scholarly journals Erythropoietin  supports the growth and function of Sca-1+ stem cells and promotes myocardial infarction repair in mice

2020 ◽  
Author(s):  
Lin Zuo ◽  
Duan-duan Li ◽  
Xiu-Xia Ma ◽  
Shan-Hui Shi ◽  
Ding-Chao Lü ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Border Zone ◽  
Adult Mice ◽  
P38mapk Signaling ◽  
And Performance ◽  
Long Acting ◽  
And Function

Abstract Background：Myocardial infarction (MI) is the leading cause of death in the world-wide population. With the improvement of clinical therapy, the mortality in acute MI cases has been significantly reduced. This study was to demonstrate that erythropoietin (EPO) is an effective supporter for Sca-1+ stem cells (SCs) and can promote the repair of myocardial infarction (MI) partially via way of enhancing Sca-1+ SCs activities. Methods: Darbepoetin alpha (a long-acting EPO analog, EPOanlg) (30 mg/kg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocytes apoptosis and regenerations and microvessels density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mice hearts and were respectively used to identify the colony forming ability and the supporting effect of EPO on these Sca-1+ SCs. Results: Compared to MI alone, EPOanlg reduced the infarct percentage and cardiomyocyte apoptosis ratio and LV chamber dilatation, improved cardiac performance, increased the regenerated cardiomyocyte ratio in the border zone and the numbers of coronary microvessels, while without obvious adverse effects in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and Stat5-p38MAPK signaling. Conclusions: EPO promotes Sca-1+ SCs activities and MI repair. The study enlightens the prospects of Sca-1+ SC supporters in the treatment of MI.

scholarly journals Erythropoietin  supports the growth and function of Sca-1+ stem cells and promotes myocardial infarction repair in mice

2020 ◽  
Author(s):  
Lin Zuo ◽  
Duan-duan Li ◽  
Xiu-Xia Ma ◽  
Shan-Hui Shi ◽  
Ding-Chao Lü ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Border Zone ◽  
Adult Mice ◽  
P38mapk Signaling ◽  
And Performance ◽  
Long Acting ◽  
And Function

Abstract Background：Myocardial infarction (MI) is the leading cause of death in the world-wide population. With the improvement of clinical therapy, the mortality in acute MI cases has been significantly reduced. This study was to demonstrate that erythropoietin (EPO) is an effective supporter for Sca-1+ stem cells (SCs) and can promote the repair of myocardial infarction (MI) partially via the way of enhancing Sca-1+ SCs activities. Methods: Darbepoetin alpha (a long-acting EPO analog, EPOanlg) (30 mg/kg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocytes apoptosis and regenerations and microvessels density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mice hearts and were respectively used to identify the colony forming ability and the supporting effect of EPO on these Sca-1+ SCs. Results: Compared to MI alone, EPOanlg reduced the infarct percentage and cardiomyocyte apoptosis ratio and LV chamber dilatation, improved cardiac performance, increased the regenerated cardiomyocyte ratio in the border zone and the numbers of coronary microvessels, while without obvious adverse effects in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin- Sca-1+ SCs likely via the EPO receptor and Stat5-p38MAPK signaling. Conclusions: EPO promotes Sca-1+ SCs activities and MI repair. The study enlightens the prospects of Sca-1+ SC supporters in the treatment of MI.

Abstract 2672: Serial in vivo Non-invasive Imaging of Intramyocardially Injected Autologous Mesenchymal Stem Cells, Modified for Transgene Expression of Positron-Emission Tomography (PET) Reporter in Porcine Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mariann Gyongyosi ◽  
Jeronimo Blanco ◽  
Terez Marian ◽  
Ors Petnehazy ◽  
Rayyan Hemetsberger ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Pet Imaging ◽  
Transgene Expression ◽  
Lentiviral Vector ◽  
Border Zone ◽  
Percutaneous Balloon ◽  
Diffuse Distribution

Objective. The aim of our study was to elaborate an in vivo tracking method of the intramyocardially injected msenchymal stem cells (MSCs), modified for transgene expression of trifusion protein (lentiviral vector, expressing renilla luciferase /RL/, red fluoroscein protein /RFP/ and herpes simplex truncated thymidine kinase /tTK, positron emmission tomography PET-reporter gene/) using serial PET imaging in pig myocardial infarction (MI). Methods. Bone marrow (100 ml) was harvested from pigs immediately before induction of MI by percutaneous balloon occlusion of the LAD followed by reperfusion. The MSCs were selected and cultivated. The lentiviral vector LV-RL-RFP-tTK was inoculated into the MSCs under control of CMV promoter. The cells with the highest fluorescence intensity (after achieving appr. 50% transfection efficacy) were sorted, and tracked in vitro by PET using 9-(4-[18F]fluoro-3-hydroxymethylbutyl)-guanine (18FHBG). The transfected MSCs (at least 3 mio MSCs/ pigs) were then injected direct intramyocardially using NOGA electromagnetic guidance in pigs in 10 locations of the infarct border zone (min. 0.3 million cells/injection), followed by PET imaging 30 hours and 7 days later, after intravenous injection of 5 mCi 18FHBG. Results. The in vitro 18FHBG uptakes of the transgene modified MSCs by PET were 10 times larger than the control JY human B-lymphoblasts and T lymphocytes. The minimum number of the cells detectable with PET was 0.2 million. MRI of the pigs revealed a mean global EF of 47+/-3.5%. PET imaging displayed diffuse distribution of the injected MSCs with high activity of the PET tracer in the anterior wall and septum at 30h, and less tracer activity in the injections sites with diffuse distribution in the pericardium and pleura indicating the wandering of the living cells at 7 days. PET imaging did not show 18FHBG accumulation in the infarcted heart of the control animals. Myocardial histology with RL and RFP staining confirmed the distribution of the injected MSCs through an elongated track around the injected area, 9 days after delivery. Conclusion. In vivo tracking of gene-modified porcine MSCs by PET imaging is feasible and allows serial noninvasive imaging of homing and propagation of MSCs in pigs after MI.

