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 The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury

2019 ◽  
Vol 20 (14) ◽  
pp. 3529 ◽  
Author(s):  
Kuo-Hua Lee ◽  
Wei-Cheng Tseng ◽  
Chih-Yu Yang ◽  
Der-Cherng Tarng
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Kidney Injury ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Therapeutic Benefits ◽  
Anti Inflammatory

Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI.

scholarly journals Is Stem Cell a Curer or an Obstruction?

2017 ◽  
Vol 1 (1) ◽  
pp. 17
Author(s):  
Siska Damayanti ◽  
Rina Triana ◽  
Angliana Chouw ◽  
Nurrani Mustika Dewi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Embryonic Stem ◽  
Cell Types ◽  
Tumor Formation ◽  
The Body ◽  
Negative Effects ◽  
Tissue Repair And Regeneration

Introduction: Each cell in human body is assigned with a specialized function to perform.  Before a cell becomes specialized, it is a stem cell. Stem cell research and therapy is progressing dramatically these days. Stem cell therapy holds enormous treatment potential for many diseases which currently have no or limited therapeutic options. Unfortunately, this potential also comes with side-effects. In this review, the positive and negative effects of regulation of stem cells will be explained.Content: Stem cells are undifferentiated cells that have potential to develop into many different cell types in the body during early life and growth. The type of stem cells are embryonic stem cells, induced pluripotent stem cells, somatic stem cells, foetal stem cells and mesenchymal stem cells. Stem cell transplantation is one form of stem cell therapy, it comes with different sources, and those are autologous and allogenic transplantation stem cells. In an autologous transplant, a patient’s own blood-forming stem cells are collected, meanwhile in an allogeneic transplant, a person’s stem cells are replaced with new stem cells obtained from a donor or from donated umbilical cord blood.Summary: Its abilities to maintain undifferentiated phenotype, self-renewing and differentiate itself into specialized cells, give rise to stem cell as a new innovation for the treatment of various diseases. In the clinical setting, stem cells are being explored in various conditions, such as in tissue repair and regeneration and autoimmune diseases therapy. But along with its benefit, stem cell therapy also holds some harm. It is known that the treatment using stem cell for curing and rehabilitation has the risk in tumor formation.

scholarly journals Constructing a cell microenvironment with biomaterial scaffolds for stem cell therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaotong Zhao ◽  
Qiong Li ◽  
Zhikun Guo ◽  
Zongjin Li
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Survival Rates ◽  
Therapeutic Effects ◽  
Tissue Repair And Regeneration ◽  
Promising Strategy ◽  
Biomaterial Scaffolds ◽  
A Cell

AbstractStem cell therapy is widely recognized as a promising strategy for exerting therapeutic effects after injury in degenerative diseases. However, limitations such as low cell retention and survival rates after transplantation exist in clinical applications. In recent years, emerging biomaterials that provide a supportable cellular microenvironment for transplanted cells have optimized the therapeutic efficacy of stem cells in injured tissues or organs. Advances in the engineered microenvironment are revolutionizing our understanding of stem cell-based therapies by co-transplanting with synthetic and tissue-derived biomaterials, which offer a scaffold for stem cells and propose an unprecedented opportunity to further employ significant influences in tissue repair and regeneration.

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.

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.

scholarly journals Stem cells in the treatment of patients with coronary heart disease. Part I

2011 ◽  
Vol 10 (2) ◽  
pp. 122-128 ◽  
Author(s):  
N. S. Zhukova ◽  
I. I. Staroverov
Keyword(s):  
Stem Cells ◽  
Coronary Heart Disease ◽  
Stem Cell ◽  
Heart Disease ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Myocardial Damage ◽  
Cellular Cardiomyoplasty ◽  
Modern Methods ◽  
Death Causes

Heart failure (HF) is one of the leading death causes in patients with myocardial infarction (MI). The modern methods of reperfusion MI therapy, such as thrombolysis, surgery and balloon revascularization, even when performed early, could fail to prevent the development of large myocardial damage zones, followed by HF. Therefore, the researches have been searching for the methods which improve functional status of damaged myocardium. This review is focused on stem cell therapy, a method aimed at cardiac function restoration. The results of experimental and clinical studies on stem cell therapy in coronary heart disease are presented. Various types of stem cells, used for cellular cardiomyoplasty, are characterised. The methods of cell transplantation into myocardium and potential adverse effects of stem cell therapy are discussed.

scholarly journals Intestinal myofibroblasts: targets for stem cell therapy

2011 ◽  
Vol 300 (5) ◽  
pp. G684-G696 ◽  
Author(s):  
R. C. Mifflin ◽  
I. V. Pinchuk ◽  
J. I. Saada ◽  
D. W. Powell
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Stem Cell ◽  
Cell Therapy ◽  
Lamina Propria ◽  
Stem Cell Therapy ◽  
Intestinal Inflammation ◽  
Mesenchymal Cells ◽  
Hematopoietic Stem ◽  
Intestinal Lamina Propria

The subepithelial intestinal myofibroblast is an important cell orchestrating many diverse functions in the intestine and is involved in growth and repair, tumorigenesis, inflammation, and fibrosis. The myofibroblast is but one of several α-smooth muscle actin-positive (α-SMA+) mesenchymal cells present within the intestinal lamina propria, including vascular pericytes, bone marrow-derived stem cells (mesenchymal stem cells or hematopoietic stem cells), muscularis mucosae, and the lymphatic pericytes (colon) and organized smooth muscle (small intestine) associated with the lymphatic lacteals. These other mesenchymal cells perform many of the functions previously attributed to subepithelial myofibroblasts. This review discusses the definition of a myofibroblast and reconsiders whether the α-SMA+ subepithelial cells in the intestine are myofibroblasts or other types of mesenchymal cells, i.e., pericytes. Current information about specific, or not so specific, molecular markers of lamina propria mesenchymal cells is reviewed, as well as the origins of intestinal myofibroblasts and pericytes in the intestinal lamina propria and their replenishment after injury. Current concepts and research on stem cell therapy for intestinal inflammation are summarized. Information about the stem cell origin of intestinal stromal cells may inform future stem cell therapies to treat human inflammatory bowel disease (IBD).

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