Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses

Background: Recently, human multipotent adipose-derived stem cells (hMADSs) have been isolated featuring extensive expansion capacity ex vivo. However, little is known about the therapeutic efficacy of hMADS in ischemic heart diseases. We tested the hypothesis that hMADS transplantation may contribute to cardiac functional recovery following myocardial infarction (MI). Methods and Results: Nude rats were either transplanted with hMADSs (5x10 5 /rat, n=10) or PBS (control, n=9) in ischemic myocardium immediately following MI induction. The cardiac function, infarct size and capillary density in the peri-infarct area were evaluated by echocardiography and immunostaining 28 days after surgery. The cardiac function was significantly greater with increased capillary density and reduced fibrosis area in the hMADS group than that in the control group. Next, we examined tissue regeneration in the infarct heart by the transplanted hMADSs. However, remarkable differentiation of hMADSs into any cardiac cell lineages was not detected. To explore another mechanism for the favorable effect of hMADSs, we further examined mRNA expression of cytokines in hMADSs under hypoxic conditions. Although hypoxia decreased the expressions, robust VEGF, bFGF, and SDF-1α expressions were detected in hMADSs. Notably, the stem/progenitor chemokine SDF-1α expression in hMADSs was significantly greater than that in human mesenchymal stem cells that are well known to have a therapeutic effect on ischemic heart diseases. We then focused on SDF-1α /CXCR4 axis and examined the contribution of bone marrow (BM)-derived endothelial progenitor cells (EPCs), that have CXCR4 receptor for SDF-1v, to ischemic myocardium using a Tie2/LacZ BM transplantation nude mouse model. β-gal positive EPCs are frequently observed in ischemic myocardium in the hMADS group compared to the control group. Conclusion: hMADSs exhibit a therapeutic effect on cardiac function following MI with the production of VEGF, bFGF, and SDF-1α demonstrating paracrine effects rather than direct contribution to cardiac regeneration. These findings suggest that transplanted hMADSs and recruited EPCs may synergistically promote angiogenesis playing a role in ischemic myocardium.

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Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction

Chinese Medical Journal ◽

10.1097/00029330-200702020-00009 ◽

2007 ◽

Vol 120 (4) ◽

pp. 300-307 ◽

Cited By ~ 47

Author(s):

Duan-zhen ZHANG ◽

Lu-yue GAI ◽

Hong-wei LIU ◽

Qin-hua JIN ◽

Jian-hua HUANG ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Cardiac Function ◽

Adipose Derived Stem Cells

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Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01082.2008 ◽

2009 ◽

Vol 297 (3) ◽

pp. H1020-H1031 ◽

Cited By ~ 90

Author(s):

Lei Wang ◽

Jixian Deng ◽

Weichen Tian ◽

Bo Xiang ◽

Tonghua Yang ◽

...

Keyword(s):

Stem Cells ◽

Growth Factor ◽

Cardiac Function ◽

Recovery Period ◽

Capillary Density ◽

Left Ventricular ◽

Border Zone ◽

Wall Thickening ◽

Adipose Derived Stem Cells ◽

Rat Hearts

This study assessed the potential therapeutic efficacy of adipose-derived stem cells (ASCs) on infarcted hearts. Myocardial infarction was induced in rat hearts by occlusion of the left anterior descending artery (LAD). One week after LAD occlusion, the rats were divided into three groups and subjected to transplantation of ASCs or transplantation of cell culture medium (CCM) or remained untreated. During a 1-mo recovery period, magnetic resonance imaging showed that the ASC-treated hearts had a significantly greater left ventricular (LV) ejection fraction and LV wall thickening than did the CCM-treated and untreated hearts. The capillary density in infarct border zone was significantly higher in the ASC-treated hearts than in the CCM-treated and untreated hearts. However, only 0.5% of the ASCs recovered from the ASC-treated hearts were stained positive for cardiac-specific fibril proteins. It was also found that ASCs under a normal culture condition secreted three cardiac protective growth factors: vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1. Results of this study suggest that ASCs were able to improve cardiac function of infarcted rat hearts. Paracrine effect may be the mechanism underlying the improved cardiac function and increased capillary density.