Abstract 16596: Immune Evasion by Human Neonatal Cardiac Mesenchymal Stem Cells Demonstrates Therapeutic Application in Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muthukumar Gunasekaran ◽  
Rachana Mishra ◽  
Progyaparamita Saha ◽  
Aakash Shah ◽  
Lauren Davidson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Cell Retention ◽  
Over Expression ◽  
And Function

Immune rejection of transplanted stem cells is a major stumbling block in designing effective therapy for myocardial infarction. Human neonatal cardiac mesenchymal stem cells (nMSCs) showed superior cardiac functional recovery compared to adult MSCs in immune competent rat MI model. However, molecular mechanisms underlying immune evasion by transplanted nMSCs in the infarcted myocardium remain unexplored. In this investigation, we demonstrate for the first-time the expression, regulation and function of CD47 in human nMSCs and its novel mechanism of immune evasion increases its regenerative potential in rat MI model. Transplanted nMSCs showed significant increased cell retention, reduced phagocytosis and CD68 + cells compared to aMSCs in rat MI model. Comparative proteomic analysis by LC-MS/MS on nMSCs and aMSCs showed that CD47 higher in nMSCs. Increased CD47 expression in nMSCs inhibited phagocytosis compared to aMSCs in vitro and in vivo . Further, CD47 blockade in nMSCs using anti-CD47, siRNA and shRNA lentiviral based approaches increased in vitro , in vivo phagocytosis, CD68 + cells and reduced cell retention and MI recovery in vivo . Microarray analysis and validation showed miR-34a was significantly higher in aMSCs than nMSCs. To unravel CD47 regulation in aMSCs, we performed target scan analysis that predicted miR-34a binds on CD47. Further, miR-34a over expression in nMSCs reduced CD47 expression, increased in vitro and in vivo phagocytosis and reduced cell retention and MI recovery. In conclusion, increased CD47 expression in nMSCs inhibit phagocytosis by CD47/SIRPα immune regulatory axis to demonstrates its immune evasion potential and its therapeutic applications in myocardial infarction.

scholarly journals Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
HuiYa Li ◽  
DanQing Hu ◽  
Guilin Chen ◽  
DeDong Zheng ◽  
ShuMei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Paracrine Factors ◽  
Dual Treatment

AbstractBoth weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.

scholarly journals The chemokine GROβ mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 860-869 ◽  
Author(s):  
Seiji Fukuda ◽  
Huimin Bian ◽  
Andrew G. King ◽  
Louis M. Pelus
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
And Function ◽  
Stimulating Factor ◽  
Cxcr4 Axis

Abstract Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GROβ (GROβΔ4/CXCL2Δ4) or the combination of GROβΔ4 plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF–mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GROβ-mobilized grafts. PBSCs mobilized by GROβΔ4 alone or with G-CSF contained significantly more Sca-1+-c-kit+-lineage− (SKL) cells and more primitive CD34−-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GROβΔ4-mobilized SKL cells adhered better to VCAM-1+ endothelial cells compared with G-CSF–mobilized cells. GROβΔ4-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1α in vitro that was associated with higher CD26 expression. However, GROβΔ4-mobilized SKL and c-Kit+ lineage− (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GROβΔ4-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GROβΔ4-mobilized cells is less dependent on the SDF-1α/CXCR4 axis.

Constructing stem cell microenvironments using bioengineering approaches

2013 ◽  
Vol 45 (23) ◽  
pp. 1123-1135 ◽  
Author(s):  
David A. Brafman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Disease Modeling ◽  
Mechanical Stimuli ◽  
Culture Methods ◽  
Stem Cell Fate ◽  
And Function

Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored.

scholarly journals Expression and Function of Murine Receptor Tyrosine Kinases, TIE and TEK, in Hematopoietic Stem Cells

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4317-4326 ◽  
Author(s):  
Michihiro Yano ◽  
Atsushi Iwama ◽  
Hitoshi Nishio ◽  
Junko Suda ◽  
Goro Takada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Stem Cell Marker ◽  
Proliferative Potential ◽  
Hematopoietic Stem ◽  
And Function

