Myocardial repair of bioengineered cardiac patches with decellularized placental scaffold and human-induced pluripotent stem cells in a rat model of myocardial infarction

Abstract Background The creation of a bioengineered cardiac patch (BCP) is a potential novel strategy for myocardial repair. Nevertheless, the ideal scaffold for BCP is unknown. Objective We investigated whether the decellularized placenta (DP) could serve as natural scaffold material to create a BCP for myocardial repair. Methods and results A BCP was created by seeding human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs; 1 × 106/cm2) onto DP. The functional and electrophysiological properties of the BCP were first characterized by in vitro analysis and optical mapping. Next, in vivo therapeutic efficacy of the BCP was evaluated in a rat model of myocardial infarction (MI), created by left descending coronary artery ligation (MI + BCP group), and compared with MI alone (MI group), transplantation of DP (MI + DP group), and hiPSC-CMs (MI + CM group). Cytokine profiling demonstrated that the BCP contained multiple growth and angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, basic fibroblast growth factor, angiogenin, and angiopoietin-2. In vitro optical mapping showed that the BCP exhibited organized mechanical contraction and synchronized electrical propagation. RNA sequencing showed that DP enhanced the maturation of hiPSC-CMs compared with the monolayer of cultured hiPSC-CMs. At 4 weeks follow-up, the BCP significantly improved left ventricular (LV) function, as determined by LV ejection fraction, fractional shortening, + dP/dtmax, and end-systolic pressure-volume relationship, compared with the MI, MI + DP, and MI + CM groups. Moreover, histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI + DP, and MI + CM groups. Conclusions Our results demonstrate that a DP scaffold contains multiple growth and angiogenic factors that enhance the maturation and survival of seeded hiPSC-CMs. Transplantation of a BCP is superior to DP or hiPSC-CMs alone in reducing infarct size and improving cell retention and neovascularization, thus providing a novel therapy for myocardial repair following MI.

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Mesenchymal Stem Cells Enhanced Cardiac Nerve Sprouting via Nerve Growth Factor in a Rat Model of Myocardial Infarction

Current Pharmaceutical Design ◽

10.2174/13816128113199990451 ◽

2014 ◽

Vol 20 (12) ◽

pp. 2023-2029 ◽

Cited By ~ 4

Author(s):

Jian Chen ◽

Shaoxin Zheng ◽

Hui Huang ◽

Suihua Huang ◽

Changqing Zhou ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Nerve Growth Factor ◽

Growth Factor ◽

Rat Model ◽

Nerve Growth ◽

Cardiac Nerve ◽

Nerve Sprouting

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Engineered Stem Cells Improve Neurogenic Bladder by Overexpressing SDF-1 in a Pelvic Nerve Injury Rat Model

Cell Transplantation ◽

10.1177/0963689720902466 ◽

2020 ◽

Vol 29 ◽

pp. 096368972090246 ◽

Cited By ~ 2

Author(s):

Guan Qun Zhu ◽

Seung Hwan Jeon ◽

Kyu Won Lee ◽

Hyuk Jin Cho ◽

U-Syn Ha ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Neurogenic Bladder ◽

