Skip to main content

Advertisement

SpringerLink
Log in

Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis

  • Regenerative Medicine (SM Wu, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Cardiac regeneration has received much attention as a possible means to treat various forms of cardiac injury. This review will explore the field of cardiac regeneration by highlighting the existing animal models, describing the involved molecular pathways, and discussing attempts to harness cardiac regeneration to treat cardiomyopathies.

Recent Findings

Light chain cardiac amyloidosis is a degenerative disease characterized by progressive heart failure due to amyloid fibril deposition and light chain–mediated cardiotoxicity. Recent findings in a zebrafish model of light chain amyloidosis suggest that cardiac regenerative confers a protective effect against this disease.

Summary

Cardiac regeneration remains an intriguing potential tool for treating cardiovascular disease. Degenerative diseases, such as light chain cardiac amyloidosis, may be particularly suited for therapeutic interventions that target cardiac regeneration. Further studies are needed to translate preclinical findings for cardiac regeneration into effective therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lepilina A, Coon AN, Kikuchi K, Holdway JE, Roberts RW, Burns CG, et al. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell. 2006;127(3):607–19.

    Article  CAS  PubMed  Google Scholar 

  2. Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002;298(5601):2188–90.

    Article  CAS  PubMed  Google Scholar 

  3. Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature. 2010;464(7288):606–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang J, Panakova D, Kikuchi K, Holdway JE, Gemberling M, Burris JS, et al. The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development. 2011;138(16):3421–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gonzalez-Rosa JM, Martin V, Peralta M, Torres M, Mercader N. Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development. 2011;138(9):1663–74.

    Article  CAS  PubMed  Google Scholar 

  6. Drenckhahn JD, Schwarz QP, Gray S, Laskowski A, Kiriazis H, Ming Z, et al. Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development. Dev Cell. 2008;15(4):521–33.

    Article  CAS  PubMed  Google Scholar 

  7. Sturzu AC, Rajarajan K, Passer D, Plonowska K, Riley A, Tan TC, et al. Fetal mammalian heart generates a robust compensatory response to cell loss. Circulation. 2015;132(2):109–21.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011;331(6020):1078–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Haubner BJ, Adamowicz-Brice M, Khadayate S, Tiefenthaler V, Metzler B, Aitman T, et al. Complete cardiac regeneration in a mouse model of myocardial infarction. Aging. 2012;4(12):966–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2013;493(7432):433–6.

    Article  CAS  PubMed  Google Scholar 

  11. Klose K, Gossen M, Stamm C. Turning fibroblasts into cardiomyocytes: technological review of cardiac transdifferentiation strategies. FASEB J. 2019;33(1):49–70.

    Article  CAS  PubMed  Google Scholar 

  12. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, et al. Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature. 2010;464(7288):601–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gupta V, Poss KD. Clonally dominant cardiomyocytes direct heart morphogenesis. Nature. 2012;484(7395):479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jonker SS, Zhang L, Louey S, Giraud GD, Thornburg KL, Faber JJ. Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol. 2007;102(3):1130–42.

    Article  PubMed  Google Scholar 

  15. Soonpaa MH, Kim KK, Pajak L, Franklin M, Field LJ. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Phys. 1996;271(5 Pt 2):H2183–9.

    CAS  Google Scholar 

  16. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell. 2014;157(3):565–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. • Mohamed TMA, Ang YS, Radzinsky E, Zhou P, Huang Y, Elfenbein A, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell. 2018;173(1):104–16 e12 This study suggests that a combination of cell cycle regulators can induce proliferation in post-mitotic mouse, rat, and human cardiomyocytes and that this strategy is beneficial in murine myocardial infarction models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. • Unno K, Oikonomopoulos A, Fujikawa Y, Okuno Y, Narita S, Kato T, et al. Alteration in ventricular pressure stimulates cardiac repair and remodeling. J Mol Cell Cardiol. 2019;133:174–87 This study suggests that proliferation of adult cardiac myocytes can be locally stimulated by changes in ventricular pressure, which can be leveraged for cardiac repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lien CL, Schebesta M, Makino S, Weber GJ, Keating MT. Gene expression analysis of zebrafish heart regeneration. PLoS Biol. 2006;4(8):e260.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, et al. Macrophages are required for neonatal heart regeneration. J Clin Invest. 2014;124(3):1382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Han C, Nie Y, Lian H, Liu R, He F, Huang H, et al. Acute inflammation stimulates a regenerative response in the neonatal mouse heart. Cell Res. 2015;25(10):1137–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lavine KJ, Epelman S, Uchida K, Weber KJ, Nichols CG, Schilling JD, et al. Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart. Proc Natl Acad Sci U S A. 2014;111(45):16029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sallin P, de Preux Charles AS, Duruz V, Pfefferli C, Jazwinska A. A dual epimorphic and compensatory mode of heart regeneration in zebrafish. Dev Biol. 2015;399(1):27–40.

