Stem cell heart clinical trials

One of the contributors is coronary artery disease in which plaque buildup causes a narrowing of arteries. Heart failure affects approximately 5. There are no therapies to reverse the damage from heart failure, and the long-term prognosis is poor. This study is the culmination of research going back 20 years, beginning with the discovery of the cardiopoiesis process at Mayo Clinic. That research translated into clinical studies engaging multiple trans-Atlantic collaborations charting the development pathway for advanced regenerative therapies.

This is particularly important in MSCs, as they lose some form of efficacy due to ageing[ 2 ]. A different approach to cellular therapy may involve using a combination of different cells to achieve maximal efficacy. The rationale behind combining cell types revolves around being able to activate different regenerative pathways because of the underlying physiologic role of each cell type. This idea was put to the test in various preclinical trials, some displaying very promising results[ 53 ].

Three separate preclinical trials showed that the co-administration of MSCs and CPCs in the treatment of chronic ischemic cardiomyopathy provided improved cardiac outcomes compared to MSCs alone or placebo[ - ].

These outcomes varied between studies but included increased EF, decreased infarct size, improved contractility and increased cell retention compared to MSCs administered alone.

Independently, MSCs are believed to act primarily via paracrine signaling mechanisms: stimulating proliferation and differentiation of endogenous CPCs, as well as pro-angiogenic effects[ ]. Cardiac progenitor cells are believed to have pro-angiogenic capabilities and the potential to promote differentiation of existing cardiac lineages.

However, evidence of their long-term engraftment has been lacking[ ]. Although numerous cell-cell interactions are likely indicated, MSCs are believed to increase the proliferation, differentiation and migration of CPCs via various signaling cascades[ ].

Recently, another combination therapy trial has sprung up on clinicaltrials. In , a novel preclinical trial using a rodent model of MI implanted an epicardial patch contained human iPSC-derived cardiomyocytes in combination with human MSCs and compared it to each respective treatment alone[ 96 ].

Not surprisingly, the combination therapy group showed a greater improvement in EF, fractional shortening, percentage of cardiac fibrosis and capillary density in the border zone. Although regenerative therapies likely still have significant potential to treat chronic cardiomyopathy, there are still several limitations preventing the outpouring of positive clinical outcomes that we have been highly anticipating.

Low cell survival rates, low cellular retention after transplantation and ineffective differentiation of progenitor cells into functional cardiomyocytes are a few of the major problems that have plagued the field thus far[ ]. Recently, tissue engineering and biomaterials have converged with the field of cardiovascular regeneration medicine and this may hold the key to improving cell delivery and retention[ ].

With regards to cardiovascular therapy, tissue engineering can be utilized via two approaches: scaffolds that provide the progenitor cells with appropriate chemical and physical signals to differentiate into the desired cell phenotype, and constructs interlaced with cells or biologically active molecules that co-transplanted into the heart to improve cell retention rates[ ].

Both of these approaches have already been validated in preclinical studies as it was demonstrated that with appropriate physical conditioning, human immature iPSC-derived cardiomyocytes could generate human heart microtissues after culture on a fibrin gel[ ]. Another preclinical trial investigated the IM transplantation of human iPSC-derived cardiomyocytes, smooth muscle cells, endothelial cells and insulin growth factor loaded onto a 3D fibrin patch.

The transplanted cells were able to integrate into the host myocardium, contribute to host vasculature, organize sarcomere structure and most importantly, demonstrated positive clinical outcomes; significantly improving LVEF, reducing infarct size and improving arteriolar density[ 34 ].

Furthermore, a separate study demonstrated that co-transplantation of human iPSC-derived cardiomyocytes in a porcine model produced significantly greater improvement in EF and cell survival rate than a cell-sheet[ ]. To date, there have been very few clinical trials assessing the feasibility of transplanting stem cells on bioengineered constructs for the treatment of HF.

With the early success of tissue engineering in preclinical and clinical trials, further investigation is most certainly warranted for this exciting new field of research.

In an attempt to lower the global burden of HF and other cardiovascular diseases, cell-based therapies are being explored at an unprecedented rate. The use of stem cells in research prompts many of the same historical issues seen before such as patient autonomy, respect, justice, risks and many others[ ].

It also generates novel ethical, political and religious concerns not seen in other types of clinical trials. The central ethical issue arises from the morality of using human ESCs in research. The process of creating a human ESC line involves the extraction of the inner cell mass from the blastocyst at the d stage.