Rat Model ◽

Bladder Wall ◽

Bladder Function ◽

Pelvic Nerve ◽

Injured Nerve

There is still a lack of sufficient research on the mechanism behind neurogenic bladder (NB) treatment. The aim of this study was to explore the effect of overexpressed stromal cell-derived factor-1 (SDF-1) secreted by engineered immortalized mesenchymal stem cells (imMSCs) on the NB. In this study, primary bone marrow mesenchymal stem cells (BM-MSCs) were transfected into immortalized upregulated SDF-1-engineered BM-MSCs (imMSCs/eSDF-1+) or immortalized normal SDF-1-engineered BM-MSCs (imMSCs/eSDF-1−). NB rats induced by bilateral pelvic nerve (PN) transection were treated with imMSCs/eSDF-1+, imMSCs/eSDF-1−, or sham. After a 4-week treatment, the bladder function was assessed by cystometry and voiding pattern analysis. The PN and bladder tissues were evaluated via immunostaining and western blotting analysis. We found that imMSCs/eSDF-1+ expressed higher levels of SDF-1 in vitro and in vivo. The treatment of imMSCs/eSDF-1+ improved NB and evidently stimulated the recovery of bladder wall in NB rats. The recovery of injured nerve was more effective in the NB+imMSCs/eSDF-1+ group than in other groups. High SDF-1 expression improved the levels of vascular endothelial growth factor and basic fibroblast growth factor. Apoptosis was decreased after imMSCs injection, and was detected rarely in the NB+imMSCs/eSDF-1+ group. Injection of imMSCs boosted the expression of neuronal nitric oxide synthase, p-AKT, and p-ERK in the NB+imMSCs/eSDF-1+ group than in other groups. Our findings demonstrated that overexpression of SDF-1 induced additional MSC homing to the injured tissue, which improved the NB by accelerating the restoration of injured nerve in a rat model.

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Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

Cells ◽

10.3390/cells9020295 ◽

2020 ◽

Vol 9 (2) ◽

pp. 295 ◽

Cited By ~ 2

Author(s):

Bernhard Wernly ◽

Vera Paar ◽

Achim Aigner ◽

Patrick M Pilz ◽

Bruno K Podesser ◽

...

Keyword(s):

Myocardial Infarction ◽

T Cell ◽

Rat Model ◽

Mirna Expression ◽

Cell Epitope ◽

Enzyme Linked Immunosorbent Assay ◽

Antibody Treatment ◽

Scar Size

Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

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The Wnt Inhibitor sFRP2 Enhances Mesenchymal Stem Cell Engraftment, Granulation Tissue Formation and Myocardial Repair

Blood ◽

10.1182/blood.v112.11.1365.1365 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1365-1365

Author(s):

Maria Paula Alfaro ◽

Matthew Pagni ◽

Alicia Vincent ◽

Michael F. Hill ◽

Ethan Lee ◽

...

Keyword(s):

Infarct Size ◽

Granulation Tissue ◽

Myocardial Infarct ◽

Left Ventricular ◽

Human Mscs ◽

Myocardial Repair ◽

Acute Myocardial Infarct ◽

Intramyocardial Injection

Abstract Cell-based therapies using bone marrow-derived mesenchymal stem cells (MSCs) for organ regeneration are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. In an attempt to elucidate a way to strengthen the regenerative potential of MSCs, preliminary studies in our lab were performed comparing MSCs isolated from wildtype and regenerative mouse strains. The MRL/MpJ mouse has been described as a “super healer” mouse that is able to repair soft tissue with minimal scaring. MSCs were isolated from the MRL/MpJ mouse (MRL-MSCs) and from C57/Bl6 mice (WT-MSCs) and their differing qualities assessed. Compared to WT-MSCs, MRL-MSCs demonstrated increased proliferation in vitro. We utilized a Poly-vinyl alcohol (PVA) sponge model of repair stimulation to assess their capacity to generate wound repair tissue. We observed that the MRL-MSCs demonstrated increased in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity. The MRL-MSCs also reduced infarct size and improved cardiac function as compared to WT-MSCs in a murine acute myocardial infarct model. Genomic and functional analyses indicated a downregulation of the canonical Wnt pathway in MRL-MSCs characterized specifically by upregulation of secreted frizzled related proteins (sFRPs). In vitro proliferation studies confirmed that recombinant sFRP2 mediated enhanced proliferation of both mouse and human MSCs. Based on these observations, we hypothesized that sFRP2 served an important role in MSC-mediated repair and regeneration. We generated WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction to test this hypothesis. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and proliferated faster than the vector only control MSCs (GFP-MSCs). When implanted in vivo in the PVA sponge model, the sFRP2-MSCs recapitulated the MRL phenotype by mediating greater, more vascularized granulation tissue. Moreover, periinfarct intramyocardial injection of sFRP2-MSCs resulted in reduced infarct size, favorable remodeling and better preserved left ventricular function following acute myocardial infarct in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype of MSCs.

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