To the content
1 . 2024

Cellular technologies in chronic heart failure: literature review

Abstract

Cardiovascular diseases are the second leading cause of death and disability worldwide after malignancies. Heart failure (HF) has a large impact not only on the economics of healthcare but also on the quality of life, functionality and life expectancy of patients. Pharmacological and non-pharmacological therapies have been developed, but these medical therapies have limited effects to cure patients with severe HF. Heart transplantation is limited due to the low number of donor organs. Human cardiac potential for spontaneous repair is insignificant, so regenerative therapy is in great demand as a new treatment strategy. Currently, there are several strategies for heart regeneration. Transplantation of somatic stem cells was safe and modestly improved cardiac function after myocardial infarction and in patients with HF mainly through paracrine mechanisms. Alternatively, new cardiomyocytes could be generated from induced pluripotent stem cells (iPSCs) to transplant into injured hearts. However, several issues remain to be resolved prior to using iPSC-derived cardiomyocytes, such as a potential risk of tumorigenesis and poor survival of transplanted cells in the injured heart. Recently, direct cardiac cell-free reprogramming has emerged as a novel technology to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells to restore cardiac function.

Many researchers have reported direct reprogramming of the heart in vivo in animal and human cells. In this review, we consider the current status of cardiac cell-based and cell-free regenerative technology, a great hope to treat cardiovascular diseases in clinical practice.

Keywords:chronic heart failure; regenerative cell therapy; cell and cell-free technologies; cardiomyocytes; fibroblasts

Funding. The study had no sponsor support.

Conflict of interest. The authors declare no conflict of interest.

For citation: Rykov M.Yu., Dolgopolov I.S. Cellular technologies in chronic heart failure: literature review. Kardiologiya: novosti, mneniya, obuchenie [Cardiology: News, Opinions, Training]. 2024; 12 (1): 50–9. DOI: https://doi.org/10.33029/2309-1908-2024-12-1-50-59 (in Russian)

References

1. Benjamin E.J., Virani S., Callaway C. et al. Heart disease and stroke statistics–2018 update: a report from the American Heart Association. Circulation. 2018; (137): e67–e492. DOI: https://doi.org/10.1161/CIR.0000000000000558

2. Yancy C.W., Jessup M., Bozkurt B., et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the Management of Heart Failure: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016; (134): e282–e293. DOI: https://doi.org/10.1016/j.cardfail.2016.07.001

3. Kasai-Brunswick T.H., Carvalho A.B., Campos de Carvalho A.C. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells. 2021; 13 (9): 1231–47. DOI: https://doi.org/10.4252/wjsc.v13.i9.1231

4. Fernandes S., Chong J.J.H., Paige S.L., Iwata M., Torok-Storb B., Keller G., Reinecke H., Murry C.E. Comparison of human embryonic stem cell-derived cardiomyocytes, cardiovascular progenitors, and bone marrow mononuclear cells for cardiac repair. Stem Cell Reports. 2015; 10 (5): 753–62. DOI: https://doi.org/10.1016/j.stemcr.2015.09.011

5. Jiang M., Mao J., He B. The effect of bone marrow-derived cells on diastolic function and exercise capacity in patients after acute myocardial infarction. Stem Cell Res. 2012; 9 (1): 49–57. DOI: https://doi.org/10.1016/j.scr.2012.03.001

6. Lee C.Y., Kim R., Ham O., Lee J., Kim P., Lee S., et al. Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases. Stem Cells Int. 2016; 20 (16): 428–593. DOI: https://doi.org/10.1155/2016/4285938

7. Geng Y.J. Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure. Ann N Y Acad Sci. 2003; (1010): 687–97. DOI: https://doi.org/10.1196/annals.1299.126

8. Porrello E.R., Mahmoud A.I., Simpson E., Hill J.A., Richardson J.A., Olson E.N., et al. Transient regenerative potential of the neonatal mouse heart. Science. 2011; (331): 1078–80. DOI: https://doi.org/10.1126/science.1200708