This destroys the embryo, terminating the potential for human life. This dilemma also begs the question; when does human life begin? Some believe that it begins immediately after fertilization of the oocyte. From this perspective, the destruction of an embryo to create an immortal cell line is akin to murder[ ]. Conversely, others believe that human life begins further down the line of development or even at birth. Thus, attempting to appease both sides of the argument is a burdensome endeavour.

In Canada, the Tri-council has implemented a policy statement ensuring various ethical beliefs, values and attitudes are taken into consideration[ ].

Article Researchers are also not allowed to coerce or entice participants to donate more embryos than are deemed necessary for reproductive purposes. In the minds of many, these guidelines ease the ethical burden surrounding the morality of human ESCs. However, some may still feel too strongly about using human ESCs for research purposes. In those cases, the use of alternative stem cell types eliminates concerns regarding the destruction of potential human life. Induced pluripotent stem cells are currently a very attractive alternative as they are derived from adult stem cells and are genetically programmed back to a higher state of potency.

Adult stem cells are also viable options. However, these cells lack the potency of ESCs and have a more limited utility[ ]. Several other concerns should be raised regarding the ethics of stem cell regenerative medicine. The rapid expansion of stem cell therapeutics has not gone unnoticed in the public eye. Stem cell treatments are often being falsely marketed as a cure for various conditions without sufficient evidence of clinical efficacy or safety to back it up.

In many instances, the public is ill-equipped to gauge whether or not treatments offered in some clinics are safe and credible. According to the Center for Disease Control and Prevention, these unregulated clinics can cause more harm than good as many patients have experienced adverse effects following stem cell injections; ranging from pain and inflammation, to secondary bacterial infections, further deteriorating the pre-existing condition[ ].

It is up to physicians to impartially analyze the literature and address the potential risks of these treatments when patients consult them about stem cell tourism[ ]. These laws suggest that critically ill patients in the United States are able to contact and ask to try such unproven therapies. Naturally, there are a lot of ethical arguments over this, yet supporters argue that terminally ill patients should be given a choice to experiment with drugs and therapies which have shown positive results[ ].

Public opinion is fluid with time; thus it is important for governments and regulatory bodies to construct laws and policies that coincide with current public views, at the same time providing an environment where stem cell research can succeed, advance, and keep patients safe. It is without question that severe breaches of scientific integrity were observed in regenerative medicine.

The findings of the Anversa investigations had a devastating impact on cardiac cell therapeutics and discredited the current advancements being made in this field. Enthusiasm and optimism are natural components of research but we must adhere to the most rigorous of standards when conducting research. Positive claims with lack-of supporting evidence cannot be viewed positively when presenting a novel therapeutic approach as it can put the lives of many in danger and promote distrust of the scientific community.

Cardiovascular diseases are the leading cause of death worldwide and mortality rates are steadily increasing[ ]. Over the past two decades, the use of stem cells to treat heart failure has been a promising novel strategy but has met considerable obstacles. Currently, therapeutic strategies rely on treating comorbidities and improving the quality of life for patients, which is why the regenerative capabilities of stem cells have created so much promise for the field. There has recently been a drastic shift from bench to bedside studies as thousands of patients have been enrolled in clinical trials within the last decade.

However, the original excitement surrounding the regenerative potential of stem cells has been dampened by the results of clinical trials that have generally produced only moderately positive or neutral clinical outcomes. This does not imply, however, that the cells have no therapeutic value.

Rather, it may reflect the infancy of clinical trials and the limited knowledge about the optimal cell type, cell dosing, method of delivery, patient parameters or even the endogenous cardiac repair mechanisms. Nonetheless, the lack of significant results has generated skepticism among the scientific community, which is likely due to the tremendous expectations that have been placed on stem cell therapeutics.

The therapeutic use of stem cells to treat HF is still a relatively novel concept and there are a plethora of clinical trials on the horizon. Many important questions still remain. Should we be focusing on techniques that involve activating endogenous repair mechanisms within the heart?

Or should we be focusing on strategies that improve the engraftment of implanted cells? What is the most effective type of cell? What is the ideal dose and route of administration? It currently appears that the field is diverging into two: one involves using 3D bioengineered scaffolds to improve retention rates of transplanted stem cells. The other involves using no cells at all but instead delivering exosomes suspended with proteins, deoxyribonucleic acid, micro ribonucleic acids, and various other growth factors.

These questions will need to be addressed in clinical trials before cellular therapeutics become a staple in clinics. All things considered, this form of therapy may save millions of lives in the future if proven to be safe and effective.

