Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The interstitium in cardiac repair: role of the immune–stromal cell interplay

Nature Reviews Cardiology volume 15, pages 601–616 (2018)Cite this article

Subjects

Abstract

Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases.

Key points

  • Cardiac interstitial cells have critical roles in cardiovascular development and in maintaining the correct 3D scaffold of the heart in homeostasis.

  • The dynamic interplay between cardiac stromal cells and circulatory immune cells can either support tissue regrowth in regenerative organisms or fail to resolve inflammation and produce fibrotic scar tissue.

  • The response to myocardial injury proceeds in three overlapping phases: inflammation, proliferation, and maturation; the dynamics of the inflammatory and proliferative phases influence the reparative outcome.

  • Understanding the development and functions of different cardiac cellular components, and the critical timing of their potential crosstalk in tissue homeostasis and disease, will help to design new regenerative therapeutic strategies.

  • Promising new therapeutic strategies are emerging, with a shifting focus from pharmacological modulation of systemic pathways and stem cell-mediated therapies to more specific targeting of the endogenous immune–stromal cell interplay.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Immune cell and fibroblast functions after myocardial injury.
Fig. 2: Ontogeny of the cardiac interstitium.
Fig. 3: Potential therapeutic strategies targeting the cardiac interstitium.

Similar content being viewed by others

References

  1. Rinn, J. L., Bondre, C., Gladstone, H. B., Brown, P. O. & Chang, H. Y. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLOS Genet. 2, e119 (2006).

    PubMed  PubMed Central  Google Scholar 

  2. Rinn, J. L. et al. A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev. 22, 303–307 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Nacu, E. et al. Connective tissue cells, but not muscle cells, are involved in establishing the proximo-distal outcome of limb regeneration in the axolotl. Development 140, 513–518 (2013).

    CAS  PubMed  Google Scholar 

  4. Benias, P. C. et al. Structure and distribution of an unrecognized interstitium in human tissues. Sci. Rep. 8, 4947 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. Forbes, S. J. & Rosenthal, N. Preparing the ground for tissue regeneration: from mechanism to therapy. Nat. Med. 20, 857–869 (2014).

    CAS  PubMed  Google Scholar 

  6. Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hulsmans, M. et al. Macrophages facilitate electrical conduction in the heart. Cell 169, 510–522 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Pellman, J., Zhang, J. & Sheikh, F. Myocyte-fibroblast communication in cardiac fibrosis and arrhythmias: mechanisms and model systems. J. Mol. Cell. Cardiol. 94, 22–31 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Vivien, C. J., Hudson, J. E. & Porrello, E. R. Evolution, comparative biology and ontogeny of vertebrate heart regeneration. NPJ Regen. Med. 1, 16012 (2016).

    PubMed  PubMed Central  Google Scholar 

  11. Almada, A. E. & Wagers, A. J. Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease. Nat. Rev. Mol. Cell Biol. 17, 267–279 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lai, S. L. et al. Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration. eLife 6, e25605 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. Hui, S. P. et al. Zebrafish regulatory T cells mediate organ-specific regenerative programs. Dev. Cell 43, 659–672 (2017).

    CAS  PubMed  Google Scholar 

  14. Godwin, J. W., Debuque, R., Salimova, E. & Rosenthal, N. A. Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape. NPJ Regen. Med. 2, 22 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Frodermann, V. & Nahrendorf, M. Neutrophil-macrophage cross-talk in acute myocardial infarction. Eur. Heart J. 38, 198–200 (2017).

    PubMed  Google Scholar 

  16. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007).

    CAS  PubMed  Google Scholar 

  17. Bertheloot, D. & Latz, E. HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell. Mol. Immunol. 14, 43–64 (2017).

    CAS  PubMed  Google Scholar 

  18. Turner, N. A. Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J. Mol. Cell. Cardiol. 94, 189–200 (2016).

    CAS  PubMed  Google Scholar 

  19. Bernardo, M. E. & Fibbe, W. E. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13, 392–402 (2013).

    CAS  PubMed  Google Scholar 

  20. Furtado, M. B. & Hasham, M. Properties and immune function of cardiac fibroblasts. Adv. Exp. Med. Biol. 1003, 35–70 (2017).

    PubMed  Google Scholar 

  21. Mescher, A. L. Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. Regeneration 4, 39–53 (2017).

    PubMed  PubMed Central  Google Scholar 

  22. Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell 168, 362–375 (2017).

    CAS  PubMed  Google Scholar 

  23. Zhang, W. et al. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J. Am. Heart Assoc. 4, e001993 (2015).

    PubMed  PubMed Central  Google Scholar 

  24. Frangogiannis, N. G. The inflammatory response in myocardial injury, repair, and remodelling. Nat. Rev. Cardiol. 11, 255–265 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Biernacka, A. & Frangogiannis, N. G. Aging and cardiac fibrosis. Aging Dis. 2, 158–173 (2011).

    PubMed  PubMed Central  Google Scholar 

  26. Shinde, A. V. & Frangogiannis, N. G. Fibroblasts in myocardial infarction: a role in inflammation and repair. J. Mol. Cell. Cardiol. 70, 74–82 (2014).

    CAS  PubMed  Google Scholar 

  27. Sattler, S. & Rosenthal, N. The neonate versus adult mammalian immune system in cardiac repair and regeneration. Biochim. Biophys. Acta 1863, 1813–1821 (2016).

    CAS  PubMed  Google Scholar 

  28. Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Pinto, A. R. et al. An abundant tissue macrophage population in the adult murine heart with a distinct alternatively-activated macrophage profile. PLOS ONE 7, e36814 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Skelly, D. A. et al. Single-cell transcriptional profiling reveals cellular diversity and intercommunication in the mouse heart. Cell Rep. 22, 600–610 (2018).