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Pharmacological priming of adipose-derived stem cells promotes myocardial repair

Journal of Investigative Medicine ◽

10.1136/jim-2015-000018 ◽

2016 ◽

Vol 64 (1) ◽

pp. 50-62 ◽

Cited By ~ 6

Author(s):

Jana S Burchfield ◽

Ashley L Paul ◽

Vishy Lanka ◽

Wei Tan ◽

Yongli Kong ◽

...

Keyword(s):

Stem Cells ◽

Cardiac Function ◽

Functional Recovery ◽

Cardiac Myocyte ◽

Left Ventricular ◽

Adipose Derived Stem Cells ◽

Myocardial Repair ◽

Myocyte Differentiation

Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.

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Preservation of the cardiac function in infarcted rat hearts by the transplantation of adipose-derived stem cells with injectable fibrin scaffolds

Experimental Biology and Medicine ◽

10.1258/ebm.2010.010175 ◽

2010 ◽

Vol 235 (12) ◽

pp. 1505-1515 ◽

Cited By ~ 61

Author(s):

Xuelian Zhang ◽

Haibin Wang ◽

Xiang Ma ◽

Azhati Adila ◽

Baozhu Wang ◽

...

Keyword(s):

Stem Cells ◽

Cardiac Function ◽

Adipose Derived Stem Cells ◽

Rat Hearts

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Self-Renewal and Differentiation of Adipose-Derived Stem Cells (ADSCs) Stimulated by Multi-Axial Tensile Strain in a Pneumatic Microdevice

10.20944/preprints201809.0503.v1 ◽

2018 ◽

Author(s):

Chih-Hao Chiu ◽

Yun-Wen Tong ◽

Wen-Ling Yeh ◽

Kin Fong Lei ◽

Alvin Chao-Yu Chen

Keyword(s):

Stem Cells ◽

Tensile Strain ◽

Soft Tissues ◽

Inflammatory Responses ◽

Adipose Derived Stem Cells ◽

Cell Viability Assay ◽

Self Renewal ◽

Viability Assay ◽

Axial Tensile ◽

Mechanical Tensile

Adipose-derived stem cells (ADSCs) were suggested for treating degenerative osteoarthritis, suppressing inflammatory responses, and repairing damaged soft tissues. Moreover, the ADSCs have the potential to undergo self-renewal and differentiate into bone, tendon, cartilage, and ligament. Recently, investigation of the self-renewal and differentiation of the ADSCs becomes an attractive area. In this work, a pneumatic microdevice has been developed to study the gene expression of the ADSCs after the stimulation of multi-axial tensile strain. The ADSCs were cultured on the microdevice and experienced multi-axial tensile strain during a 3-day culture course. Self-renewal and differentiation abilities were investigated by mRNA expressions of NANOG, SOX2, OCT4, SOX9, PPAR-γ, and RUNX2. The result showed that the genes related self-renewal were significantly up-regulated after the tensile stimulation. Higher proliferation ratio of the ADSCs was also shown by cell viability assay. The microdevice provides a promising platform for cell-based study under mechanical tensile stimulation.

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Adipose-derived stem cells significantly improve cardiac function of the infarct rat hearts

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2007.03.210 ◽

2007 ◽

Vol 42 (6) ◽

pp. S97 ◽

Cited By ~ 1

Author(s):

L Wang ◽

J Deng ◽

G Li ◽

J Wang ◽

B Xiang ◽

...

