Skip to content
naulon

No retraction, correction or concern found when last checked on Oct 29, 2026.

Cells of the adult human heart

Monika Litviňuková, Carlos Talavera-López, Henrike Maatz and 30 more

Nature · 2020

doi:10.1038/s41586-020-2797-4

Abstract

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 100

  1. 1.

    Meilhac SM, Buckingham ME. The deployment of cell lineages that form the mammalian heart. Nat. Rev. Cardiol. 2018;15:705-724.

    Not in our library10.1038/s41569-018-0086-9

  2. 2.

    Svensson V, Vento-Tormo R, Teichmann SA. Exponential scaling of single-cell RNA-seq in the past decade. Nat. Protocols. 2018;13:599-604.

    Not in our library10.1038/nprot.2017.149

  3. 3.

    Wang L, et al. Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function. Nat. Cell Biol. 2020;22:108-119.

    Not in our library10.1038/s41556-019-0446-7

  4. 4.

    Tucker NR, et al. Transcriptional and cellular diversity of the human heart. Circulation. 2020;142:466-482.

    Not in our library10.1161/circulationaha.119.045401

  5. 5.

    Chung AK, et al. Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study. Circulation. 2006;113:1597-1604.

    Not in our library10.1161/circulationaha.105.574400

  6. 6.

    Johnson EK, Matkovich SJ, Nerbonne JM. Regional differences in mRNA and lncRNA expression profiles in non-failing human atria and ventricles. Sci. Rep. 2018;8:13919.

    Not in our library10.1038/s41598-018-32154-2

  7. 7.

    Delplancq G, et al. Cardiomyopathy due to PRDM16 mutation: first description of a fetal presentation, with possible modifier genes. Am. J. Med. Genet. C. Semin. Med. Genet. 2020;184:129-135.

    Not in our library10.1002/ajmg.c.31766

  8. 8.

    Kim S-Y, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protocadherin. Cell Adhes. Migr. 2011;5:97-105.

    Not in our library10.4161/cam.5.2.14374

  9. 9.

    Donlin LT, et al. Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes Dev. 2012;26:114-119.

    Not in our library10.1101/gad.177758.111

  10. 10.

    Mazzotta S, et al. Distinctive roles of canonical and noncanonical Wnt signaling in human embryonic cardiomyocyte development. Stem Cell Reports. 2016;7:764-776.

    Not in our library10.1016/j.stemcr.2016.08.008

  11. 11.

    Shenton FC, Pyner S. Expression of transient receptor potential channels TRPC1 and TRPV4 in venoatrial endocardium of the rat heart. Neuroscience. 2014;267:195-204.

    Not in our library10.1016/j.neuroscience.2014.02.047

  12. 12.

    Gao M, et al. Conserved expression of the PRELI domain containing 2 gene (Prelid2) during mid-later-gestation mouse embryogenesis. J. Mol. Histol. 2009;40:227-233.

    Not in our library10.1007/s10735-009-9234-1

  13. 13.

    Putku M, et al. CDH13 promoter SNPs with pleiotropic effect on cardiometabolic parameters represent methylation QTLs. Hum. Genet. 2015;134:291-303.

    Not in our library10.1007/s00439-014-1521-6

  14. 14.

    Liu R, Jin J-P. Calponin isoforms CNN1, CNN2 and CNN3: regulators for actin cytoskeleton functions in smooth muscle and non-muscle cells. Gene. 2016;585:143-153.

    Not in our library10.1016/j.gene.2016.02.040

  15. 15.

    Besnard S, et al. Smooth muscle dysfunction in resistance arteries of the staggerer mouse, a mutant of the nuclear receptor RORα. Circ. Res. 2002;90:820-825.

    Not in our library10.1161/01.res.0000014489.24705.71

  16. 16.

    Mikhailov AT, Torrado M. The enigmatic role of the ankyrin repeat domain 1 gene in heart development and disease. Int. J. Dev. Biol. 2008;52:811-821.

    Not in our library10.1387/ijdb.082655am

  17. 17.

    Kwapiszewska G, et al. Fhl-1, a new key protein in pulmonary hypertension. Circulation. 2008;118:1183-1194.

    Not in our library10.1161/circulationaha.107.761916

  18. 18.

    Geng T, et al. H19 lncRNA promotes skeletal muscle insulin sensitivity in part by targeting AMPK. Diabetes. 2018;67:2183-2198.

    Not in our library10.2337/db18-0370

  19. 19.

