@article{839084e11e9f441583e4d64502ae1c66,
title = "Profiling proliferative cells and their progeny in damaged murine hearts",
abstract = "The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.",
keywords = "Cardiac regeneration, Fibroblasts, Lineage tracing, Single-cell transcriptomics, Stem cells",
author = "Kai Kretzschmar and Yorick Post and Marie Bannier-H{\'e}laou{\"e}t and Andrea Mattiotti and Jarno Drost and Onur Basak and Li, {Vivian S.W.} and {van den Born}, Maaike and Gunst, {Quinn D.} and Danielle Versteeg and Lieneke Kooijman and {van der Elst}, Stefan and {van Es}, {Johan H.} and {van Rooij}, Eva and {van den Hoff}, {Maurice J.B.} and Hans Clevers",
note = "Funding Information: We thank Benedetta Artegiani and Talya Dayton for discussions and critical reading of the manuscript; Reinier van den Linden for help with flow cytometry; Judith Vivi{\'e} for help with SORT-seq; the Utrecht Sequencing Facility for sequencing; Mauro Muraro and Anna Alemany Arias for help with bioinformatics analysis; and Anko de Graaff and the Hubrecht Imaging Centre for assistance with microscopy. This work was supported by a Cardiovasculair Onderzoek Nederland (CVON)–Human Stem Cells for Cardiac Repair (HUSTCARE) project grant (to H.C.) and a CVON-HUSTCARE Young Talent Grant (to K.K.). K.K. is a long-term fellow of the Human Frontier Science Program Organisation (LT771/2015) and was the recipient of a VENI grant from the Netherlands Organisation for Scientific Research (NWO-ZonMW) (016.166.140). Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",
year = "2018",
month = dec,
day = "26",
doi = "10.1073/pnas.1805829115",
language = "English",
volume = "115",
pages = "E12245--E12254",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "52",
}