    CAS  PubMed  Google Scholar 

  31. Ma, Y., Yabluchanskiy, A. & Lindsey, M. L. Neutrophil roles in left ventricular remodeling following myocardial infarction. Fibrogen. Tissue Repair 6, 11 (2013).

    CAS  Google Scholar 

  32. Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

    PubMed  Google Scholar 

  33. Summers, C. et al. Neutrophil kinetics in health and disease. Trends Immunol. 31, 318–324 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ravichandran, K. S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35, 445–455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ortega-Gomez, A., Perretti, M. & Soehnlein, O. Resolution of inflammation: an integrated view. EMBO Mol. Med. 5, 661–674 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Leuschner, F. et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ. Res. 107, 1364–1373 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Seeley, E. J., Barry, S. S., Narala, S., Matthay, M. A. & Wolters, P. J. Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice. J. Immunol. 190, 4717–4724 (2013).

    CAS  PubMed  Google Scholar 

  39. Martelli, D., McKinley, M. J. & McAllen, R. M. The cholinergic anti-inflammatory pathway: a critical review. Auton. Neurosci. 182, 65–69 (2014).

    CAS  PubMed  Google Scholar 

  40. Frangogiannis, N. G., Smith, C. W. & Entman, M. L. The inflammatory response in myocardial infarction. Cardiovasc. Res. 53, 31–47 (2002).

    CAS  PubMed  Google Scholar 

  41. Gonzalez-Rosa, J. M. et al. Myocardial polyploidization creates a barrier to heart regeneration in zebrafish. Dev. Cell 44, 433–446 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mohamed, T. M. A. et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 173, 104–116 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Gourko H. In The Evolutionary Biology Papers of Elie Metchnikoff. (eds. Gourko H., Williamson D. I. & Tauber A.I.) 207–216 (Springer, Dordrecht, 2000).

  44. Guilliams, M. et al. Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat. Rev. Immunol. 14, 571–578 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tauber, A. I. Metchnikoff and the phagocytosis theory. Nat. Rev. Mol. Cell Biol. 4, 897–901 (2003).

    CAS  PubMed  Google Scholar 

  46. Ramos, G. C. Inflammation as an animal development phenomenon. Clin. Dev. Immunol. 2012, 983203 (2012).

    PubMed  Google Scholar 

  47. Leid, J. et al. Primitive embryonic macrophages are required for coronary development and maturation. Circ. Res. 118, 1498–1511 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Aurora, A. B. et al. Macrophages are required for neonatal heart regeneration. J. Clin. Invest. 124, 1382–1392 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Honold, L. & Nahrendorf, M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ. Res. 122, 113–127 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lavine, K. J. et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc. Natl Acad. Sci. USA 111, 16029–16034 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Barth, M. W., Hendrzak, J. A., Melnicoff, M. J. & Morahan, P. S. Review of the macrophage disappearance reaction. J. Leukoc. Biol. 57, 361–367 (1995).

    CAS  PubMed  Google Scholar 

  53. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

    PubMed  PubMed Central  Google Scholar 

  55. Nahrendorf, M. & Swirski, F. K. Abandoning M1/M2 for a network model of macrophage function. Circ. Res. 119, 414–417 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    CAS  PubMed  Google Scholar 

  57. Price, J. G. et al. CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nat. Immunol. 16, 1060–1068 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  60. Hoeffel, G. et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J. Exp. Med. 209, 1167–1181 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  62. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  63. Gautier, E. L. et al. Systemic analysis of PPARgamma in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. J. Immunol. 189, 2614–2624 (2012).

    CAS  PubMed  Google Scholar 

  64. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lavin, B. et al. Nitric oxide prevents aortic neointimal hyperplasia by controlling macrophage polarization. Arterioscler. Thromb. Vasc. Biol. 34, 1739–1746 (2014).

    CAS  PubMed  Google Scholar 

  66. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Pinto, A. R. et al. Age-related changes in tissue macrophages precede cardiac functional impairment. Aging 6, 399–413 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. Steinman, R. M. & Cohn, Z. A. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 137, 1142–1162 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang, Y. & Zhang, C. Role of dendritic cells in cardiovascular diseases. World J. Cardiol. 2, 357–364 (2010).

    PubMed  PubMed Central  Google Scholar 

  71. Merad, M. & Manz, M. G. Dendritic cell homeostasis. Blood 113, 3418–3427 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang, J., Yu, Z. X., Fujita, S., Yamaguchi, M. L. & Ferrans, V. J. Interstitial dendritic cells of the rat heart. Quantitative and ultrastructural changes in experimental myocardial infarction. Circulation 87, 909–920 (1993).

    CAS  PubMed  Google Scholar 

  73. Gallego-Colon, E. et al. Cardiac-restricted IGF-1Ea overexpression reduces the early accumulation of inflammatory myeloid cells and mediates expression of extracellular matrix remodelling genes after myocardial infarction. Mediators Inflamm. 2015, 484357 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. Anzai, A. et al. Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling. Circulation 125, 1234–1245 (2012).

    PubMed  Google Scholar 

  75. Hofmann, U. et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 125, 1652–1663 (2012).

    CAS  PubMed  Google Scholar 

  76. Nagai, T. et al. Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans. J. Am. Heart Assoc. 3, e000839 (2014).

    PubMed  PubMed Central  Google Scholar 

  77. Sattler, S., Fairchild, P., Watt, F. M., Rosenthal, N. & Harding, S. E. The adaptive immune response to cardiac injury-the true roadblock to effective regenerative therapies? NPJ Regen. Med. 2, 19 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Godwin, J. W., Pinto, A. R. & Rosenthal, N. A. Chasing the recipe for a pro-regenerative immune system. Semin. Cell Dev. Biol. 61, 71–79 (2017).