We remain cautiously optimistic that the therapeutic use of stem cells could represent the next generation of treatment for heart failure. The primary author would like to thank the World Journal of Stem Cells for the opportunity and acknowledge the hard work of all supporting authors.

Conflict-of-interest statement: We have no conflicts of interest to declare. Manuscript source: Invited manuscript. Peer-review started: October 30, First decision: November 30, Article in press: March 22, Specialty type: Cardiac and cardiovascular systems. Grade A Excellent : A. Grade B Very good : B, B. Michael BB, Barbados. National Center for Biotechnology Information , U. World J Stem Cells. Published online Apr Author information Article notes Copyright and License information Disclaimer.

Author contributions: Rheault-Henry M, White I, Grover D collected the data and contributed to the writing of the manuscript; Atoui R devised the project, developed the main conceptual ideas and edited the manuscript; all authors revised and approved the final version.

Published by Baishideng Publishing Group Inc. All rights reserved. This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.

Abstract Heart failure continues to be one of the leading causes of morbidity and mortality worldwide. Open in a separate window. Figure 1. Figure 2. Adult stem cells The use of cardiac stem cells CSCs in clinical research showed great promise in the literature until it was discovered that the field was heavily compromised due to Dr. Table 1 Summary of landmark human clinical trials. Cell type Clinical trial Sample size Results Ref. Table 2 Safety parameters of various stem cell types.

Cell type Safety parameters Ref. Cell type At this moment, there is no consensus on the best cell source and type suitable for cardiac regeneration. Dosage The ideal dosage of stem cells to achieve a therapeutic effect has yet to be discovered. Cell retention, engraftment, survival and rejection Cell retention, engraftment and survival rates are one of the most important obstacles to overcome in cardiac stem cell therapy.

Route of administration To date, there is no consensus on the most effective method of delivery, yet it is one of the most important factors in successful stem cell treatment[ 53 ]. Figure 3. Patient characteristics Patient-related comorbidities play a role in the effectiveness of stem cell therapy. Combination therapy A different approach to cellular therapy may involve using a combination of different cells to achieve maximal efficacy.

Ethical issues In an attempt to lower the global burden of HF and other cardiovascular diseases, cell-based therapies are being explored at an unprecedented rate.

Footnotes Conflict-of-interest statement: We have no conflicts of interest to declare. References 1. Nair N, Gongora E. Stem cell therapy in heart failure: Where do we stand today? Congestive heart failure: Diagnosis, pathophysiology, therapy, and implications for respiratory care. Respir Care. Tanai E, Frantz S. Pathophysiology of Heart Failure. Compr Physiol. Heart failure after myocardial infarction in the era of primary percutaneous coronary intervention: Mechanisms, incidence and identification of patients at risk.

World J Cardiol. Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding. Anyanwu A, Treasure T. Prognosis after heart transplantation: transplants alone cannot be the solution for end stage heart failure. Heart failure after myocardial infarction: clinical implications and treatment.

Clin Cardiol. Stem cells: past, present, and future. Stem Cell Res Ther. Glicksman MA. Clin Ther. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Front Cell Dev Biol.

Multipotent Stem Cell and Current Application. Acta Med Iran. Heart regeneration in zebrafish. Comparison between a low dose and high dose of autologous one's own CDpositive cells stem cells delivered via injections into the heart muscle.

Outcome Measures. Secondary Outcome Measures : Effects of intramyocardial injections of autologous CDpositive cells on clinical outcomes. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.

Inclusion Criteria: Subjects 21 to 80 years old inclusive. Subjects who have attempted "best" cardiac medical therapy including long-acting nitrates, maximal use of beta-adrenergic blocking agents, and angiotensin-converting enzyme ACE inhibitors without control of symptoms. Subjects must be identified as non-candidates for conventional revascularization by their referring cardiologist.

All subjects must have a recent coronary angiogram within the last 6 months to document the coronary anatomy and insure the presence of coronary disease that is not amenable to standard revascularization procedures. Successful coronary revascularization procedures within 3 months of study enrollment.

Documented stroke or transient ischemic attack TIA within 60 days of study enrollment. Implantation of biventricular pacemaker within 90 days of study treatment. Severe co-morbidity associated with a reduction in life expectancy of less than 1 year, such as chronic medical illness i.

Contacts and Locations. Heart regeneration via stem cell therapy could improve the functional outcome for millions of patients. A goal of cardiac stem cell research is to foster the engraftment of new, beating cardiac cells into the ischemic region of the heart after a myocardial infarction.

The key elements of cell therapy for myocardial repair reviewed here are the source of cells and the mechanisms by which these cells improve cardiac function.