Abstract Two highly related receptor tyrosine kinases, TIE and TEK, comprise a family of endothelial cell-specific kinase. We established monoclonal antibodies against them and performed detailed analyses on their expression and function in murine hematopoietic stem cells (HSCs). TIE and TEK were expressed on 23.7% and 33.3% of lineage marker-negative, c-Kit+ and Sca-1+ (Lin− c-Kit+ Sca-1+) HSCs that contain the majority of day-12 colony-forming units-spleen (CFU-S) and long-term reconstituting cells, but not committed progenitor cells. Lin− c-Kit+ Sca-1+ cells were further divided by the expression of TIE and TEK. TIE+ and TEK+ HSCs as well as each negative counterpart contained high proliferative potential colony-forming cells and differentiated into lymphoid and myeloid progenies both in vitro and in vivo. However, day-12 CFU-S were enriched in TIE+ and TEK+ HSCs. Our findings define TIE and TEK as novel stem cell marker antigens that segregate day-12 CFU-S, and provide evidence of novel signaling pathways that are involved in the functional regulation of HSCs at a specific stage of differentiation, particularly of day-12 CFU-S.

scholarly journals Chitosan as Functional Biomaterial for Designing Delivery Systems in Cardiac Therapies

Gels ◽  
2021 ◽  
Vol 7 (4) ◽  
pp. 253
Author(s):  
Bhaumik Patel ◽  
Ravi Manne ◽  
Devang B. Patel ◽  
Shashank Gorityala ◽  
Arunkumar Palaniappan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Tissue Engineering ◽  
Stem Cells ◽  
Cardiac Tissue ◽  
Mechanical Stability ◽  
Cardiac Tissue Engineering ◽  
Delivery Systems ◽  
Pharmaceutical Industries

Cardiovascular diseases are a leading cause of mortality across the globe, and transplant surgeries are not always successful since it is not always possible to replace most of the damaged heart tissues, for example in myocardial infarction. Chitosan, a natural polysaccharide, is an important biomaterial for many biomedical and pharmaceutical industries. Based on the origin, degree of deacetylation, structure, and biological functions, chitosan has emerged for vital tissue engineering applications. Recent studies reported that chitosan coupled with innovative technologies helped to load or deliver drugs or stem cells to repair the damaged heart tissue not just in a myocardial infarction but even in other cardiac therapies. Herein, we outlined the latest advances in cardiac tissue engineering mediated by chitosan overcoming the barriers in cardiac diseases. We reviewed in vitro and in vivo data reported dealing with drug delivery systems, scaffolds, or carriers fabricated using chitosan for stem cell therapy essential in cardiac tissue engineering. This comprehensive review also summarizes the properties of chitosan as a biomaterial substrate having sufficient mechanical stability that can stimulate the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering.

Abstract 217: Long Non-coding RNA Myocardial Infarction-associated Transcript (MIAT) Protects Cardiac Progenitor Cells From Oxidative Stress-induced Cell Death

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Liu Yang ◽  
Yang Yu ◽  
Baron Arnone ◽  
Chan Boriboun ◽  
Jiawei Shi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cell Death ◽  
Progenitor Cells ◽  
Cardiac Cells ◽  
Border Zone ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells

Background: Long non-coding RNAs (lncRNAs) are an emerging class of RNAs with no or limited protein-coding capacity; a few of which have recently been shown to regulate critical biological processes. Myocardial infarction-associated transcript (MIAT) is a conserved mammalian lncRNA, and single nucleotide polymorphisms (SNPs) in 6 loci of this gene have been identified to be strongly associated with the incidence and severity of human myocardial infarction (MI). However, whether and how MIAT impacts on the pathogenesis of MI is unknown. Methods & Results: Quantitative RT-PCR analyses revealed that MIAT is expressed in neonatal mouse heart and to a lesser extent in adult heart. After surgical induction of MI in adult mice, MIAT starts to increase in 2 hours, peaks at 6 hours in atria and 12 hours in ventricles, and decreases to baseline at 24 hours. Fluorescent in situ hybridization (FISH) revealed a slight increase in the number of MIAT-expressing cells in the infarct border zone at 12 hours post-MI. Moreover, qRT-PCR analyses of isolated cardiac cells revealed that MIAT is predominantly expressed in cardiosphere-derived cardiac progenitor cells (CPCs). Treatment of CPCs with H 2 O 2 led to a marked upregulation of MIAT, while knockdown (KD) of MIAT resulted in a significantly impaired cell survival in vitro with H 2 O 2 treatment and in vivo after administered in the ischemic/reperfused heart. Notably, bioinformatics prediction and RNA immunoprecipitation identified FUS (fused in sarcoma) as a novel MIAT-interacting protein. FUS-KD CPCs displayed reduced cell viability and increased apoptosis under oxidative stress. Furthermore, MIAT overexpression enhanced survival of WT CPCs but not FUS-KD CPCs, suggesting that the protective role of MIAT is mediated by FUS. Conclusions: MIAT interacts with FUS to protect CPCs from oxidative stress-induced cell death.

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