    CAS  PubMed  Google Scholar 

  79. Hofmann, U. & Frantz, S. Role of lymphocytes in myocardial injury, healing, and remodeling after myocardial infarction. Circ. Res. 116, 354–367 (2015).

    CAS  PubMed  Google Scholar 

  80. Zouggari, Y. et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat. Med. 19, 1273–1280 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Nian, M., Lee, P., Khaper, N. & Liu, P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ. Res. 94, 1543–1553 (2004).

    CAS  PubMed  Google Scholar 

  82. Porter, K. E. & Turner, N. A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol. Ther. 123, 255–278 (2009).

    CAS  PubMed  Google Scholar 

  83. Tang, T. T. et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res. Cardiol. 107, 232 (2012).

    PubMed  Google Scholar 

  84. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

    CAS  PubMed  Google Scholar 

  85. Furtado, M. B., Nim, H. T., Boyd, S. E. & Rosenthal, N. A. View from the heart: cardiac fibroblasts in development, scarring and regeneration. Development 143, 387–397 (2016).

    CAS  PubMed  Google Scholar 

  86. Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

    CAS  PubMed  Google Scholar 

  87. Goldsmith, E. C. et al. Organization of fibroblasts in the heart. Dev. Dyn. 230, 787–794 (2004).

    CAS  PubMed  Google Scholar 

  88. Bowers, S. L., Borg, T. K. & Baudino, T. A. The dynamics of fibroblast-myocyte-capillary interactions in the heart. Ann. NY Acad. Sci. 1188, 143–152 (2010).

    PubMed  Google Scholar 

  89. Camelliti, P., Borg, T. K. & Kohl, P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc. Res. 65, 40–51 (2005).

    CAS  PubMed  Google Scholar 

  90. Kohl, P., Kamkin, A. G., Kiseleva, I. S. & Noble, D. Mechanosensitive fibroblasts in the sino-atrial node region of rat heart: interaction with cardiomyocytes and possible role. Exp. Physiol. 79, 943–956 (1994).

    CAS  PubMed  Google Scholar 

  91. Ongstad, E. & Kohl, P. Fibroblast-myocyte coupling in the heart: potential relevance for therapeutic interventions. J. Mol. Cell. Cardiol. 91, 238–246 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ali, S. R. et al. Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ. Res. 115, 625–635 (2014).

    CAS  PubMed  Google Scholar 

  93. Moore-Morris, T. et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J. Clin. Invest. 124, 2921–2934 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Moore-Morris, T., Tallquist, M. D. & Evans, S. M. Sorting out where fibroblasts come from. Circ. Res. 115, 602–604 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Tallquist, M. D. & Molkentin, J. D. Redefining the identity of cardiac fibroblasts. Nat. Rev. Cardiol. 14, 484–491 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. Bani, D. & Nistri, S. New insights into the morphogenic role of stromal cells and their relevance for regenerative medicine. lessons from the heart. J. Cell. Mol. Med. 18, 363–370 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Ieda, M. et al. Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev. Cell 16, 233–244 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lajiness, J. D. & Conway, S. J. The dynamic role of cardiac fibroblasts in development and disease. J. Cardiovasc. Transl Res. 5, 739–748 (2012).

    PubMed  PubMed Central  Google Scholar 

  99. Quaife-Ryan, G. A. et al. Multicellular transcriptional analysis of mammalian heart regeneration. Circulation 136, 1123–1139 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Kanisicak, O. et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat. Commun. 7, 12260 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Moore-Morris, T. et al. Infarct fibroblasts do not derive from bone marrow lineages. Circ. Res. 122, 583–590 (2018).

    CAS  PubMed  Google Scholar 

  102. Acharya, A. et al. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 139, 2139–2149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Bryant, D. M. et al. A systematic analysis of neonatal mouse heart regeneration after apical resection. J. Mol. Cell. Cardiol. 79, 315–318 (2015).

    CAS  PubMed  Google Scholar 

  104. Notari, M. et al. The local microenvironment limits the regenerative potential of the mouse neonatal heart. Sci. Adv. 4, eaao5553 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. Furtado, M. B., Costa, M. W. & Rosenthal, N. A. The cardiac fibroblast: origin, identity and role in homeostasis and disease. Differentiation 92, 93–101 (2016).

    CAS  PubMed  Google Scholar 

  106. Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Eroglu, E. & Chien, K. R. Heart regeneration 4.0: matrix medicine. Dev. Cell 42, 7–8 (2017).

    CAS  PubMed  Google Scholar 

  108. Furtado, M. B. et al. Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair. Circ. Res. 114, 1422–1434 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ivey, M. J. & Tallquist, M. D. Defining the cardiac fibroblast. Circ. J. 80, 2269–2276 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Doppler, S. A. et al. Cardiac fibroblasts: more than mechanical support. J. Thorac. Dis. 9, S36–S51 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Ivey, M. J. et al. Resident fibroblast expansion during cardiac growth and remodeling. J. Mol. Cell. Cardiol. 114, 161–174 (2018).

    CAS  PubMed  Google Scholar 

  112. El Agha, E. et al. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis. Cell Stem Cell 20, 261–273 (2017).

    CAS  PubMed  Google Scholar 

  113. Paylor, B., Fernandes, J., McManus, B. & Rossi, F. Tissue-resident Sca1+ PDGFRalpha+ mesenchymal progenitors are the cellular source of fibrofatty infiltration in arrhythmogenic cardiomyopathy. F1000Res. 2, 141 (2013).

    PubMed  PubMed Central  Google Scholar 

  114. Lombardi, R. et al. Cardiac fibro-adipocyte progenitors express desmosome proteins and preferentially differentiate to adipocytes upon deletion of the desmoplakin gene. Circ. Res. 119, 41–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Pillai, I. C. L. et al. Cardiac fibroblasts adopt osteogenic fates and can be targeted to attenuate pathological heart calcification. Cell Stem Cell 20, 218–232 (2017).

