Efficacy and Mode of Action of Mesenchymal Stem Cells in Non-Ischemic Dilated Cardiomyopathy: A Systematic Review

Abstract

Non-ischemic dilated cardiomyopathy (NIDCM) constitutes one of the most common causes to non-ischemic heart failure. Despite treatment, the disease often progresses, causing severe morbidity and mortality, making novel treatment strategies necessary. Due to the regenerative actions of mesenchymal stem cells (MSCs), they have been proposed as a treatment for NIDCM. This systematic review aims to evaluate efficacy and mode of action (MoA) of MSC-based therapies in NIDCM. A systematic literature search was conducted in Medline (Pubmed) and Embase. A total of 27 studies were included (3 clinical trials and 24 preclinical studies). MSCs from different tissues and routes of delivery were reported, with bone marrow-derived MSCs and direct intramyocardial injections being the most frequent. All included clinical trials and 22 preclinical trials reported an improvement in cardiac function following MSC treatment. Furthermore, preclinical studies demonstrated alterations in tissue structure, gene, and protein expression patterns, primarily related to fibrosis and angiogenesis. Consequently, MSC treatment can improve cardiac function in NIDCM patients. The MoA underlying this effect involves anti-fibrosis, angiogenesis, immunomodulation, and anti-apoptosis, though these processes seem to be interdependent. These encouraging results calls for larger confirmatory clinical studies, as well as preclinical studies utilizing unbiased investigation of the potential MoA.

Keywords: dilated cardiomyopathy; mesenchymal stem cells; mode of action; regeneration.

Figure 1

PRISMA flow chart illustrating the inclusion process of literature. PubMed and Embase were used for identification of existing literature.

Figure 2

Overview of LVEF values for each preclinical study providing numerical endpoint LVEF values. The preclinical studies not reporting on this are not included in the figure. The y-axis is presented with reference number. Additionally, r is repeated injections, s single injection, a AT-MSCs and b BM-MSCs. Data from both MSC and control croup is presented as LVEF mean with standard deviations.

Figure 3

Illustrates the number of studies that have investigated specific regenerative tissue processes, and potential underlying molecular mechanisms.

Figure 4

Timeline illustrating functional and molecular outcomes investigated in the included studies. Five studies investigated molecular outcomes within the first four weeks after treatment, whereas the remaining investigated at one-month post treatment or later. Gene expression in italics, asterisk (*) depicts dual protein and gene expression, ↑ represents and upregulation and ↓ a downregulation. Abbreviations; Brain natriuretic peptide (BNP), Leukocyte inhibitory factor (LIF), Granulocyte- macrophage colony-stimulating factor (GM-CSF), Insulin-like growth factor-1 (IGF-1), Collagen Type III Alpha 1 Chain (Col3a1), C-reactive protein (CRP).

Figure 5

The PPI network. Red are proteins involved in blood vessel development, purple ECM organization, green regulation of immune system processes and yellow apoptosis. Red interaction lines illustrate inhibition, green activation, pink post-translational modification, blue binding, purple catalysis, yellow transcriptional regulation, and black reaction. Abbreviations; Transcription factor GATA-4 (GATA4), Brain natriuretic peptide (NPPB), Growth Associated Protein 43 (GAP43), Cholineacetyltransferase (CHAT), Synaptophysin (SYN), Leukocyte inhibitory factor (LIF), Granulocyte-macrophage colony-stimulating factor (CSF2), Insulin-like growth factor-1 (IGF-1), Troponin T (TNNT2), Collagen Type III Alpha 1 Chain (Col3a1), Collagen Type 1 Alpha 1 Chain (Col1a1), Endothelial NOS (NOS3), C-reactive protein (CRP), Caspase 3 (CASP3), Desmin (Des).