Journal of Stem Cells Research Development & Therapy Category: Medical Type: Short Commentary

Cell Therapy Moving in the Right Direction

Marcos Valadares1*, Rafael Dariolli1,2, Estela Cruvinel1 and Diogo Biagi1

1 Pluricell Biotech, São Paulo 05508-000, Brazil
2 Department Of Pharmacological Sciences, Icahn School Of Medicine At Mount Sinai, New York, NY 10029, United States

*Corresponding Author(s):
Marcos Valadares
Pluricell Biotech, São Paulo 05508-000, Brazil
Email:marcos.valadares@lizar.bio

Received Date: May 28, 2021
Accepted Date: Jun 14, 2021
Published Date: Jun 21, 2021

Introduction

Recently, Biagi et al., 2021 published results of yet another successful demonstration of how hiPSC-derived cardiomyocytes can engraft in rats' hearts and improve their cardiac function [1]. According to the work, these results are probably due to the segmental improvement in areas where the grafts were found. Importantly, paracrine effects observed in previous studies [2] cannot be ruled out, but specific data on radial and circumferential strain support that structural and contractile implications of the graft presence should reliably account for some of the results. 

The publication joins others [3-8] in stating the limitations of the current rat model pointing towards more in depth studies currently being carried out in pigs [9-13] or non-human primates [14-17], two options of more clinically relevant models. However, why should we celebrate and encourage an ever-increasing number of studies in this area? There are many answers to this question, but we will focus on three aspects: i) relevance of the problem, ii) potential of cell-based restorative technology and iii) unidentified critical quality attributes (CQAs) of the proposed cell therapy product and delivery methods. 

First, it is hardly a problem to convince anyone of the burden of cardiovascular disease, Heart Failure (HF) specifically, to humanity as a whole and, more particularly, to the health care system everywhere. There are currently around 26 million patients suffering from the disease [18]. Some more conservative studies predict that HF costs more than 108 billion dollars to the health care system worldwide and roughly 40% of this is only in the US [19]. It’s believed that the UK, arguably the most sophisticated public health care system in the world, spends 2% of its entire health care budget on this single disease [20] and the main cause of hospitalizations in South America are due to HF [21]. It has been a while since any relevant medication has been approved for this patient population and everything approved so far is generally focused on palliative rather than restorative care. 

This leads to our second point: the potential of cell-based restorative technology. Producing or cultivating cells ex-vivo has always been a money-intensive and challenging process. Complexity around protocols and scaling up challenges has hampered previous attempts and aside from hemopoietic stem cell transplantation, cell sourcing has always been a relevant bottleneck. 

However, in the past 15 years, progress in the field such as the advent of induced pluripotent stem cells [22,23], relevant improvements in cultivation systems based on suspension culture bioreactors [24-29], and significant reduction in the cost of media [30] has entirely reshaped the opportunities in the field inviting new possibilities spurring well-founded options to be explored as potentially new curative solutions to decades-old problems. 

Never before in the history of humankind were we able to industrially produce meaningful amounts of cells to treat patients by actually replacing their cells. Now we are. In the beginning, we foresee allogeneic applications being developed, taking advantage of gene-edited universal cells [31-33] profiting from an economy of scale but slowly progressing towards more autologous personalized applications when relevant. 

Finally, for all that promise to be realized, we need to tackle the hard questions related to the CQAs of these newly developed potentially curative cell therapies. From a regulatory standpoint, it is vital to clearly understand what matters in a product to be injected into patients. Due to the novelty of the process, it is improbable that one group or team alone would address all the potentially relevant points. Therefore, when analyzed as a whole, several independent efforts would eventually bear more compelling evidence of the beneficial aspects of the therapy. As for delivery methods, the most straight forward approach would be to do transepicardial delivery of cells in patients undergoing CABG procedure and indeed is being pursued in current clinical trials (NCT03763136). We anticipate a move towards more non-invasive methods of delivery such as the ones based on catheter-like devices. This field will definitely take advantage of technology previously developed for adult stem cell therapies [34] and others still yet to be developed. 

Additionally, large animal studies are notoriously hard and expensive to undertake and therefore, more extensive sets of tests are welcomed specially coming from independent groups. This increases confidence in the field as a whole and establishes benchmarks for future developments. The potential safety problems associated with arrhythmias arising from engrafting large patches of autonomous cells are also being more closely studied [11,14,15,17] and should be the focus of groups developing such technologies as safety remains the number one priority for regulatory agencies when considering IND applications. 

We recognize that these three major points could be extrapolated to several diseases and cell types and not only to HF and hiPSC-derived cardiomyocytes, but this is intentional and speaks to the breath of the ex-vivo cell production technology and its potential applications. 

Finally, we also acknowledge numerous potentially relevant efforts to use cells without the need to replace damaged/non-functional tissue, but solely based on its paracrine effect. Even though this is true, we chose to focus on the potential of cell-replacement therapy as a ground for future technologies aiming to replace entire tissues and organs that will eventually emerge as a possibility.