    CAS  PubMed  Google Scholar 

  116. Fu, X. et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J. Clin. Invest. 128, 2127–2143 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. Chang, Y., Li, H. & Guo, Z. Mesenchymal stem cell-like properties in fibroblasts. Cell. Physiol. Biochem. 34, 703–714 (2014).

    CAS  PubMed  Google Scholar 

  118. Denu, R. A. et al. Fibroblasts and mesenchymal stromal/stem cells are phenotypically indistinguishable. Acta Haematol. 136, 85–97 (2016).

    CAS  PubMed  Google Scholar 

  119. Haniffa, M. A., Collin, M. P., Buckley, C. D. & Dazzi, F. Mesenchymal stem cells: the fibroblasts’ new clothes? Haematologica 94, 258–263 (2009).

    CAS  PubMed  Google Scholar 

  120. Hematti, P. Mesenchymal stromal cells and fibroblasts: a case of mistaken identity? Cytotherapy 14, 516–521 (2012).

    CAS  PubMed  Google Scholar 

  121. Covas, D. T. et al. Mesenchymal stem cells can be obtained from the human saphena vein. Exp. Cell Res. 309, 340–344 (2005).

    CAS  PubMed  Google Scholar 

  122. Covas, D. T. et al. Mesenchymal stem cells, fibroblasts and pericytes: different functional states of the same cell? Blood 106, 4310 (2005).

    Google Scholar 

  123. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  124. Menard, C. & Tarte, K. Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application. Stem Cell Res. Ther. 4, 64 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Cai, C. L. & Molkentin, J. D. The elusive progenitor cell in cardiac regeneration: slip slidin’ away. Circ. Res. 120, 400–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    CAS  PubMed  Google Scholar 

  127. Chen, C. et al. Perivascular multi-lineage progenitor cells in human organs: regenerative units, cytokine sources or both? Cytokine Growth Factor Rev. 20, 429–434 (2009).

    CAS  PubMed  Google Scholar 

  128. Katare, R. et al. Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circul. Res. 109, 894–906 (2011).

    CAS  Google Scholar 

  129. Corselli, M., Chen, C. W., Crisan, M., Lazzari, L. & Peault, B. Perivascular ancestors of adult multipotent stem cells. Arterioscler. Thromb. Vasc. Biol. 30, 1104–1109 (2010).

    CAS  PubMed  Google Scholar 

  130. Ferland-McCollough, D., Slater, S., Richard, J., Reni, C. & Mangialardi, G. Pericytes, an overlooked player in vascular pathobiology. Pharmacol. Ther. 171, 30–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kramann, R. et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16, 51–66 (2015).

    CAS  PubMed  Google Scholar 

  132. Halade, G. V. Targeting resolution of inflammation following myocardial infarction. J. Cardiol. Clin. Res. 1, 1008 (2013).

    Google Scholar 

  133. Prabhu, S. D. & Frangogiannis, N. G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ. Res. 119, 91–112 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Zeigler, A. C., Richardson, W. J., Holmes, J. W. & Saucerman, J. J. Computational modeling of cardiac fibroblasts and fibrosis. J. Mol. Cell. Cardiol. 93, 73–83 (2016).

    CAS  PubMed  Google Scholar 

  135. Baudino, T. A., Carver, W., Giles, W. & Borg, T. K. Cardiac fibroblasts: friend or foe? Am. J. Physiol. Heart Circ. Physiol. 291, H1015–H1026 (2006).

    CAS  PubMed  Google Scholar 

  136. Martin, M. L. & Blaxall, B. C. Cardiac intercellular communication: are myocytes and fibroblasts fair-weather friends? J. Cardiovasc. Transl Res. 5, 768–782 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. Emanueli, C., Shearn, A. I., Angelini, G. D. & Sahoo, S. Exosomes and exosomal miRNAs in cardiovascular protection and repair. Vascul. Pharmacol. 71, 24–30 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Yuan, M. J., Maghsoudi, T. & Wang, T. Exosomes mediate the intercellular communication after myocardial infarction. Int. J. Med. Sci. 13, 113–116 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhang, Y., Hu, Y. W., Zheng, L. & Wang, Q. Characteristics and roles of exosomes in cardiovascular disease. DNA Cell Biol. 36, 202–211 (2017).

    CAS  PubMed  Google Scholar 

  140. Turner, N. A. et al. Mechanism of TNFalpha-induced IL-1alpha, IL-1beta and IL-6 expression in human cardiac fibroblasts: effects of statins and thiazolidinediones. Cardiovasc. Res. 76, 81–90 (2007).

    CAS  PubMed  Google Scholar 

  141. Turner, N. A. et al. Interleukin-1alpha stimulates proinflammatory cytokine expression in human cardiac myofibroblasts. Am. J. Physiol. Heart Circ. Physiol. 297, H1117–H1127 (2009).

    CAS  PubMed  Google Scholar 

  142. Ma, Y., Iyer, R. P., Jung, M., Czubryt, M. P. & Lindsey, M. L. Cardiac fibroblast activation post-myocardial infarction: current knowledge gaps. Trends Pharmacol. Sci. 38, 448–458 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Kawaguchi, M. et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123, 594–604 (2011).

    CAS  PubMed  Google Scholar 

  144. Lindner, D. et al. Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res. Cardiol. 109, 428 (2014).

    PubMed  Google Scholar 

  145. Nakaya, M. et al. Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J. Clin. Invest. 127, 383–401 (2017).

    PubMed  Google Scholar 

  146. Bhide, V. M. et al. Collagen phagocytosis by fibroblasts is regulated by decorin. J. Biol. Chem. 280, 23103–23113 (2005).

