Abstract 679: Pdgf/snail-mediated Endothelial Plasticity Drives Non-productive Neovascularization and Impedes Tissue Repair After Myocardial Infarction

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

Download Full-text

Abstract 13: Plasminogen Is Required for Hematopoietic Stem Cell-Mediated Cardiac Repair After Myocardial Infarction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a13 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Yanqing Gong ◽

Jane Hoover-Plow ◽

Ying Li

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Tissue Repair ◽

Critical Role ◽

Cardiac Repair ◽

Internal Diameter ◽

Hematopoietic Stem

Ischemic heart disease, including myocardial infarction (MI), is the primary cause of death throughout the US. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize hematopoietic progenitor and stem cells (HPSC) to improve cardiac recovery after MI. However, poor-mobilization to G-CSF is observed in 25% of patients and 10-20% of healthy donors. Therefore, a better understanding of the underlying mechanisms regulating G-CSF-induced cardiac repair may offer novel approaches for strengthening stem cell-mediated therapeutics. Our previous studies have identified an essential role of Plg in HPSC mobilization from bone marrow (BM) in response to G-CSF. Here, we investigate the role of Plg in G-CSF-stimulated cardiac repair after MI. Our data show that G-CSF significantly improves cardiac tissue repair including increasing neovascularization in the infarct area, and improving ejection fraction and LV internal diameter by echocardiogram in wild-type mice. No improvement in tissue repair and heart function by G-CSF is observed in Plg -/- mice, indicating that Plg is required for G-CSF-regulated cardiac repair after MI. To investigate whether Plg regulates HPSC recruitment to ischemia area, bone marrow transplantion (BMT) with EGFP-expressing BM cells was performed to visualize BM-derived stem cells in infarcted tissue. Our data show that G-CSF dramatically increases recruitment of GFP+ cells (by 16 fold) in WT mice but not in Plg -/- mice, suggesting that Plg is essential for HPSC recruitment from BM to the lesion sites after MI. In further studies, we investigated the role of Plg in the regulation of SDF-1/CXCR-4 axis, a major regulator for HPSC recruitment. Our results show that G-CSF significantly increases CXCR-4 expression in infarcted area in WT mice. While G-CSF-induced CXCR-4 expression is markedly decreased (80%) in Plg -/- mice, suggesting Plg may regulate CXCR-4 expression during HSPC recruitment to injured heart. Interestingly, Plg does not affect SDF-1 expression in response to G-CSF treatment. Taken together, our findings have identified a critical role of Plg in HSPC recruitment to the lesion site and subsequent tissue repair after MI. Thus, targeting Plg may offer a new therapeutic strategy to improve G-CSF-mediated cardiac repair after MI.

Download Full-text

Stem cell-derived cell sheet transplantation for heart tissue repair in myocardial infarction

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1536-y ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 6

Author(s):

Rui Guo ◽

Masatoshi Morimatsu ◽

Tian Feng ◽

Feng Lan ◽

Dehua Chang ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cell ◽

Tissue Repair ◽

Cardiac Tissue ◽

Cell Sheet ◽

Clinical Manifestations ◽

Induced Pluripotent Stem Cell ◽

Heart Tissue ◽

Therapeutic Effects ◽

Cell Sheets

AbstractStem cell-derived sheet engineering has been developed as the next-generation treatment for myocardial infarction (MI) and offers attractive advantages in comparison with direct stem cell transplantation and scaffold tissue engineering. Furthermore, induced pluripotent stem cell-derived cell sheets have been indicated to possess higher potential for MI therapy than other stem cell-derived sheets because of their capacity to form vascularized networks for fabricating thickened human cardiac tissue and their long-term therapeutic effects after transplantation in MI. To date, stem cell sheet transplantation has exhibited a dramatic role in attenuating cardiac dysfunction and improving clinical manifestations of heart failure in MI. In this review, we retrospectively summarized the current applications and strategy of stem cell-derived cell sheet technology for heart tissue repair in MI.

Download Full-text

P5374Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice

European Heart Journal ◽

10.1093/eurheartj/ehz746.0337 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Yamamoto ◽

H Yasukawa ◽

J Takahashi ◽

S Nohara ◽

T Sasak ◽

...

Keyword(s):

Myocardial Infarction ◽

Real Time ◽

Real Time Pcr ◽

Tissue Repair ◽

Repair Process ◽

Cardiac Rupture ◽

Blue Dye ◽

Border Area ◽

Infarct Area

Abstract Background Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which mainly targets epithelial cells and does not target immune cells. Recently, it has been reported that IL-22 play roles in tissue repair in the skin and the liver; however, role of IL-22 in the process of tissue repair after myocardial infarction (MI) is unknown. Here, we investigated the role of IL-22 in tissue repair process after MI. Methods and results First, we examined the expression of IL-22 and its receptor IL-22RA1 in the wild type (WT) mice by real-time PCR. The expression of IL-22 and IL-22RA1 in the hearts were significantly increased 3 days after MI (p<0.05). To clarify the role of IL-22 in the heart after MI, we produced MI model in the WT mice and IL-22 knockout (KO) mice. We found that the IL-22 KO mice had significantly higher mortality than the WT mice after MI (p<0.05). Approximately 80% of the IL-22 KO mice died with cardiac rupture after MI. The infarct size which was estimated by evans blue dye and triphenyltetrazolium chloride staining at 3 days after MI was comparable between the IL-22 KO mice and the WT mice. Next, we performed real time PCR and PCR array analysis for tissue fibrosis and repair genes. We found that alpha-smooth muscle actin (aSMA), NF-kB, TNF-a and MMP13 (also known as collagenase-3) were significantly increased in the infarct area of IL-22 KO mice compared to WT mice. Immunostaining showed that the myofibroblast marker aSMA positive cells in the border area after MI were markedly higher in the IL-22 KO mice compared with the WT mice (p<0.05). Approximately 70% of cardiac rupture after MI in the IL-22 KO mice were occurred in the infarct area adjacent to the border area. Furthermore, we found aSMA positive cells and MMP13 positive cells around the ruptured site of the heart. Conclusion Thus, IL-22 KO mice exhibit high mortality and increased cardiac rupture after MI. And expression of aSMA and MMP13 were highly expressed in the ruptured site after MI in the IL-22 KO mice. These results suggest that IL-22 may play an important role in the tissue repair process after MI.