9. Bergmann O., Bhardwaj R.D., Bernard S., Zdunek S., Barnabe-Heider F., Walsh S., et al. Evidence for cardiomyocyte renewal in humans. Science. 2009; (324): 98–102. DOI: https://doi.org/10.1126/science.1164680

10. Behfar A., Crespo-Diaz R., Terzic A., Gersh B.J. Cell therapy for cardiac repair –lessons from clinical trials. Nat Rev Cardiol. 2014; 11: 232–46. DOI: https://doi.org/10.1038/nrcardio.2014.9

11. Beltrami A.P., Barlucchi L., Torella D., Baker M., Limana F., Chimenti S., et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003; (114): 763–76. DOI: https://doi.org/10.1016/s0092-8674(03)00687-1

12. Makkar R.R., Smith R.R., Cheng K., Malliaras K., Thomson L.E., Berman D., et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012; 379: 895–904. DOI: https://doi.org/10.1016/S0140-6736(12)60195-0

13. Mitrečić D., Hribljan V., Jagečić D., Isaković J., Lamberto F., Horánszky A., et al. Regenerative Neurology and Regenerative Cardiology: Shared Hurdles and Achievements. Int J Mol Sci. 2022; 23 (2): 855. DOI: https://doi.org/10.3390/ijms23020855

14. Ieda M., Fu J.D., Delgado-Olguin P., Vedantham V., Hayashi Y., Bruneau B.G. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; (142): 375–86. DOI: https://doi.org/10.1016/j.cell.2010.07.002

15. Orlic D., Kajstura J., Chimenti S., Jakoniuk I., Anderson S.M., Li B., et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410 (6829): 701–5. DOI: https://doi.org/10.1038/35070587

16. Bolli R., Tang X.L., Sanganalmath S.K., Rimoldi O., Mosna F., Abdel-Latif A., et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation. 2013; (128): 122–31. DOI: https://doi.org/10.1161/CIRCULATIONAHA.112.001075

17. Hirsch A., Nijveldt R., van der Vleuten P., Tijssen J., van der Giessen W., Tio R., et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. 2011; (32): 1736–47. DOI: https://doi.org/10.1093/eurheartj/ehq449

18. Dixon J.A., Gorman R.C., Stroud R.E., Bouges S., Hirotsugu H., Gorman 3rd J.H., et al. Mesenchymal cell transplantation and myocardial remodeling after myocardial infarction. Circulation. 2009; 120: S 220–9. DOI: https://doi.org/10.1161/CIRCULATIONAHA.108.842302

19. Hare J.M., Fishman J.E., Gerstenblith G., DiFede Velazquez D.L., Zambrano J.P., Suncion V.Y., et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012; (308): 2369–79. DOI: https://doi.org/10.1001/jama.2012.25321

20. van Berlo J.H., Kanisicak O., Maillet M., Vagnozzi R.J., Karch J., Lin S.C., et al. C-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014; (509): 337– 41. DOI: https://doi.org/10.1038/nature13309

21. Balsam L.B., Wagers A.J., Christensen J.L., Kofidis T., Weissman I.L., Robbins R.C. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004; 428 (6983): 668–73. DOI: https://doi.org/10.1038/nature02460

22. Murry C.E., Soonpaa M.H., Reinecke H., Nakajima H., Nakajima H.O., Rubart M., et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004; 428 (6983): 664–8. DOI: https://doi.org/10.1038/nature02446

23. van Berlo J., Kanisicak O., Maillet M., Vagnozzi R., Karch J., Lin S., et al. C-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014; 509 (7500): 337–41. DOI: https://doi.org/10.1038/nature13309

24. Zhang L., Sultana N., Yan J., Yang F., Chen F., Chepurko E., Yang F.C., Du Q., Zangi L., Xu M., Bu L., Cai C.L. Cardiac Sca-1+ cells are not intrinsic stem cells for myocardial development, renewal, and repair. Circulation. 2018; (138): 2919–30. DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.035200