    CAS  PubMed  Google Scholar 

  147. Hall, S. E., Savill, J. S., Henson, P. M. & Haslett, C. Apoptotic neutrophils are phagocytosed by fibroblasts with participation of the fibroblast vitronectin receptor and involvement of a mannose/fucose-specific lectin. J. Immunol. 153, 3218–3227 (1994).

    CAS  PubMed  Google Scholar 

  148. Arlein, W. J., Shearer, J. D. & Caldwell, M. D. Continuity between wound macrophage and fibroblast phenotype: analysis of wound fibroblast phagocytosis. Am. J. Physiol. 275, R1041–R1048 (1998).

    CAS  PubMed  Google Scholar 

  149. Aurora, A. B. & Olson, E. N. Immune modulation of stem cells and regeneration. Cell Stem Cell 15, 14–25 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Heredia, J. E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Swonger, J. M., Liu, J. S., Ivey, M. J. & Tallquist, M. D. Genetic tools for identifying and manipulating fibroblasts in the mouse. Differentiation 92, 66–83 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Liehn, E. A., Postea, O., Curaj, A. & Marx, N. Repair after myocardial infarction, between fantasy and reality: the role of chemokines. J. Am. Coll. Cardiol. 58, 2357–2362 (2011).

    PubMed  Google Scholar 

  153. Saxena, A. et al. IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J. Immunol. 191, 4838–4848 (2013).

    CAS  PubMed  Google Scholar 

  154. Wang, Y., Chen, X., Cao, W. & Shi, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol. 15, 1009–1016 (2014).

    CAS  PubMed  Google Scholar 

  155. Kaplan, J. M., Youd, M. E. & Lodie, T. A. Immunomodulatory activity of mesenchymal stem cells. Curr. Stem Cell Res. Ther. 6, 297–316 (2011).

    CAS  PubMed  Google Scholar 

  156. Qi, K., Li, N., Zhang, Z. & Melino, G. Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response. Cell. Immunol. 326, 86–93 (2017).

    PubMed  Google Scholar 

  157. Dobaczewski, M. et al. Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ. Res. 107, 418–428 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhou, B. et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J. Clin. Invest. 121, 1894–1904 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Rog-Zielinska, E. A., Norris, R. A., Kohl, P. & Markwald, R. The living scar — cardiac fibroblasts and the injured heart. Trends Mol. Med. 22, 99–114 (2016).

    PubMed  PubMed Central  Google Scholar 

  160. Minicucci, M. F., Azevedo, P. S., Polegato, B. F., Paiva, S. A. & Zornoff, L. A. Heart failure after myocardial infarction: clinical implications and treatment. Clin. Cardiol. 34, 410–414 (2011).

    PubMed  PubMed Central  Google Scholar 

  161. Lakhin, A. V., Tarantul, V. Z. & Gening, L. V. Aptamers: problems, solutions and prospects. Acta Naturae 5, 34–43 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Dou, X. Q. et al. Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity. Int. J. Nanomed. 13, 763–776 (2018).

    Google Scholar 

  163. Ngo, D. et al. Aptamer-based proteomic profiling reveals novel candidate biomarkers and pathways in cardiovascular disease. Circulation 134, 270–285 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Sakai, H. et al. A cell-penetrating phospholamban-specific RNA aptamer enhances Ca2+ transients and contractile function in cardiomyocytes. J. Mol. Cell. Cardiol. 76, 177–185 (2014).

    CAS  PubMed  Google Scholar 

  165. Li, J., Yousefi, K., Ding, W., Singh, J. & Shehadeh, L. A. Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure. Cardiovasc. Res. 113, 633–643 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Wallukat, G. et al. Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: a vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. Atherosclerosis 244, 44–47 (2016).

    CAS  PubMed  Google Scholar 

  167. Haberland, A. et al. Neutralization of pathogenic beta1-receptor autoantibodies by aptamers in vivo: the first successful proof of principle in spontaneously hypertensive rats. Mol. Cell. Biochem. 393, 177–180 (2014).

    CAS  PubMed  Google Scholar 

  168. Port, J. D. & Bristow, M. R. Aptamer therapy for heart failure? Circ. Res. 109, 982–983 (2011).

    CAS  PubMed  Google Scholar 

  169. Nimjee, S. M., Povsic, T. J., Sullenger, B. A. & Becker, R. C. Translation and clinical development of antithrombotic aptamers. Nucleic Acid. Ther. 26, 147–155 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Jilma, B. et al. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb. Haemost. 104, 563–570 (2010).

    CAS  PubMed  Google Scholar 

  171. Lincoff, A. M. et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 387, 349–356 (2016).

    CAS  PubMed  Google Scholar 

  172. Povsic, T. J. et al. A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: design and rationale of the RADAR Phase IIb trial. Am. Heart J. 161, 261–268 (2011).

    CAS  PubMed  Google Scholar 

  173. Povsic, T. J. et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur. Heart J. 34, 2481–2489 (2013).

    CAS  PubMed  Google Scholar 

  174. Povsic, T. J. et al. Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and pharmacodynamic substudy. Eur. Heart J. 32, 2412–2419 (2011).

    CAS  PubMed  Google Scholar 

  175. Staudacher, D. L. et al. Direct factor IXa inhibition with the RNA-aptamer pegnivacogin reduces platelet reactivity in vitro and residual platelet aggregation in patients with acute coronary syndromes. Eur. Heart J. Acute Cardiovasc. Care https://doi.org/10.1177/2048872617703065 (2017).