Keyword(s):

Stem Cells ◽

Cardiac Function ◽

Adipose Derived Stem Cells ◽

Rat Hearts

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Self-Renewal and Differentiation of Adipose-Derived Stem Cells (ADSCs) Stimulated by Multi-Axial Tensile Strain in a Pneumatic Microdevice

Micromachines ◽

10.3390/mi9110607 ◽

2018 ◽

Vol 9 (11) ◽

pp. 607 ◽

Cited By ~ 1

Author(s):

Chih-Hao Chiu ◽

Yun-Wen Tong ◽

Wen-Ling Yeh ◽

Kin Lei ◽

Alvin Chen

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Tensile Strain ◽

Soft Tissues ◽

Inflammatory Responses ◽

Peroxisome Proliferator ◽

Adipose Derived Stem Cells ◽

Cell Viability Assay ◽

Self Renewal ◽

Axial Tensile

Adipose-derived stem cells (ADSCs) were suggested for treating degenerative osteoarthritis, suppressing inflammatory responses, and repairing damaged soft tissues. Moreover, the ADSCs have the potential to undergo self-renewal and differentiate into bone, tendon, cartilage, and ligament. Recently, investigation of the self-renewal and differentiation of the ADSCs has become an attractive area. In this work, a pneumatic microdevice has been developed to study the gene expression of the ADSCs after the stimulation of multi-axial tensile strain. The ADSCs were cultured on the microdevice and experienced multi-axial tensile strain during a three-day culture course. Self-renewal and differentiation abilities were investigated by mRNA expressions of NANOG, sex determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), sex determining region Y-box9 (SOX9), peroxisome proliferator-activated receptor gamma (PPAR-γ), and runt-related transcription factor 2 (RUNX2). The result showed that the genes related self-renewal were significantly up-regulated after the tensile stimulation. Higher proliferation ratio of the ADSCs was also shown by cell viability assay. The microdevice provides a promising platform for cell-based study under mechanical tensile stimulation.

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Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1353-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 10

Author(s):

Peisen Huang ◽

Li Wang ◽

Qing Li ◽

Jun Xu ◽

Junyan Xu ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Stem Cells ◽

Stem Cell ◽

Cardiac Function ◽

Inflammatory Responses ◽

Heart Function ◽

Border Zone ◽

Inflammatory Factor ◽

Intramyocardial Injection

Abstract Background Bone marrow mesenchymal stem cells (MSCs) are among the most common cell types to be used and studied for cardiac regeneration. Low survival rate and difficult retention of delivered MSCs in infarcted heart remain as major challenges in the field. Co-delivery of stem cell-derived exosomes (Exo) is expected to improve the recruitment and survival of transplanted MSCs. Methods Exo was isolated from MSCs and delivered to an acute myocardial infarction (AMI) rat heart through intramyocardial injection with or without intravenous infusion of atrovastatin-pretreated MSCs on day 1, day 3, or day 7 after infarction. Echocardiography was performed to evaluate cardiac function. Histological analysis and ELISA test were performed to assess angiogenesis, SDF-1, and inflammatory factor expression in the infarct border zone. The anti-apoptosis effect of Exo on MSCs was evaluated using flow cytometry and Hoechst 33342 staining assay. Results We found that intramyocardial delivery of Exo followed by MSC transplantation (in brief, Exo+MSC treatment) into MI hearts further improved cardiac function, reduced infarct size, and increased neovascularization when compared to controls treated with Exo or MSCs alone. Of note, comparing the three co-transplanting groups, intramyocardially injecting Exo 30 min after AMI combined with MSCs transplantation at day 3 after AMI achieved the highest improvement in heart function. The observed enhanced heart function is likely due to an improved microenvironment via Exo injection, which is exemplified as reduced inflammatory responses and better MSC recruitment and retention. Furthermore, we demonstrated that pre-transplantation injection of Exo enhanced survival of MSCs and reduced their apoptosis both in vitro and in vivo. Conclusions Combinatorial delivery of exosomes and stem cells in a sequential manner effectively reduces scar size and restores heart function after AMI. This approach may represent as an alternative promising strategy for stem cell-based heart repair and therapy.

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