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Research Lab - Laura Ueberham, MD

Cardiac Progenitor Cells In the late 1990s and turn of the millennium, the paradigm of the fully differentiated heart changed and efforts for cardiac regenerative therapies were born (1, 2). Evidence for adult cardiac progenitor cells (CPCs) was first described in 2002, when it was recognized that cardiac chimerism occurred in a heart-transplanted patient (3). Subsequently, several CPC populations have been identified with the highly recurrent markers c-kit (CD117), insulin gene enhancer protein 1 (islet-1) and stem cell antigen 1 (Sca-1) (4-6). Additionally, protocols were established to differentiate c-kit+ CPCs into cardiomyocytes, smooth muscle cells and endothelial cells (7). Sca-1+ cells have been shown to be able to differentiate into functionally mature cardiomyocytes (5). However, early high expectations were dampened, because the minority of c-kit+ cells differentiate into mature cardiomyocytes (8-10). Nevertheless, it has been acknowledged that CPCs could be differentiated into cardiomyocytes in vitro and in vivo (10). For instance, Végh and colleagues showed that Sca-1+ CPCs can be lentivirally transfected with the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and subsequently exhibit pacemaker function and couple to neonatal rat ventricular cardiomyocytes (11). The atria and atrial appendages contain a promising reservoir for multiple types of CPCs (12-16). When surgical excision of the LAA is performed, the tissue can be used for characterization of CPCs. The aim of our project is to detect, characterize and isolate CPCs from atrial tissue, especially in relation to fibrotic remodeling in patients with atrial fibrillation.

Publications Kajstura J, et al. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8801-8805 Beltrami AP, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001 Jun 7;344(23):1750-1757 Quaini F, et al. Chimerism of the transplanted heart. N Engl J Med 2002 Jan 3;346(1):5-15 Aghila Rani KG, et al. Isolation of ckit-positive cardiosphere-forming cells from human atrial biopsy. Asian Cardiovasc Thorac Ann 2008 Jan;16(1):50-56 Smits AM, et al. Human cardiomyocyte progenitor cells differentiate into functional mature cardiomyocytes: an in vitro model for studying human cardiac physiology and pathophysiology. Nat Protoc 2009;4(2):232-243 Khattar P, et al. Distinction between two populations of islet-1-positive cells in hearts of different murine strains. Stem Cells Dev 2011 Jun;20(6):1043-1052 Beltrami AP, et al. Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell 2003;114(6):763-776 Sultana N, et al. Resident c-kit(+) cells in the heart are not cardiac stem cells. Nat Commun 2015 Oct 30;6:8701 van Berlo JH, et al. Most of the Dust Has Settled: cKit+ Progenitor Cells Are an Irrelevant Source of Cardiac Myocytes In Vivo. Circ Res 2016 Jan 08;118(1):17-19 Vagnozzi RJ, et al. Genetic Lineage Tracing of Sca-1(+) Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart. Circulation 2018 Dec 18;138(25):2931-2939 Vegh AMD, et al. Cardiomyocyte Progenitor Cells as a Functional Gene Delivery Vehicle for Long-Term Biological Pacing. Molecules 2019 Jan 5;24(1) Leinonen JV, et al. Left atrial appendages from adult hearts contain a reservoir of diverse cardiac progenitor cells. PLoS One 2013;8(3):e59228. Sandstedt J, et al. Human C-kit+CD45- cardiac stem cells are heterogeneous and display both cardiac and endothelial commitment by single-cell qPCR analysis. Biochem Biophys Res Commun 2014 Jan 03;443(1):234-238 Di Nardo P, et al. Cardiac Progenitor Cell Extraction from Human Auricles. Methods Mol Biol 2017;1553:145-154 Chan HH, et al. Human cardiosphere-derived cells from patients with chronic ischaemic heart disease can be routinely expanded from atrial but not epicardial ventricular biopsies. J Cardiovasc Transl Res 2012 Oct;5(5):678-687 Sandstedt J, et al. Left atrium of the human adult heart contains a population of side population cells. Basic Res Cardiol 2012 Mar;107(2):255

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