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Cao J, Dickson AL, Poss KD. Epicardial regeneration is guided by cardiac outflow tract and Hedgehog signalling. Nature. 2015;522(7555):226–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei K, Serpooshan V, Hurtado C, Diez-Cunado M, Zhao M, Maruyama S, et al. Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature. 2015;525(7570):479–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Epelman S, Liu PP, Mann DL. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol. 2015;15(2):117–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. • Das S, Goldstone AB, Wang H, Farry J, D'Amato G, Paulsen MJ, et al. A unique collateral artery development program promotes neonatal heart regeneration. Cell. 2019;176(5):1128–42 e18 This study identifies a mechanism involving CXCR4 and its ligand CXCL12 by which neonatal heart can form collateral arteries that contribute to cardiac regeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. • Zhao L, Ben-Yair R, Burns CE, Burns CG. Endocardial notch signaling promotes cardiomyocyte proliferation in the regenerating zebrafish heart through wnt pathway antagonism. Cell Rep. 2019;26(3):546–54 e5 This study finds that during zebrafish heart regeneration, endocardial Notch signaling supports cardiomyocyte proliferation by attenuating myocardial Wnt signaling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. • Mahmoudi M, Yu M, Serpooshan V, Wu JC, Langer R, Lee RT, et al. Multiscale technologies for treatment of ischemic cardiomyopathy. Nat Nanotechnol. 2017;12(9):845–55 This review highlights major advancements in nanotechonology for the prevention and treatment of cardiovascular disease, particularly ischemic cardiomyopathy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. • Palmquist-Gomes P, Perez-Pomares JM, Guadix JA. Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates. Heart Fail Rev. 2019;24(1):133–42 This review discusses current approaches to study cardiac repair and regeneration using various animal models.

    Article  CAS  PubMed  Google Scholar 

  31. Behfar A, Crespo-Diaz R, Terzic A, Gersh BJ. Cell therapy for cardiac repair—lessons from clinical trials. Nat Rev Cardiol. 2014;11(4):232–46.

    Article  PubMed  Google Scholar 

  32. Nguyen PK, Rhee JW, Wu JC. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review. JAMA Cardiol. 2016;1(7):831–41.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O'Fallon WM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79(7):1817–22.

    Article  CAS  PubMed  Google Scholar 

  34. •• Falk RH, Alexander KM, Liao R, Dorbala S. AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol. 2016;68(12):1323–41 This review discusses current and novel approaches to the diagnosis and treatment of light chain cardiac amyloidosis.

    Article  PubMed  Google Scholar 

  35. Guan J, Mishra S, Qiu Y, Shi J, Trudeau K, Las G, et al. Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity. EMBO Mol Med. 2014;6(11):1493–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guan J, Mishra S, Shi J, Plovie E, Qiu Y, Cao X, et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol. 2013;108(5):378.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Liao R, Jain M, Teller P, Connors LH, Ngoy S, Skinner M, et al. Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts. Circulation. 2001;104(14):1594–7.

    Article  CAS  PubMed  Google Scholar 

  38. Mishra S, Guan J, Plovie E, Seldin DC, Connors LH, Merlini G, et al. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol. 2013;305(1):H95–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shi J, Guan J, Jiang B, Brenner DA, Del Monte F, Ward JE, et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway. Proc Natl Acad Sci U S A. 2010;107(9):4188–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kastritis E, Papassotiriou I, Merlini G, Milani P, Terpos E, Basset M, et al. Growth differentiation factor-15 is a new biomarker for survival and renal outcomes in light chain amyloidosis. Blood. 2018;131(14):1568–75.

    Article  CAS  PubMed  Google Scholar 

  41. Wang T, Liu J, McDonald C, Lupino K, Zhai X, Wilkins BJ, et al. GDF15 is a heart-derived hormone that regulates body growth. EMBO Mol Med. 2017;9(8):1150–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Carrillo-Garcia C, Prochnow S, Simeonova IK, Strelau J, Holzl-Wenig G, Mandl C, et al. Growth/differentiation factor 15 promotes EGFR signalling, and regulates proliferation and migration in the hippocampus of neonatal and young adult mice. Development. 2014;141(4):773–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang X, Krebbers J, Charalambous P, Machado V, Schober A, Bosse F, et al. Growth/differentiation factor-15 and its role in peripheral nervous system lesion and regeneration. Cell Tissue Res. 2015;362(2):317–30.

    Article  PubMed  Google Scholar 

  44. Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S, et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood. 1998;91(10):3662–70.

    Article  CAS  PubMed  Google Scholar 

  45. Sperry BW, Ikram A, Hachamovitch R, Valent J, Vranian MN, Phelan D, et al. Efficacy of chemotherapy for light-chain amyloidosis in patients presenting with symptomatic heart failure. J Am Coll Cardiol. 2016;67(25):2941–8.

    Article  CAS  PubMed  Google Scholar 

  46. Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, et al. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011;118(25):6610–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. •• Mishra S, Joshi S, Ward JE, Buys EP, Mishra D, Mishra D, et al. Zebrafish model of amyloid light chain cardiotoxicity: regeneration versus degeneration. Am J Physiol Heart Circ Physiol. 2019;316(5):H1158–H66 This study describes a novel transgenic zebrafish model of light chain amyloidosis to gain insights into underlying disease mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Dr. Liao is supported by the National Institutes of Health (R01 grants HL 128135 and HL 132511). Dr. Alexander is supported the American Heart Association-Amos Medical Faculty Development Program.

Author information

Authors and Affiliations

  1. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Shaurya Joshi

  2. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA

    Alessandro Evangelisti, Ronglih Liao & Kevin M. Alexander

  3. Stanford Amyloid Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, 1651 Page Mill Road, Room 2330, Palo Alto, CA, 94304, USA

    Alessandro Evangelisti, Ronglih Liao & Kevin M. Alexander

Authors
  1. Shaurya Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandro Evangelisti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronglih Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin M. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin M. Alexander.

Ethics declarations

Conflict of Interest

Shaurya Joshi, Alessandro Evangelisti, and Ronglih Liao declare that they have no conflict of interest. Kevin Alexander has received a grant from Pfizer and participated on advisory boards for Alnylam and Eidos.

Human and Animal Rights and Informed Consent

The article does not contain any studies with human or animal subjects performed by any of the authors.

Disclaimer

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Regenerative Medicine

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Joshi, S., Evangelisti, A., Liao, R. et al. Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis. Curr Cardiol Rep 22, 1 (2020). https://doi.org/10.1007/s11886-020-1252-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-020-1252-3

Keywords

Search

Navigation