25. Tallini Y.N., Greene K.S., Craven M., Spealman A., Breitbach M., Smith J., et al. С-kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci U S A. 2009; 106 (6): 1808–13. DOI: https://doi.org/10.1073/pnas.0808920106

26. Zaruba M.M., Soonpaa M., Reuter S., Field L.J. Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation. 2010; 121 (18): 1992–2000. DOI: https://doi.org/10.1161/CIRCULATIONAHA.109.90909

27. Nair N., Gongora E. Stem cell therapy in heart failure: Where do we stand today? Biochim Biophys Acta Mol Basis Dis. 2020; 1866 (4): 165489. DOI: https://doi.org/10.1016/j.bbadis.2019.06.003

28. Siminiak T., Kalawski R., Fiszer D., Jerzykowska O., Rzeźniczak J., Rozwadowska N., Kurpisz M. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J. 2004; (148): 531–7. DOI: https://doi.org/10.1016/j.ahj.2004.03.043

29. Leobon B., Garcin I., Menasche P., et al., Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci USA. 2003; (100): 7808–11. DOI: https://doi.org/10.1073/pnas.1232447100

30. Menasche P., Alfieri O., Janssens S., McKenna W., Reichenspurner H., Trinquart L., Vilquinet J.-T., al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008; (117): 1189–200. DOI: https://doi.org/10.1161/CIRCULATIONAHA.107.734103

31. Brickwedel J., Gulbins H., Reichenspurner H. Long-term follow-up after autologous skeletal myoblast transplantation in ischaemic heart disease. Interact Cardiovasc Thorac Surg. 2014; (18): 61–6. DOI: https://doi.org/10.1093/icvts/ivt434

32. Nso N., Bookani K.R., Enoru S., Radparvar F., Gordon R. The efficacy of bone marrow mononuclear stem cell transplantation in patients with non-ischemic dilated cardiomyopathy – a meta-analysis. Heart Fail Rev. 2021; 27 (3): 8811–820. DOI: https://doi.org/10.1007/s10741-021-10082-0

33. Vrtovec B., Poglajen G., Lezaic L., Sever M., Domanovic D., Cernelc P., et al. Effects of intracoronary CD 34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res. 2013; (112): 165–73. DOI: https://doi.org/10.1161/CIRCRESAHA.112.276519

34. Rai B., Shukla J., Henry T.D., Quesada O. Angiogenic cd34 stem cell therapy in coronary microvascular repair – a systematic review. Cells. 2021; 10 (5): 1137. DOI: https://doi.org/10.3390/cells10051137

35. Henry T.D., Losordo D.W., Traverse J.H., Schatz R.A., Jolicoeur E.M., Schaer G.L., et al. Autologous CD 34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur Heart J. 2018; 39 (23): 2208–216. DOI: https://doi.org/10.1093/eurheartj/ehx764

36. Tongers J., Roncalli J.G., Losordo D.W. Role of endothelial progenitor cells during ischemia-induced vasculogenesis and collateral formation. Microvasc Res. 2010; 79: 200–6. DOI: https://doi.org/10.1016/j.mvr.2010.01.012

37. Roncalli J.G., Tongers J., Renault M.A., Losordo D.W. Endothelial progenitor cells in regenerative medicine and cancer: a decade of research. Trends Biotechnol. 2008; 26 (5): 276–83. DOI: https://doi.org/10.1016/j.tibtech.2008.01.005

38. Yuan Z., Huang W. New Developments in Exosomal lncRNAs in Cardiovascular Diseases. Front Cardiovasc Med. 2021; (8): 70–91. DOI: https://doi.org/10.3389/fcvm.2021.709169

39. Passier R., Van Laake L.W., Mummery C. Stem-cell-based therapy and lessons from the heart. Nature. 2008; (453): 322–9. DOI: https://doi.org/10.1038/nature07040

40. Nussbaum J., Minami E., Laflamme M., Jitka A., Virag C., Ware A., et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 2007; (21): 1345–57. DOI: https://doi.org/10.1096/fj.06-6769com