Download Full-text

S1P–S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair and Functional Recovery After Acute Myocardial Infarction

Circulation Research ◽

10.1161/circresaha.117.311648 ◽

2018 ◽

Vol 122 (8) ◽

pp. 1069-1083 ◽

Cited By ~ 33

Author(s):

Yoshihisa Yamada ◽

Shohei Wakao ◽

Yoshihiro Kushida ◽

Shingo Minatoguchi ◽

Atsushi Mikami ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Functional Recovery ◽

Tissue Repair ◽

Muse Cells

Download Full-text

PEMANFAATAN SEL PUNCA PADA INFARK MIOKARD

JURNAL BIOMEDIK (JBM) ◽

10.35790/jbm.3.1.2011.854 ◽

2013 ◽

Vol 3 (1) ◽

Author(s):

Loretta C. Wangko ◽

J. H. Awaloei ◽

Janry A. Pangemanan

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Stem Cell ◽

Growth Factors ◽

Tissue Repair ◽

Heart Function ◽

Improve Heart Function ◽

Β Blockers ◽

Causes Of Deaths ◽

Myocardial Thickness

Abstract: World-wide, myocardial infarction and heart failure are still the leading causes of deaths and use up a great deal of money. In myocardial infarction there frequently incur cardiomyocyte injuries. Naturally, resident cardiomyocytes will undergo proliferation and contribute to the increasing and repairing of myocardium post infarction. Unfortunately, this capacity of regeneration is very limited. Moreover, injured cardiomyocytes are replaced by scar tissues. Pharmacotherapy with ACE-Inhibitors and β blockers can give some clinical improvement, but can not inhibit the loss of cardiomyocytes. Nowadays, stem cell therapy has proclaimed some promising benefits. Among all the introduced stem cells, mesenchymal stem cells are the most popular since they have the capability to differentiate and then to develop into cardiomyocytes, maintain the myocardial thickness, reduce heart remodeling of the non infarct myocardium, improve heart function, and can be used from allogenic donors. Besides that, these cells are easier to obtain and isolate, are genetically stable, have the capacity for angiogenesis, homing to the injured areas or inflammation, and supplying growth factors and cytokines for tissue repair. Key words: stem cell, cardiomyocyte, transplantation, donor. Abstrak: Infark miokard dan gagal jantung masih merupakan penyebab kematian utama di dunia dan menyerap biaya pengobatan yang tinggi. Pada infark miokard sering terjadi cedera kardiomiosit. Secara alamiah kardiomiosit residen akan mengalami proliferasi dan mengambil bagian dalam meningkatkan dan memulihkan miokard pasca infark. Kapasitas regenerasi ini sangat terbatas. Selain itu kardiomiosit yang cedera akan digantikan oleh jaringan ikat. Farmakoterapi dengan penghambat ACE dan β bloker dapat memberikan perbaikan klinis, tetapi tidak dapat menghambat kehilangan kardiomiosit. Dewasa ini terapi sel punca telah mengumandangkan manfaat yang menjanjikan. Dari berbagai sel punca yang dikemukakan, sel punca mesensimal yang paling diminati oleh karena kemampuannya berdiferensiasi dan berkembang menjadi kardiomiosit, mempertahankan ketebalan miokard, menurunkan remodeling jantung pada bagian yang tidak infark, memperbaiki fungsi jantung. dan dapat diambil dari donor alogenik. Disamping itu, sel-sel ini lebih mudah diperoleh dan diisolasi, stabil secara genetik, berkapasitas angiogenesis, homing ke tempat cedera atau inflamasi, dan memasok growth factors dan sitokin untuk perbaikan jaringan. Kata kunci: sel punca, kardiomiosit, transplantasi, donor.

Download Full-text

No hearty reception: infusion of CXCL4 impedes tissue repair by macrophages after myocardial infarction

Cardiovascular Research ◽

10.1093/cvr/cvy241 ◽

2018 ◽

Vol 115 (2) ◽

pp. 264-265

Author(s):

Rory R Koenen

Keyword(s):

Myocardial Infarction ◽

Tissue Repair

Download Full-text

Angiogenesis after acute myocardial infarction

Cardiovascular Research ◽

10.1093/cvr/cvaa287 ◽

2020 ◽

Author(s):

Xuekun Wu ◽

Marc R Reboll ◽

Mortimer Korf-Klingebiel ◽

Kai C Wollert

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Tissue Repair ◽

Left Ventricular ◽

Lineage Tracing ◽

Border Zone ◽

Angiogenic Response ◽

Mechanistic Understanding ◽

Infarct Border Zone ◽

Infarct Border

Abstract Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies.

Download Full-text