    Huang L, et al. Critical roles of Xirp proteins in cardiac conduction and their rare variants identified in sudden unexplained nocturnal death syndrome and Brugada syndrome in Chinese Han population. J. Am. Heart Assoc. 2018;7:e006320.

    Not in our library10.1161/jaha.117.006320

  20. 20.

    Fittipaldi S, et al. Alpha B-crystallin induction in skeletal muscle cells under redox imbalance is mediated by a JNK-dependent regulatory mechanism. Free Radic. Biol. Med. 2015;86:331-342.

    Not in our library10.1016/j.freeradbiomed.2015.05.035

  21. 21.

    Rajakumari S, et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 2013;17:562-574.

    Not in our library10.1016/j.cmet.2013.01.015

  22. 22.

    2016 AHA late-breaking basic science abstracts. Circ. Res. 119, e160–e171 (2016).

    Not in our library10.1161/res.0000000000000126

  23. 23.

    Bolotta A, et al. New insights into the hepcidin-ferroportin axis and iron homeostasis in iPSC-derived cardiomyocytes from Friedreich’s ataxia patient. Oxid. Med. Cell. Longev. 2019;2019:7623023.

    Not in our library10.1155/2019/7623023

  24. 24.
  25. 25.

    Medioni C, et al. Expression of Slit and Robo genes in the developing mouse heart. Dev. Dyn. 2010;239:3303-3311.

    Not in our library10.1002/dvdy.22449

  26. 26.

    Lee JH, Protze SI, Laksman Z, Backx PH, Keller GM. Human pluripotent stem cell-derived atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Cell Stem Cell. 2017;21:179-194.e4.

    Not in our library10.1016/j.stem.2017.07.003

  27. 27.

    Liu C, Luo N, Tung C-Y, Perrin BJ, Zhao B. GRXCR2 regulates taperin localization critical for stereocilia morphology and hearing. Cell Rep. 2018;25:1268-1280.e4.

    Not in our library10.1016/j.celrep.2018.09.063

  28. 28.

    Liu X, et al. Single-cell RNA-Seq of the developing cardiac outflow tract reveals convergent development of the vascular smooth muscle cells. Cell Rep. 2019;28:1346-1361.e4.

    Not in our library10.1016/j.celrep.2019.06.092

  29. 29.

    Kalucka J, et al. Single-cell transcriptome atlas of murine endothelial cells. Cell. 2020;180:764-779.e20.

    Not in our library10.1016/j.cell.2020.01.015

  30. 30.
  31. 31.

    Corada M, Morini MF, Dejana E. Signaling pathways in the specification of arteries and veins. Arterioscler. Thromb. Vasc. Biol. 2014;34:2372-2377.

    Not in our library10.1161/atvbaha.114.303218

  32. 32.

    Kashiwazaki M, et al. A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions. Int. Immunol. 2003;15:1219-1227.

    Not in our library10.1093/intimm/dxg121

  33. 33.

    Awwad K, et al. Role of secreted modular calcium-binding protein 1 (SMOC1) in transforming growth factor β signalling and angiogenesis. Cardiovasc. Res. 2015;106:284-294.

    Not in our library10.1093/cvr/cvv098

  34. 34.

    Tang J, et al. Genetic fate mapping defines the vascular potential of endocardial cells in the adult heart. Circ. Res. 2018;122:984-993.

    Not in our library10.1161/circresaha.117.312354

  35. 35.

    Stallcup WB. The NG2 proteoglycan in pericyte biology. Adv. Exp. Med. Biol. 2018;1109:5-19.

    Not in our library10.1007/978-3-030-02601-1_2

  36. 36.
  37. 37.

    Barker N, Clevers H. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology. 2010;138:1681-1696.

    Not in our library10.1053/j.gastro.2010.03.002

  38. 38.

    Daniel J-M, et al. Regulator of G-protein signaling 5 prevents smooth muscle cell proliferation and attenuates neointima formation. Arterioscler. Thromb. Vasc. Biol. 2016;36:317-327.

    Not in our library10.1161/atvbaha.115.305974

  39. 39.

    Vanlandewijck M, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554:475-480.

    Not in our library10.1038/nature25739

  40. 40.
  41. 41.

    Zhou B, et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J. Clin. Invest. 2011;121:1894-1904.

    Not in our library10.1172/jci45529

  42. 42.

    Burstein B, Libby E, Calderone A, Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for platelet-derived growth factor in atrial-ventricular remodeling differences. Circulation. 2008;117:1630-1641.

    Not in our library10.1161/circulationaha.107.748053

  43. 43.

    Zhang F, Li C, Halfter H, Liu J. Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene. 2003;22:894-905.