    Article  PubMed  Google Scholar 

  176. Hinderer, S., Brauchle, E. & Schenke-Layland, K. Generation and assessment of functional biomaterial scaffolds for applications in cardiovascular tissue engineering and regenerative medicine. Adv. Healthc. Mater. 4, 2326–2341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Reis, L. A., Chiu, L. L., Feric, N., Fu, L. & Radisic, M. Biomaterials in myocardial tissue engineering. J. Tissue Eng. Regen Med. 10, 11–28 (2016).

    CAS  PubMed  Google Scholar 

  178. Amir, G. et al. Evaluation of a peritoneal-generated cardiac patch in a rat model of heterotopic heart transplantation. Cell Transplant. 18, 275–282 (2009).

    PubMed  Google Scholar 

  179. Dvir, T. et al. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc. Natl Acad. Sci. USA 106, 14990–14995 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Christman, K. L. et al. Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J. Am. Coll. Cardiol. 44, 654–660 (2004).

    CAS  PubMed  Google Scholar 

  181. Yu, J. et al. Restoration of left ventricular geometry and improvement of left ventricular function in a rodent model of chronic ischemic cardiomyopathy. J. Thorac. Cardiovasc. Surg. 137, 180–187 (2009).

    PubMed  Google Scholar 

  182. Chiu, L. L. & Radisic, M. Scaffolds with covalently immobilized VEGF and Angiopoietin-1 for vascularization of engineered tissues. Biomaterials 31, 226–241 (2010).

    CAS  PubMed  Google Scholar 

  183. Zimmermann, W. H. et al. Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat. Med. 12, 452–458 (2006).

    CAS  PubMed  Google Scholar 

  184. Zimmermann, W. H. et al. Tissue engineering of a differentiated cardiac muscle construct. Circ. Res. 90, 223–230 (2002).

    CAS  PubMed  Google Scholar 

  185. Matsubayashi, K. et al. Improved left ventricular aneurysm repair with bioengineered vascular smooth muscle grafts. Circulation 108 (Suppl. 1), 219–225 (2003).

    Google Scholar 

  186. Madden, L. R. et al. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc. Natl Acad. Sci. USA 107, 15211–15216 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Yeong, W. Y. et al. Porous polycaprolactone scaffold for cardiac tissue engineering fabricated by selective laser sintering. Acta Biomater. 6, 2028–2034 (2010).

    CAS  PubMed  Google Scholar 

  188. Lesman, A. et al. Transplantation of a tissue-engineered human vascularized cardiac muscle. Tissue Eng. Part A 16, 115–125 (2010).

    CAS  PubMed  Google Scholar 

  189. Rai, R. et al. Biomimetic poly(glycerol sebacate) (PGS) membranes for cardiac patch application. Mater. Sci. Eng. C Mater. Biol. Appl. 33, 3677–3687 (2013).

    CAS  PubMed  Google Scholar 

  190. Ott, H. C. et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat. Med. 14, 213–221 (2008).

    CAS  PubMed  Google Scholar 

  191. Guyette, J. P. et al. Bioengineering human myocardium on native extracellular matrix. Circ. Res. 118, 56–72 (2016).

    CAS  PubMed  Google Scholar 

  192. Sanchez, P. L. et al. Acellular human heart matrix: a critical step toward whole heart grafts. Biomaterials 61, 279–289 (2015).

    CAS  PubMed  Google Scholar 

  193. Kitahara, H. et al. Heterotopic transplantation of a decellularized and recellularized whole porcine heart. Interact. Cardiovasc. Thorac Surg. 22, 571–579 (2016).

    PubMed  PubMed Central  Google Scholar 

  194. Kinch, M. S. An overview of FDA-approved biologics medicines. Drug Discov. Today 20, 393–398 (2015).

    CAS  PubMed  Google Scholar 

  195. Alvarez, P. & Briasoulis, A. Immune modulation in heart failure: the promise of novel biologics. Curr. Treat. Options Cardiovasc. Med. 20, 26 (2018).

    PubMed  Google Scholar 

  196. Roubille, C., Martel-Pelletier, J., Haraoui, B., Tardif, J. C. & Pelletier, J. P. Biologics and the cardiovascular system: a double-edged sword. Antiinflamm. Antiallergy Agents Med. Chem. 12, 68–82 (2013).

    CAS  PubMed  Google Scholar 

  197. Becker, N. P., Muller, J., Gottel, P., Wallukat, G. & Schimke, I. Cardiomyopathy — an approach to the autoimmune background. Autoimmun. Rev. 16, 269–286 (2017).

    CAS  PubMed  Google Scholar 

  198. Kapur, N. K. et al. Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation 125, 2728–2738 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Zhou, Y., Li, Y. & Mu, T. HMGB1 neutralizing antibody attenuates cardiac injury and apoptosis induced by hemorrhagic shock/resuscitation in rats. Biol. Pharm. Bull. 38, 1150–1160 (2015).

    CAS  PubMed  Google Scholar 

  200. Small, E. M. & Olson, E. N. Pervasive roles of microRNAs in cardiovascular biology. Nature 469, 336–342 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Ali, S. S. et al. Pathological microRNAs in acute cardiovascular diseases and microRNA therapeutics. J. Acute Dis. 5, 9–15 (2016).

    CAS  Google Scholar 

  202. Chistiakov, D. A., Orekhov, A. N. & Bobryshev, Y. V. Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction). J. Mol. Cell. Cardiol. 94, 107–121 (2016).

    CAS  PubMed  Google Scholar 

  203. Yu, X., Hong, F. & Zhang, Y. Q. Bio-effect of nanoparticles in the cardiovascular system. J. Biomed. Mater. Res. A 104, 2881–2897 (2016).

    CAS  PubMed  Google Scholar 

  204. Suarez, S., Almutairi, A. & Christman, K. L. Micro- and nanoparticles for treating cardiovascular disease. Biomater. Sci. 3, 564–580 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Chang, M. Y. et al. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. J. Control. Release 170, 287–294 (2013).

