title: Mesenchymal stem cell secreted platelet derived growth factor exerts a pro-migratory effect on resident Cardiac Atrial appendage Stem Cells.
abstract: Mesenchymal stem cells (MSCs) modulate cardiac healing after myocardial injury through the release of paracrine factors, but the exact mechanisms are still unknown. One possible mechanism is through mobilization of endogenous cardiac stem cells (CSCs). This study aimed to test the pro-migratory effect of MSC conditioned medium (MSC-CM) on endogenous CSCs from human cardiac tissue. By using a three-dimensional collagen assay, we found that MSC-CM improved migration of cells from human cardiac tissue. Cell counts, perimeter and area measurements were utilized to quantify migration effects. To examine whether resident stem cells were among the migrating cells, specific stem cell properties were investigated. The migrating cells displayed strong similarities with resident Cardiac Atrial appendage Stem Cells (CASCs), including a clonogenic potential of ~21.5% and expression of pluripotency associated genes like Oct-4, Nanog, c-Myc and Klf-4. Similar to CASCs, migrating cells demonstrated high aldehyde dehydrogenase activity and were able to differentiate towards cardiomyocytes. Receptor tyrosine kinase analysis and collagen assays performed with recombinant platelet derived growth factor (PDGF)-AA and Imatinib Mesylate, a PDGF receptor inhibitor, suggested a role for the PDGF-AA/PDGF receptor α axis in enhancing the migration process of CASCs. In conclusion, our findings demonstrate that factors present in MSC-CM improve migration of resident stem cells from human cardiac tissue. These data open doors towards future therapies in which MSC secreted factors, like PDGF-AA, can be utilized to enhance the recruitment of CASCs towards the site of myocardial injury.
authors: Laboratory of Experimental Hematology, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium. Electronic address: severina.windmolders@uhasselt.be.
authors: Severina
authors: S
authors: Windmolders
authors: Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: adeboeck@ucalgary.ca.
authors: Astrid
authors: A
authors: De Boeck
authors: Laboratory of Experimental Hematology, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium. Electronic address: remco.koninckx@jessazh.be.
authors: Remco
authors: R
authors: Koninckx
authors: Laboratory of Experimental Hematology, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium. Electronic address: annick.daniels@jessazh.be.
authors: Annick
authors: A
authors: Daniëls
authors: Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: olivier.dewever@ugent.be.
authors: Olivier
authors: O
authors: De Wever
authors: Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: marc1.bracke@ugent.be.
authors: Marc
authors: M
authors: Bracke
authors: Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium; Department of Cardiothoracic Surgery, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium. Electronic address: marc.hendrikx@jessazh.be.
authors: Marc
authors: M
authors: Hendrikx
authors: Laboratory of Experimental Hematology, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium. Electronic address: karen.hensen@jessazh.be.
authors: Karen
authors: K
authors: Hensen
authors: Laboratory of Experimental Hematology, Jessa Hospital, Campus Virga Jesse, Stadsomvaart 11, 3500 Hasselt, Belgium; Faculty of Medicine and Life Sciences, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium. Electronic address: jean-luc.rummens@jessazh.be.
authors: Jean-Luc
authors: JL
authors: Rummens
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D015870:Gene Expression; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D061251:Primary Cell Culture; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D010982:Platelet-Derived Growth Factor; D016271:Proto-Oncogene Proteins c-myc
keywords: 3D; ALDH; AT; Aldehyde dehydrogenase; Annealing temperature; Axl receptor; AxlR; BM-SCs; Bone marrow stem cells; CASCs; CFU-Fs; CSCs; Cardiac Atrial appendage Stem Cells; Cardiac stem cells; Cardiac troponin; Colony-forming-unit fibroblasts; Conditioned medium; DEAB; Diethylamino-benzaldehyde; EGFR; ELISA; Enzyme-linked immunosorbent assay; Epidermal growth factor receptor; FAK; FCS; FGFR; FMO; Fetal calf serum; Fibroblast growth factor receptor; Fluorescence minus one; Focal adhesion kinase; GFP; Green fluorescent protein; IHD; InsR; Insulin receptor; Ischemic heart disease; LG-DMEM; Low-glucose Dulbecco's Modified Eagle Medium; MI; MMPs; MSC-CM; MSCs; Matrix metalloproteinases; Mesenchymal stem cell conditioned medium; Mesenchymal stem cells; Migration; Myocardial infarction; NRCMs; Neonatal rat cardiomyocytes; P/S; PDGF; PDGFR; PI3K; PLC-γ; Penicillin/streptomycin; Phospho-inositide-3 kinase; Phospholipase C-γ; Platelet derived growth factor; Platelet derived growth factor receptor; RALDH2; RT-PCR; RTK; Receptor tyrosine kinase; Retinaldehyde dehydrogenase 2; Reverse transcriptase PCR; T-Box 18; TGF-β; Tbx18; Three-dimensional; Thymosin β4; Transforming growth factor-β; Tβ4; VEGF; VEGFR; Vascular endothelial growth factor; Vascular endothelial growth factor receptor; Wilm's tumor 1; Wt1; cTn