexiau ◽  
C. Dumitrache ◽  
...  
Keyword(s):  
Stem Cells ◽  
Type 1 Diabetes ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy

The promises of stem cells: stem cell therapy for movement disorders

2014 ◽  
Vol 20 ◽  
pp. S128-S131 ◽  
Author(s):  
Hideki Mochizuki ◽  
Chi-Jing Choong ◽  
Toru Yasuda
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Movement Disorders

scholarly journals Optimizing Stem Cell Therapy after Ischemic Brain Injury

2020 ◽  
Vol 22 (3) ◽  
pp. 286-305 ◽  
Author(s):  
Shuai Zhang ◽  
Brittany Bolduc Lachance ◽  
Bilal Moiz ◽  
Xiaofeng Jia
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Cardiac Arrest ◽  
Stem Cell ◽  
Brain Injury ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Injury Treatment

Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

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