References

  1. Biagi D, Fantozzi ET, Campos-Oliveira JC, Naghetini MV, Ribeiro Jr AF, et al. (2021) In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats. J Personalized Medicine11: 374.
  2. Jiang X, Yang Z, Dong M (2020) Cardiac repair in a murine model of myocardial infarction with human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Res Ther 11: 297.
  3. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, et al. (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25: 1015-1024.
  4. Laflamme MA, Gold J, Xu C, Hassanipour M, Rosler E, Police S, et al. (2005) Formation of human myocardium in the rat heart from human embryonic stem cells. Am J Pathol 167: 663-671.
  5. Fernandes S, Chong JJH, Paige SL, Iwata M, Torok-Storb B, et al. (2015) Comparison of Human Embryonic Stem Cell-Derived Cardiomyocytes,  Cardiovascular Progenitors, and Bone Marrow Mononuclear Cells for  Cardiac Repair. Stem Cell Reports 5: 753-762.
  6. Caspi O, Huber I, Kehat I, Habib M, Arbel G, et al. (2007) Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol 50: 1884-1893.
  7. Rojas SV, Kensah G, Rotaermel A, Baraki H, Kutschka I, et al. (2017) Transplantation of purified iPSC-derived cardiomyocytes in myocardial infarction. PLoS One 12: e0173222.
  8. Zhao M, Fan C, Ernst PJ, Tang Y, Zhu H, et al. (2018) Y-27632 Preconditioning Enhances Transplantation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Myocardial Infarction Mice. Cardiovasc Res 115: 343-356.
  9. Ye L, Chang Y-H, Xiong Q, Zhang P, Zhang L, et al. (2014) Cardiac Repair in a Porcine Model of Acute Myocardial Infarction with Human Induced Pluripotent Stem Cell-Derived Cardiovascular Cells. Cell Stem Cell 15: 750-761.
  10. Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, et al. (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22: 1282-1289.
  11. Romagnuolo R, Masoudpour H, Porta-Sánchez A, Qiang B, Barry J, et al. (2019) Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate the Infarcted Pig Heart but Induce Ventricular Tachyarrhythmias. Stem Cell Reports 12: 967-981.
  12. Kawaguchi S, Soma Y, Nakajima K, Kanazawa H, Tohyama S, et al. (2021) Intramyocardial Transplantation of Human iPS Cell–Derived Cardiac Spheroids Improves Cardiac Function in Heart Failure Animals. JACC Basic Transl Sci 6: 239-254.
  13. Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri J-R. et al. (2012) Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression. Circulation 126: 430-439.
  14. Chong JJH, Yang X, Don CW, Minami E, Liu Y-W, et al. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510: 273-277.
  15. Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, et al. (2016) Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538: 388-391.
  16. Kawamura T, Miyagawa S, Fukushima S, Maeda A, Kashiyama N, et al. (2016) Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates. Stem Cell Reports 6: 312-320.
  17. Liu Y-W, Chen B, Yang X, Fugate JA, Kalucki FA, et al. (2017) Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol 36: 597-605.
  18. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV, Ponikowski P, et al. (2008) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 10: 933-989.
  19. Cook C, Cole G, Asaria P, Jabbour R, Francis DP (2014) The annual global economic burden of heart failure. Int J Cardiol 171: 368-376.
  20. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, et al. (2002) The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail 4: 361-371.
  21. Bocchi EA (2013) Heart Failure in South America. Curr Cardiol Rev 9: 147-156.
  22. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.
  23. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872.
  24. Fonoudi H, Ansari H, Abbasalizadeh S, Larijani MR, Kiani S, et al. (2015) A Universal and Robust Integrated Platform for the Scalable Production of Human Cardiomyocytes From Pluripotent Stem Cells. Stem Cells Transl Med 4: 1482-1494.
  25. Zweigerdt R, Andree B, Kropp C, Kempf H (2016) Bioreactors for expansion of pluripotent stem cells and their differentiation to cardiac cells. Bioreactors: Design, Operation and Novel Applications, Wiley-VCH Verlag GmbH & Co., Weinheim, Germany.
  26. Kempf H, Kropp C, Olmer R, Martin U, Zweigerdt R (2015) Cardiac differentiation of human pluripotent stem cells in scalable suspension culture. Nature protocols 10: 1345-1361.
  27. Halloin C, Schwanke K, Löbel W, Franke A, Szepes M, et al. (2019) Continuous WNT Control Enables Advanced hPSC Cardiac Processing and Prognostic Surface Marker Identification in Chemically Defined Suspension Culture. Stem Cell Reports 13: 775.
  28. Kempf H, Olmer R, Kropp C, Rückert M, Jara-Avaca M, et al. (2014) Controlling Expansion and Cardiomyogenic Differentiation of Human Pluripotent Stem Cells in Scalable Suspension Culture. Stem Cell Reports 3: 1132–1146.
  29. Chen VC, Ye J, Shukla P, Hua G, Chen D, et al. (2015) Development of a scalable suspension culture for cardiac differentiation from human pluripotent stem cells. Stem Cell Res 15: 365-375.
  30. Kuo H-H, Gao X, DeKeyser J-M, Fetterman KA, Pinheiro EA, et al. (2020) Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture. Stem Cell Rep 14: 256-270.
  31. Gornalusse GGG, Hirata RK, Funk SE, Riolobos L, Lopes VS, et al. (2017) HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol 35: 765-772.
  32. Han X, Wang M, Duan S, Franco PJ, Kenty JH-R, et al. (2019) Generation of hypoimmunogenic human pluripotent stem cells. Proceedings of the National Academy of Sciences 116: 10441-10446.
  33. Deuse T, Hu X, Gravina A, Wang D, Tediashvili G, et al. (2019) Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat Biotechnol  37: 252-258.
  34. Sherman W, Martens TP, Viles-Gonzalez JF, Siminiak T (2006) Catheter-based delivery of cells to the heart. Nat Clin Pract Cardiovasc Med 3: S57–S64.

Citation: Valadares M, Dariolli R, Cruvinel E, Biagi D (2021) Cell Therapy Moving in the Right Direction. J Stem Cell Res Dev Ther 7: 074.

Copyright: © 2021  Marcos Valadares, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

© 2021, Copyrights Herald Scholarly Open Access. All Rights Reserved!