    Not in our library10.1038/sj.onc.1206158

  44. 44.

    Lim HY, et al. Hyaluronan receptor LYVE-1-expressing macrophages maintain arterial tone through hyaluronan-mediated regulation of smooth muscle cell collagen. Immunity. 2018;49:326-341.e7.

    Not in our library10.1016/j.immuni.2018.06.008

  45. 45.

    Dick SA, et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat. Immunol. 2019;20:29-39.

    Not in our library10.1038/s41590-018-0272-2

  46. 46.

    Jaitin DA, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178:686-698.e14.

    Not in our library10.1016/j.cell.2019.05.054

  47. 47.

    Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010;121:2437-2445.

    Not in our library10.1161/circulationaha.109.916346

  48. 48.

    Heinrichs D, et al. Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74. Proc. Natl Acad. Sci. USA. 2011;108:17444-17449.

    Not in our library10.1073/pnas.1107023108

  49. 49.

    Valiño-Rivas L, et al. CD74 in kidney disease. Front. Immunol. 2015;6:483.

    Not in our library10.3389/fimmu.2015.00483

  50. 50.

    Hortells L, Johansen AKZ, Yutzey KE. Cardiac fibroblasts and the extracellular matrix in regenerative and nonregenerative hearts. J. Cardiovasc. Dev. Dis. 2019;6:29.

    Not in our library10.3390/jcdd6030029

  51. 51.

    Bajpai G, et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 2018;24:1234-1245.

    Not in our library10.1038/s41591-018-0059-x

  52. 52.

    Kegel L, Aunin E, Meijer D, Bermingham JR. LGI proteins in the nervous system. ASN Neuro. 2013;5:167-181.

    Not in our library10.1042/an20120095

  53. 53.

    Struk AA, et al. Self-regulation and the foraging gene (PRKG1) in humans. Proc. Natl Acad. Sci. USA. 2019;116:4434-4439.

    Not in our library10.1073/pnas.1809924116

  54. 54.

    Sahara M, et al. Population and single-cell analysis of human cardiogenesis reveals unique LGR5 ventricular progenitors in embryonic outflow tract. Dev. Cell. 2019;48:475-490.e7.

    Not in our library10.1016/j.devcel.2019.01.005

  55. 55.

    Lerman BB. Outflow tract ventricular arrhythmias: an update. Trends Cardiovasc. Med. 2015;25:550-558.

    Not in our library10.1016/j.tcm.2015.01.011

  56. 56.

    Dagda RK, et al. The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bβ2 antagonizes neuronal survival by promoting mitochondrial fission. J. Biol. Chem. 2008;283:36241-36248.

    Not in our library10.1074/jbc.m800989200

  57. 57.

    Wang L, et al. Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease. Ann. Hum. Genet. 2008;72:443-453.

    Not in our library10.1111/j.1469-1809.2008.00433.x

  58. 58.

    Bruce KD, et al. Lipoprotein lipase is a feature of alternatively-activated microglia and may facilitate lipid uptake in the CNS during demyelination. Front. Mol. Neurosci. 2018;11:57.

    Not in our library10.3389/fnmol.2018.00057

  59. 59.

    Kim H-S, et al. Schwann cell precursors from human pluripotent stem cells as a potential therapeutic target for myelin repair. Stem Cell Reports. 2017;8:1714-1726.

    Not in our library10.1016/j.stemcr.2017.04.011

  60. 60.

    Antonopoulos AS, Antoniades C. The role of epicardial adipose tissue in cardiac biology: classic concepts and emerging roles. J. Physiol. (Lond.). 2017;595:3907-3917.

    Not in our library10.1113/jp273049

  61. 61.

    Vijay J, et al. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat. Metab. 2020;2:97-109.

    Not in our library10.1038/s42255-019-0152-6

  62. 62.
  63. 63.

    Hoffmann M, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271-280.

    Not in our library10.1016/j.cell.2020.02.052

  64. 64.
  65. 65.

    Leid J, et al. Primitive embryonic macrophages are required for coronary development and maturation. Circ. Res. 2016;118:1498-1511.

    Not in our library10.1161/circresaha.115.308270

  66. 66.

    Chen B, Brickshawana A, Frangogiannis NG. The functional heterogeneity of resident cardiac macrophages in myocardial injury CCR2+ cells promote inflammation, whereas CCR2− cells protect. Circ. Res. 2019;124:183-185.

    Not in our library10.1161/circresaha.118.314357

  67. 67.

    Vaduganathan M, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N. Engl. J. Med. 2020;382:1653-1659.