41. Kawamura M., Miyagawa S., Miki K., Saito A., Fukushima S., Higuchi T., et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation 2012; (126): S 29–37. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.084343

42. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; (126): 663–76. DOI: https://doi.org/10.1016/j.cell.2006.07.024

43. Takahashi K., Tanabe K., Ohnuki M., Narita M., Ichisaka T., Tomoda K., et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; (131): 861–72. DOI: https://doi.org/10.1016/j.cell.2007.11.019

44. Guenther M., Frampton G., Soldner F., et al. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell. 2010; (7): 249–57. DOI: https://doi.org/10.1016/j.stem.2010.06.015

45. Shiba Y., Gomibuchi T., Seto T., Wada Y., Ichimura H., Tanaka Y., et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016; (538): 388–91. DOI: https://doi.org/10.1038/nature19815

46. Tohyama S., Hattori F., Sano M., Hishiki T., Nagahata Y., Matsuura T., et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013; (12): 127–37. DOI: https://doi.org/10.1016/j.stem.2012.09.013

47. Faiella W., Atoui R. Therapeutic use of stem cells for cardiovascular disease. Clin Transl Med. 2016; (5): 34–46. DOI: https://doi.org/10.1186/s40169-016-0116-3

48. Ahmed R.P., Ashraf M., Buccini S., Shujia J., Haider HKh. Cardiac tumorigenic potential of induced pluripotent stem cells in an immunocompetent host with myocardial infarction. Regen Med. 2011; 6 (2): 171–8. DOI: https://doi.org/10.2217/rme.10.103

49. Gong R., Jiang Z., Zagidullin N., Liu T., Cai B. Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration. Signal Transduct Target Ther. 2021; 6 (1): 31. DOI: https://doi.org/10.1038/s41392-020-00413-2

50. Witman N., Zhou C., Grote Beverborg N., Sahara M., Chien K.R. Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration. Semin Cell Dev Biol. 2020; (100): 29–51. DOI: https://doi.org/10.1016/j.semcdb.2019.10.011

51. Chimenti I., Smith R., Li T.S., Gerstenblith G., Messina E., Giacomello A., Marbán E. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010; 106: 971–80. DOI: https://doi.org/10.1161/CIRCRESAHA.109.210682

52. Kawamura M., Miyagawa S., Miki K., Saito A., Fukushima S., Higuchi T., Kawamura T., et al. Feasibility, safety, and therapeutic efficacy of human induced pluripotent stem cell-derived cardiomyocyte sheets in a porcine ischemic cardiomyopathy model. Circulation. 2012; (126): S 29–S 37. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.084343

53. Chong J.J., Yang X., Don C.W., Minami E., Liu Y.W., Weyers J.J., et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature. 2014; 510 (7504): 273–7. DOI: https://doi.org/10.1038/nature13233

54. Ong S.G., Huber B.C., Lee W.H., Kodo K., Ebert A.D., Ma Y., Nguyen P.K., Diecke S., Chen W.Y., Wu J.C. Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes After Acute Myocardial Infarction. Circulation. 2015; 132 (8): 762–71. DOI: https://doi.org/10.1161/CIRCULATIONAHA.114.015231

55. Khan K., Caron C., Mahmoud I., Derish I., Schwertani A., Cecere R. Extracellular vesicles as a cell-free therapy for cardiac repair: a systematic review and meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models. Stem Cell Rev Rep. 2022; 18 (3): 1143–67. DOI: https://doi.org/10.1007/s12015-021-10289-6

56. Tachibana A., Santoso M., Mahmoudi M., Shukla P., Wang L., Bennett M., Yang P. Paracrine effects of the pluripotent stem cell-derived cardiac myocytes salvage the injured myocardium. Circulation Research. 2017; 121 (6): e22. DOI: https://doi.org/10.1161/CIRCRESAHA.117.310803

57. Ibrahim A., Cheng, Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports. 2014; 2 (5): 606–19. DOI: https://doi.org/10.1016/j.stemcr.2014.04.006

