Cell-Free Treatments: A New Generation of Targeted Therapies for Treatment of Ischemic Heart Disease

Document Type : Review Article


1 School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

2 Faculty of Medicine, Graduate School of Health Science, Near East University, Nicosia, Northern Cyprus, Cyprus

3 Private Baskent Hospital, Nicosia, Northern Cyprus, Cyprus

4 Paediatric Ward, Department of Allergy and Immunology, Near East University Affiliated Hospital, Nicosia, Northern Cyprus, Cypru

5 Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran

6 Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Ira

7 Cancer Gene Therapy Research Centre, Zanjan University of Medical Sciences, Zanjan, Iran

8 Immunotherapy Research and Technology Group, Zanjan University of Medical Sciences, Zanjan, Iran


Although recent progress in medicine has substantially reduced cardiovascular diseases (CVDs)-related
mortalities, current therapeutics have failed miserably to be beneficial for all patients with CVDs. A wide array of
evidence suggests that newly-introduced cell-free treatments (CFT) have more reliable results in the improvement
of cardiac function. The main regeneration activity of CFT protocols is based on bypassing cells and using paracrine
factors. In this article, we aim to compare various stem cell secretomes, a part of a CFT strategy, to generalize their
effective clinical outcomes for patients with CVDs. Data for this review article were collected from 70 published articles
(original, review, randomized clinical trials (RCTs), and case reports/series studies done on human and animals)
obtained from Cochrane, Science Direct, PubMed, Scopus, Elsevier, and Google Scholar) from 2015 to April 2020
using six keywords. Full-text/full-length articles, abstract, section of book, chapter, and conference papers in English
language were included. Studies with irrelevant/insufficient/data, or undefined practical methods were excluded. CFT
approaches involved in growth factors (GFs); gene-based therapies; microRNAs (miRNAs); extracellular vesicles (EVs)
[exosomes (EXs) and microvesicles (MVs)]; and conditioned media (CM). EXs and CM have shown more remarkable
results than stem cell therapy (SCT). GF-based therapies have useful results as well as side effects like pathologic
angiogenesis side effect. Cell source, cell′s aging and CM affect secretomes. Genetic manipulation of stem cells
can change the secretome’s components. Growing progression to end stage heart failure (HF), propounds CFT as
an advantageous method with practical and clinical values for replacement of injured myocardium, and induction of
neovascularization. To elucidate the secrets behind amplifying the expansion rate of cells, increasing life-expectancy,
and improving quality of life (QOL) for patients with ischemic heart diseases (IHDs), collaboration among cell biologist,
basic medical scientists, and cardiologists is highly recommended.