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Mobilization of very small embryonic-like stem cells in acute coronary syndromes and stroke

Mobilisierung sehr kleiner, embryonalen Stammzellen ähnelnde Zellen bei akutem Koronarsyndrom und Schlaganfall

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Abstract

The bone marrow (BM) niche contains small heterogenous populations of cells which may contribute to cardiac and endothelial repair, including committed lineages [endothelial progenitor cells (EPCs), multipotent mesenchymal stromal cells (MSCs) and more primitive very small embryonic-like cells (VSELs) expressing pluripotent stem cell (PSC) markers (Oct-4, Nanog, SSEA-1)]. VSELs are present in BM, peripheral blood and some solid organs in mice and were recently identified in peripheral blood in patients with acute coronary syndromes and stroke. VSELs can be expanded in vitro and differentiated into cells from all three germ layers. This population of cells displays the morphology of primitive PSC (small size, open type chromatin, large nucleus, narrow rim of cytoplasm) and express PSC markers. The isolation of human VSELs is based on their size and presence of several surface markers (CXCR4, CD133, CD34) and lack of markers of hematopoietic lineage (lin, CD45). In acute myocardial infarction and ischemic stroke VSELs are rapidly mobilized into peripheral blood, and express increased levels of PSC markers as well as early cardiac (GATA-4, Nkx2.5/Csx), neural (GFAP, nestin, beta-III-tubulin, Olig1, Olig2, Sox2, Musashi) and endothelial lineage markers (VE-cadherin, von Willebrand factor). The number of VSELs mobilized in acute myocardial infarction is inversely correlated with left ventricular ejection fraction and the release of cardiac necrosis markers. Mobilization of these cells is also reduced in patients with diabetes and in the elderly. BM-derived VSELs were expanded and after cardiogenic pre-differentiation injected intramyocardially in mice models of myocardial infarction leading to improved left ventricular contractility. VSELs are probably progeny of epiblast cells which migrated to the BM and developing organs during embryonic development. The cells are present in a quiescent state in the adult BM and solid organs and might serve as a reserve pool of resident stem cells. VSELs are promising candidates for further pre-clinical and clinical studies on cellular cardiovascular therapy.

Zusammenfassung

Das Knochenmark enthält kleine heterogene Zellpopulationen, die an der kardialen und endothelialen Reparatur beteiligt sein dürften. Dazu gehören Zelllinien wie die endothelilalen Progenitorzellen (EPC), die multipotetente mesenchymalen Stromazellen (MSC) sowie noch primitivere sehr kleine Zellen, die embryonalen Stammzellen ähneln, sog. VSELs. Sie exprimieren die Marker pluripotenter Stammzellen (PSC) wie Oct-4, Nanog, SSEA-1. Diese VSELs finden sich im Knochenmark, im peripheren Blut und in einigen Organen bei der Maus. Sie konnten auch beim akuten Koronarsyndrom und Schlaganfall von Patienten gezeigt werden. VSELs können in vitro expandieren und in Zellen aller 3 Keimblätter differenzieren. Diese Zellpopulationen besitzen die Morphologie primitiver pluripotenter Stammzellen (kleine Größe, exponiertes Chromatin, großer Kern, schmaler Plasmasaum) und exprimieren auch deren Marker. Sie lassen sich auf Grund ihrer Größe und der Oberflächenmarker CXCR4, CD133, CD34 isolieren und sind durch das Fehlen von Markern hämatopoetischer Zellinien (lin. CD45) beschrieben. Beim akuten Herzinfarkt und beim ischämisch bedingten Schlaganfall werden VSELs rasch ins periphere Blut freigesetzt. Sie exprimieren dann vermehrt die Marker pluripotenter Stammzellen und der früher kardialen Zelllinien wie GATA4, Nkx2,5/C‘sx) nuraler Zelllinien wie GFAP, Neestin, β-III-Tubulin, Olig1, Olig 2, Sox2, Musashi) und endothlialer Zelllinien wie VE-Cadherin, Willbrand-Faktor. Die Zahl mobilisierter VSELs bei akutem Myokardinfarkt korreliert umgekehrt mit der Ejektionsfraktion und der Freisetzung kardialer Nekrosemarker. Die Mobilisierung von VSELs ist auch bei Patienten mit Diabetes und bei älteren Menschen vermindert. VSELs aus dem Knochenmarker wurden expandiert und nach kardiogener Prädifferenzierung ins Myokard von Mäusen mit Herzinfarkt eingebracht. Sie führten zu einer Verbesserung der linksventrikulären Kontraktion. Wahrscheinlich sind VSELs die Vorläuferzellen von Epiblasten, die in der Embryonalphase ins Knochenmark einwandern und an der Organentwicklung beteiligt sind. Im Ruhezustand befinden sie sich auch im adulten Knochenmark und in einigen Organen. Sie dürften eine Reserve für die residenten Stammzellen darstellen. VSELs sind deshalb Kandidaten für eine zelluläre Therapie zur Organregeneration bei präklinischen und klinischen Studien.

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The corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Third Division of Cardiology, Medical University of Silesia, 45–47 Ziolowa Street, 40–635 , Katowice, Poland

    W. Wojakowski MD, PhD & M. Tendera

  2. Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    M.Z. Ratajczak

Authors
  1. W. Wojakowski MD, PhD
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  2. M.Z. Ratajczak
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  3. M. Tendera
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Correspondence to W. Wojakowski MD, PhD.

Additional information

Funding: National Institutes of Health (R01 CA106281–01), European Union structural funds – Innovative Economy Operational Programme, grant No. POIG 01.02–00–109/09 “Innovative methods of stem cells applications in medicine” and Polish Ministry of Science and Higher Education grants 0651/P01/2007/32, 2422/P01/2007/32.

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Wojakowski, W., Ratajczak, M. & Tendera, M. Mobilization of very small embryonic-like stem cells in acute coronary syndromes and stroke. Herz 35, 467–473 (2010). https://doi.org/10.1007/s00059-010-3389-0

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