Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.
Animals; Apoptosis/physiology; Cardiac/cytology/physiology; Cell Movement/physiology; Chemokine CXCL12/*metabolism; Coronary Circulation/physiology; CXCR4/*genetics/metabolism; Gene Expression/physiology; Green Fluorescent Proteins/genetics; Inbred C57BL; Knockout; Mesenchymal Stem Cell Transplantation/*methods; Mesenchymal Stem Cells/*metabolism; Mice; Myocardial Infarction/genetics/pathology/*therapy; Myocardium/cytology; Myocytes; Paracrine Communication/physiology; Receptors; Ventricular Remodeling/physiology
BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100,000 MSC or saline via tail vein. We show alpha-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P\textless0.01), increased cardiac progenitor cell recruitment (100.9%, P\textless0.01), and increased cardiac myosin-positive area (39%, P\textless0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P\textless0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and
Dong Feng; Harvey James; Finan Amanda; Weber Kristal; Agarwal Udit; Penn Marc S
Circulation
2012
2012-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCULATIONAHA.111.082453" target="_blank" rel="noreferrer noopener">10.1161/CIRCULATIONAHA.111.082453</a>
Overview of studies comparing human normal cartilage with minimal and advanced osteoarthritic cartilage.
Humans; Cell Proliferation; Apoptosis/physiology; Gene Expression/physiology; Cartilage; Cartilage Diseases/*physiopathology; Chondrocytes/physiology; Osteoarthritis/*physiopathology; Biological; Models; Articular/*physiopathology
A major area under study in the osteoarthritis (OA) research field is the characterization of specific molecular and biochemical changes that distinguish advanced diseased cartilage from less involved or normal tissue. This information is important to better define the pathogenic mechanisms that are operating during OA progression and to identify disease-specific markers. This review describes recent studies that have addressed changes in chondrocyte gene expression, proliferation, and apoptosis in "experimental" (more advanced OA cartilage) versus "control" (less involved or non-OA cartilage). Included is a comprehensive listing of recently published studies in this area with general findings. The review also includes a discussion of study design and the strengths and weaknesses of the various approaches. In addition, specific strategies to deal with some of the important issues are discussed. One particular model utilizing minimal and advanced OA cartilage obtained from the same patient is described in more detail.
Horton W E Jr; Yagi R; Laverty D; Weiner S
Clinical and experimental rheumatology
2005
2005-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction.
Animal; Animals; Apoptosis/physiology; Cardiac/pathology/physiology; Collagen Type VI/*genetics/*metabolism; Disease Models; Echocardiography; Extracellular Matrix/metabolism/pathology; Fibrosis/genetics/pathology/physiopathology; Knockout; Male; Mice; Myocardial Infarction/diagnostic imaging/*genetics/*physiopathology; Myocytes; Ventricular Remodeling/*physiology
RATIONALE: We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this nonfibrillar collagen has not been explored in the setting of myocardial infarction (MI). OBJECTIVE: To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury. METHODS AND RESULTS: Wild-type and Col6a1(-/-) mice were subjected to MI, followed by serial echocardiographic and histological assessments. At 8 weeks after MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9% +/- 3.3% versus 29.1% +/- 4.3% for wild-type), and left ventricular chamber dilation was attenuated in the Col6a1(-/-) MI group (25.8% +/- 7.9% increase versus 62.6% +/- 16.5% for wild-type). The improvement in cardiac remodeling was evident as early as 10 days after MI in the Col6a1(-/-) mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1(-/-) group 3 days after MI, but by day 14 this was significantly reduced. Collagen deposition also was reduced in the infarcted and remote areas of the Col6a1(-/-) hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes. CONCLUSIONS: These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role after MI by limiting infarct size, chronic apoptosis, aberrant remodeling, and fibrosis, leading to preservation of cardiac function.
Luther Daniel J; Thodeti Charles K; Shamhart Patricia E; Adapala Ravi K; Hodnichak Cheryl; Weihrauch Dorothee; Bonaldo Paolo; Chilian William M; Meszaros J Gary
Circulation research
2012
2012-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.252734" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.252734</a>