    CAS  PubMed  Google Scholar 

  206. Dvir, T. et al. Nanoparticles targeting the infarcted heart. Nano Lett. 11, 4411–4414 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Feld, S. et al. Reduction of canine infarct size by bolus intravenous administration of liposomal prostaglandin E1: comparison with control, placebo liposomes, and continuous intravenous infusion of prostaglandin E1. Am. Heart J. 132, 747–757 (1996).

    CAS  PubMed  Google Scholar 

  208. Scott, R. C. et al. Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 23, 3361–3367 (2009).

    CAS  PubMed  Google Scholar 

  209. Verma, D. D., Hartner, W. C., Levchenko, T. S., Bernstein, E. A. & Torchilin, V. P. ATP-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction. Pharm. Res. 22, 2115–2120 (2005).

    CAS  PubMed  Google Scholar 

  210. Verma, D. D., Levchenko, T. S., Bernstein, E. A. & Torchilin, V. P. ATP-loaded liposomes effectively protect mechanical functions of the myocardium from global ischemia in an isolated rat heart model. J. Control. Release 108, 460–471 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Batrakova, E. V. & Kim, M. S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J. Control. Release 219, 396–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Sahoo, S. & Losordo, D. W. Exosomes and cardiac repair after myocardial infarction. Circ. Res. 114, 333–344 (2014).

    CAS  PubMed  Google Scholar 

  213. Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Gladka, M. M. et al. Single-cell sequencing of the healthy and diseased heart reveals ckap4 as a new modulator of fibroblasts activation. Circulation 138, 166–180 (2018).

    CAS  PubMed  Google Scholar 

  215. Waardenberg, A. J., Ramialison, M., Bouveret, R. & Harvey, R. P. Genetic networks governing heart development. Cold Spring Harb. Perspect. Med. 4, a013839 (2014).

    PubMed  PubMed Central  Google Scholar 

  216. Zeng, B., Ren, X. F., Cao, F., Zhou, X. Y. & Zhang, J. Developmental patterns and characteristics of epicardial cell markers Tbx18 and Wt1 in murine embryonic heart. J. Biomed. Sci. 18, 67 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Epstein, J. A. & Franklin, H. Epstein lecture. Cardiac development and implications for heart disease. N. Engl. J. Med. 363, 1638–1647 (2010).

    CAS  PubMed  Google Scholar 

  218. Beltrami, A. P. et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776 (2003).

    CAS  PubMed  Google Scholar 

  219. Oh, H. et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc. Natl Acad. Sci. USA 100, 12313–12318 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Noseda, M. et al. PDGFRalpha demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium. Nat. Commun. 6, 6930 (2015).

    CAS  PubMed  Google Scholar 

  221. Asakura, A. & Rudnicki, M. A. Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp. Hematol. 30, 1339–1345 (2002).

    PubMed  Google Scholar 

  222. Chong, J. J. et al. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell 9, 527–540 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Laugwitz, K. L. et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature 474, 640–644 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Norris, R. A. et al. Expression of the familial cardiac valvular dystrophy gene, filamin-A, during heart morphogenesis. Dev. Dyn. 239, 2118–2127 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Takeda, N. et al. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J. Clin. Invest. 120, 254–265 (2010).

    CAS  PubMed  Google Scholar 

  227. Sato, T. N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).

    CAS  PubMed  Google Scholar 

  228. Newman, P. J. et al. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247, 1219–1222 (1990).

    CAS  PubMed  Google Scholar 

  229. Xiao, Q. et al. Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury. Arterioscler. Thromb. Vasc. Biol. 26, 2244–2251 (2006).

    CAS  PubMed  Google Scholar 

  230. Zachary, I. & Gliki, G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc. Res. 49, 568–581 (2001).

    CAS  PubMed  Google Scholar 

  231. Wilhelmi, M. H., Leyh, R. G., Wilhelmi, M. & Haverich, A. Upregulation of endothelial adhesion molecules in hearts with congestive and ischemic cardiomyopathy: immunohistochemical evaluation of inflammatory endothelial cell activation. Eur. J. Cardiothorac. Surg. 27, 122–127 (2005).

    PubMed  Google Scholar 

  232. Duim, S. N., Kurakula, K., Goumans, M. J. & Kruithof, B. P. Cardiac endothelial cells express Wilms’ tumor-1: Wt1 expression in the developing, adult and infarcted heart. J. Mol. Cell. Cardiol. 81, 127–135 (2015).

    CAS  PubMed  Google Scholar 

  233. Breviario, F. et al. Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler. Thromb. Vasc. Biol. 15, 1229–1239 (1995).

    CAS  PubMed  Google Scholar 

  234. Katz, T. C. et al. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev. Cell 22, 639–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Jackson, D. G. The lymphatics revisited: new perspectives from the hyaluronan receptor LYVE-1. Trends Cardiovasc. Med. 13, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  236. Srinivasan, R. S. et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 21, 2422–2432 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Rensen, S. S., Doevendans, P. A. & van Eys, G. J. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth. Heart J. 15, 100–108 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Mellgren, A. M. et al. Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations. Circ. Res. 103, 1393–1401 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Wetzel, U., Lutsch, G., Haase, H., Ganten, U. & Morano, I. Expression of smooth muscle myosin heavy chain B in cardiac vessels of normotensive and hypertensive rats. Circ. Res. 83, 204–209 (1998).

    CAS  PubMed  Google Scholar 

  240. Bochmann, L. et al. Revealing new mouse epicardial cell markers through transcriptomics. PLOS ONE 5, e11429 (2010).

    PubMed  PubMed Central  Google Scholar 

  241. Braitsch, C. M. & Yutzey, K. E. Transcriptional control of cell lineage development in epicardium-derived cells. J. Dev. Biol. 1, 92–111 (2013).