58. Zaborowski M., Balaj L., Breakefield X., Lai C. Extracellular vesicles: composition, biological relevance, and methods of study. BioScience. 2015; 65 (8): 783–97. DOI: https://doi.org/10.1093/biosci/biv084

59. Zhang Y., Liu Y., Liu H., Tang W. Exosomes: biogenesis, biologic function and clinical potential. Cell & Bioscience. 2019; 9 (1): 19. DOI: https://doi.org/10.1186/s13578-019-0282-2

60. Vicencio J.M., Yellon D.M., Sivaraman V., Das D., Boi-Doku C., Arjun S., Zheng Y., Riquelme J.A., Kearney J., Sharma V. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol. 2015; (65): 1525–36. DOI: https://doi.org/10.1016/j.jacc.2015.02.026

61. Sahoo S., Mathiyalagan P., Hajjar R.J. Pericardial fluid exosomes: a new material to treat cardiovascular disease. Mol Ther. 2017; (25): 568–69. DOI: https://doi.org/10.1016/j.ymthe.2017.02.002

62. Chakraborty C., Sharma A.R., Sharma G., Lee S.S. Therapeutic advances of miRNAs: A preclinical and clinical update. J Adv Res. 2021; (28): 127–38. DOI: https://doi.org/10.1016/j.jare.2020.08.012

63. Isomi M., Sadahiro T., Ieda M. Progress and Challenge of Cardiac Regeneration to Treat Heart Failure. J Cardiol. 2019; (73): 97–101. DOI: https://doi.org/10.1016/j.jjcc.2018.10.002

64. Wada R., Muraoka N., Inagawa K., Yamakawa H., Miyamoto K., Sadahiro T., et al. Induction of human cardiomyocyte-like cells from fibroblasts by defined factors. Proc Natl Acad Sci U S A. 2013; (110): 12667–72. DOI: https://doi.org/10.1073/pnas.1304053110

65. Cao N., Huang Y., Zheng J., Spencer C.I., Zhang Y., Fu J.D., et al. Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science. 2016; (352): 1216–20. DOI: https://doi.org/10.1126/science.aaf1502

66. Ifkovits J.L., Addis R.C., Epstein J.A., Gearhart J.D. Inhibition of TGFbeta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS ONE. 2014; (9): e89678. DOI: https://doi.org/10.1371/journal.pone.0089678

67. Mohamed T.M., Stone N.R., Berry E.C., Radzinsky E., Huang Y., Pratt K., et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation. 2017; (135): 978–95. DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.024692

68. Zhou Y., Wang L., Vaseghi H.R., Liu Z., Lu R., Alimohamadi S., et al. Bmi1 is a key epigenetic barrier to direct cardiac reprogramming. Cell Stem Cell. 2016; 18: 382–95. DOI: https://doi.org/10.1016/j.stem.2016.02.003

69. Qian L., Huang Y., Spencer C.I., Foley A., Vedantham V., Liu L., et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012; (485): 593–8. DOI: https://doi.org/10.1038/nature11044

70. Jayawardena T.M., Finch E.A., Zhang L., Zhang H., Hodgkinson C., Pratt R.E., et al. MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res. 2015; (116): 418–24. DOI: https://doi.org/10.1161/CIRCRESAHA.116.304510

71. Miyamoto K., Akiyama M., Tamura F., Isomi M., Yamakawa H., Sadahiro T., et al. Direct in vivo reprogramming with Sendai virus vectors improves cardiac function after myocardial infarction. Cell Stem Cell. 2018; (22): 91–103 e5. DOI: https://doi.org/10.1016/j.stem.2017.11.010

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITOR
CHIEF EDITOR
Andrey G. Obrezan
MD, Professor, Head of the Hospital Therapy Department of the Saint Petersburg State University, Chief Physician of SOGAZ MEDICINE Clinical Group, St. Petersburg, Russian Federation

Journals of «GEOTAR-Media»