    Not in our library10.1056/nejmsr2005760

  68. 68.
  69. 69.
  70. 70.

    Litvinukova, M. et al. Single cell and single nuclei analysis human heart tissue. 10.17504/protocols.io.veae3ae (2018).

    Not in our library

  71. 71.
  72. 72.

    Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods. 2012;9:676-682.

    Not in our library10.1038/nmeth.2019

  73. 73.

    Wolock SL, Lopez R, Klein AM. Scrublet: computational identification of cell doublets in single-cell transcriptomic data. Cell Syst. 2019;8:281-291.e9.

    Not in our library10.1016/j.cels.2018.11.005

  74. 74.

    McInnes, L. & Healy, J. UMAP: Uniform manifold approximation and projection for dimension reduction. Preprint at https://arxiv.org/abs/1802.03426 (2018).

    Not in our library

  75. 75.

    Popescu D-M, et al. Decoding human fetal liver haematopoiesis. Nature. 2019;574:365-371.

    Not in our library10.1038/s41586-019-1652-y

  76. 76.
  77. 77.
  78. 78.
  79. 79.

    Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37:W305-W311.

    Not in our library10.1093/nar/gkp427

  80. 80.

    Kuleshov MV, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90-W97.

    Not in our library10.1093/nar/gkw377

  81. 81.

    Lotfollahi M, Wolf FA, Theis F. J. scGen predicts single-cell perturbation responses. Nat. Methods. 2019;16:715-721.

    Not in our library10.1038/s41592-019-0494-8

  82. 82.

    Miao Z, et al. Putative cell type discovery from single-cell gene expression data. Nat. Methods. 2020;17:621-628.

    Not in our library10.1038/s41592-020-0825-9

  83. 83.

    Soneson C, Robinson MD. Bias, robustness and scalability in single-cell differential expression analysis. Nat. Methods. 2018;15:255-261.

    Not in our library10.1038/nmeth.4612

  84. 84.

    La Manno G, et al. RNA velocity of single cells. Nature. 2018;560:494-498.

    Not in our library10.1038/s41586-018-0414-6

  85. 85.

    Bergen, V., Lange, M., Peidli, S., Alexander Wolf, F. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 10.1038/s41587-020-0591-3 (2020).

    Not in our library10.1038/s41587-020-0591-3

  86. 86.
  87. 87.

    Miragaia RJ, et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity. 2019;50:493-504.e7.

    Not in our library10.1016/j.immuni.2019.01.001

  88. 88.

    Dey G, et al. Signaling network of oncostatin M pathway. J. Cell Commun. Signal. 2013;7:103-108.

    Not in our library10.1007/s12079-012-0186-y

  89. 89.
  90. 90.

    Bian Z, et al. Deciphering human macrophage development at single-cell resolution. Nature. 2020;582:571-576.

    Not in our library10.1038/s41586-020-2316-7

  91. 91.

    Wong AP, Nili N, Strauss BH. In vitro differences between venous and arterial-derived smooth muscle cells: potential modulatory role of decorin. Cardiovasc. Res. 2005;65:702-710.

    Not in our library10.1016/j.cardiores.2004.10.012

  92. 92.

    Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat. Rev. Immunol. 2007;7:803-815.

    Not in our library10.1038/nri2171

  93. 93.

    McDonald AI, et al. Endothelial regeneration of large vessels is a biphasic process driven by local cells with distinct proliferative capacities. Cell Stem Cell. 2018;23:210-225.e6.

    Not in our library10.1016/j.stem.2018.07.011

  94. 94.

    Chen S-C, Liu Y-C, Shyu K-G, Wang DL. Acute hypoxia to endothelial cells induces activating transcription factor 3 (ATF3) expression that is mediated via nitric oxide. Atherosclerosis. 2008;201:281-288.

    Not in our library10.1016/j.atherosclerosis.2008.02.014

  95. 95.
  96. 96.

    Roychoudhuri R, et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat. Immunol. 2016;17:851-860.

    Not in our library10.1038/ni.3441

  97. 97.
  98. 98.

    Kimmel, J. C. & Kelley, D. R. scNym: Semi-supervised adversarial neural networks for single cell classification. Preprint at 10.1101/2020.06.04.132324 (2020).

    Not in our library

  99. 99.

    Stewart BJ, et al. Spatiotemporal immune zonation of the human kidney. Science. 2019;365:1461-1466.

    Not in our library10.1126/science.aat5031

  100. 100.

    James KR, et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 2020;21:343-353.

    Not in our library10.1038/s41590-020-0602-z

Cited by papers we hold 34

and 14 more

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.