    CAS  PubMed  Google Scholar 

  242. Geijtenbeek, T. B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000).

    CAS  PubMed  Google Scholar 

  243. Kuijpers, T. W. et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J. Clin. Invest. 120, 214–222 (2010).

    CAS  PubMed  Google Scholar 

  244. Hak, L. et al. NK cell compartment in patients with coronary heart disease. Immun. Ageing 4, 3 (2007).

    PubMed  PubMed Central  Google Scholar 

  245. Biassoni, R. et al. Human natural killer cell receptors: insights into their molecular function and structure. J. Cell. Mol. Med. 7, 376–387 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Ryan, J. C., Turck, J., Niemi, E. C., Yokoyama, W. M. & Seaman, W. E. Molecular cloning of the NK1.1 antigen, a member of the NKR-P1 family of natural killer cell activation molecules. J. Immunol. 149, 1631–1635 (1992).

    CAS  PubMed  Google Scholar 

  247. Sewell, W. A. et al. The murine homologue of the T lymphocyte CD2 antigen: molecular cloning, chromosome assignment and cell surface expression. Eur. J. Immunol. 17, 1015–1020 (1987).

    CAS  PubMed  Google Scholar 

  248. Clevers, H. et al. Characterization and expression of the murine CD3-epsilon gene. Proc. Natl Acad. Sci. USA 85, 8623–8627 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. Pillars article: the CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. 1994. J. Immunol. 185, 2650–2657 (2010).

    CAS  PubMed  Google Scholar 

  250. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    CAS  PubMed  Google Scholar 

  251. Dahlin, J. S., Ding, Z. & Hallgren, J. Distinguishing mast cell progenitors from mature mast cells in mice. Stem Cells Dev. 24, 1703–1711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Eadie, A. L., Simpson, J. A. & Brunt, K. R. “Fibroblast” pharmacotherapy — advancing the next generation of therapeutics for clinical cardiology. J. Mol. Cell. Cardiol. 94, 176–179 (2016).

    CAS  PubMed  Google Scholar 

  253. Metcalfe, D. D. et al. Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases. World Allergy Organ. J. 9, 7 (2016).

    PubMed  PubMed Central  Google Scholar 

  254. Bonecchi, R. et al. Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils. J. Immunol. 162, 474–479 (1999).

    CAS  PubMed  Google Scholar 

  255. Panopoulos, A. D. & Watowich, S. S. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and ‘emergency’ hematopoiesis. Cytokine 42, 277–288 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J. Immunol. 170, 3233–3242 (2003).

    CAS  PubMed  Google Scholar 

  257. Fregoso, S. P. & Hoover, D. B. Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart. Neuroscience 221, 28–36 (2012).

    CAS  PubMed  Google Scholar 

  258. Doerflinger, N. H., Macklin, W. B. & Popko, B. Inducible site-specific recombination in myelinating cells. Genesis 35, 63–72 (2003).

    CAS  PubMed  Google Scholar 

  259. Deng, Y. et al. Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP. Genesis 52, 341–349 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Part of the work from the authors’ group cited here was supported by grants from the British Heart Foundation (Regenerative Medicine Network of Excellence), the UK Regenerative Medicine Platform (UKRMP) Immunomodulation Hub, and the Australian Regenerative Medicine Institute (supported by grants from the State Government of Victoria and the Australian Government).

Reviewer information

Nature Reviews Cardiology thanks N. G. Frangogiannis and the other anonymous reviewers for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Elvira Forte, Milena Furtado.

Authors and Affiliations

  1. The Jackson Laboratory, Bar Harbor, ME, USA

    Elvira Forte, Milena Bastos Furtado & Nadia Rosenthal

  2. National Heart and Lung Institute, Imperial College London, Faculty of Medicine, Imperial Centre for Translational and Experimental Medicine, London, UK

    Nadia Rosenthal

Authors
  1. Elvira Forte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milena Bastos Furtado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadia Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

Corresponding author

Correspondence to Nadia Rosenthal.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Myofibroblasts

Specialized fibroblasts that have developed some phenotypic and functional features of smooth muscle cells, including expression of aortic smooth muscle actin (ACTA2) and contraction capabilities upon stimulation.

Granulation tissue

Highly vascularized, connective tissue with granular projections that temporarily replaces lost tissue during the repair process.

Yolk sac

A membranous sac that normally provides nutrition (yolk) to the developing embryo. In mammals, the yolk sac is part of the early circulatory system, linked to the primitive aorta, and primitive blood cells are formed as ‘blood islands’ in the yolk sac during early development (around embryonic day 7 in mice).

Plasma cells

Circulating, mature B cells that produce large amounts of a specific antibody.

Memory T cells

A subset of T cells that has previously encountered and responded to their cognate antigen; they provide rapid protection upon re-exposure to the same antigen owing to improved function (memory of antigen encounter) and lower activation threshold.

Regulatory T cells

(Treg cells). A subset of CD4+ T cells that regulates and suppresses other immune cells, thus maintaining tolerance to self-antigens and preventing autoimmune diseases.

Tolerogenic phenotype

The phenotype of immune cells that are tolerant to a particular antigen.

Effector T cells

T cells (CD4+,CD8+, and Treg) that actively respond to a stimulus, such as co-stimulation.

Autoreactive T cells

A subset of T cells that has bypassed the negative selection in lymphatic organs and responds to self-antigen stimulation.

Biologic therapies

Treatments that make use of natural biological molecules, such as antibodies and growth factors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Forte, E., Furtado, M.B. & Rosenthal, N. The interstitium in cardiac repair: role of the immune–stromal cell interplay. Nat Rev Cardiol 15, 601–616 (2018). https://doi.org/10.1038/s41569-018-0077-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-018-0077-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research