Human Endomyocardial Biopsy Specimen-Derived Stromal Cells Modulate Angiotensin II-Induced Cardiac Remodeling

Abstract

Cardiac-derived adherent proliferating cells (CardAPs) are cells derived from human endomyocardial biopsy specimens; they share several properties with mesenchymal stromal cells. The aims of this study were to evaluate whether intramyocardial injection of CardAPs modulates cardiac fibrosis and hypertrophy in a mouse model of angiotensin II (Ang II)-induced systolic heart failure and to analyze underlying mechanisms. Intramyocardial application of 200,000 CardAPs improved left ventricular function. This was paralleled by a decline in left ventricular remodeling, as indicated by a reduction in cardiac fibrosis and hypertrophy. CardAPs reduced the ratio of the left ventricle to body weight and cardiac myosin expression (heavy chain), and decreased the Ang II-induced phosphorylation state of the cardiomyocyte hypertrophy mediators Akt, extracellular-signal regulated kinase (ERK) 1, and ERK2. In accordance with the antifibrotic and antihypertrophic effects of CardAPs shown in vivo, CardAP supplementation with cardiac fibroblasts decreased the Ang II-induced reactive oxygen species production, a-SMA expression, fibroblast proliferation, and collagen production. Coculture of CardAPs with HL-1 cardiomyocytes downregulated the Ang II-induced expression of myosin in HL-1. All antifibrotic and antihypertrophic features of CardAPs were mediated in a nitric oxide-and interleukin (IL)-10-dependent manner. Moreover, CardAPs induced a systemic immunomodulation, as indicated by a decrease in the activity of splenic mononuclear cells and an increase in splenic CD4CD25FoxP3, CD4-IL-10, and CD8-IL-10 T-regulatory cells in Ang II mice. Concomitantly, splenocytes from Ang II CardAPs mice induced less collagen in fibroblasts compared with splenocytes from Ang II mice. We conclude that CardAPs improve Ang II-induced cardiac remodeling involving antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1707-1718 SIGNIFICANCEDespite effective pharmacological treatment with angiotensin II type I receptor antagonists or angiotensin II-converting enzyme inhibitors, morbidity and mortality associated with heart failure are still substantial, prompting the search of novel therapeutic strategies. There is accumulating evidence supporting the use of cell therapy for cardiac repair. This study demonstrates that cells derived from human endomyocardial biopsies, cardiac-derived adherent proliferating cells (CardAPs), have the potential to reduce angiotensin II-induced cardiac remodeling and improve left ventricular function in angiotensin II mice. The mechanism involves antifibrotic and antihypertrophic effects via paracrine actions and immunomodulatory properties. These findings support the potential of CardAPs for the treatment of heart failure.

The atrial appendage as a suitable source to generate cardiac‐derived adherent proliferating cells for regenerative cell‐based therapies

“…Taking these findings together, CD90 low atrial appendage‐derived cells express a variety of pro‐angiogenic genes, as do CardAP cells, which have been previously shown in vivo to be cardioprotective (Miteva et al, ).…”

“…CardAP cells have cardioprotective potential, meaning they are pro‐angiogenic (Dehne et al, ; Haag, Ritterhoff et al, ) as well as anti‐fibrotic and anti‐hypertrophic (Miteva et al, ). They show low immunogenicity, reduce the level of inflammatory cytokines, and have immunomodulatory properties (Haag, Stolk, et al, ; Miteva, Haag, Peng, et al, ; Miteva & Tschope, ).…”

“…They show low immunogenicity, reduce the level of inflammatory cytokines, and have immunomodulatory properties (Haag, Stolk, et al, ; Miteva, Haag, Peng, et al, ; Miteva & Tschope, ). They have been studied in different animal models (Miteva et al, ; Miteva et al, ) and will be tested in a phase I/II study on patients with dilated cardiomyopathy (DCM) who will be treated in an autologous manner.…”

Low‐intensity Pulsed Ultrasound Ameliorates Angiotension Ii-induced Cardiac Fibrosisbyalleviating Inflammation via a Caveolin-1-dependent Pathway

“…The continuous accumulation of α-SMA-expressing myo broblasts may result in excessive deposition and remodeling of the ECM ( [43]). Additionally, injury to left ventricular structure and function and activation of fetal genes including ANP, BNP, α-MHC, and β-MHC are observed in cardiac hypertrophy and are crucial pathological changes during the progression of cardiac remodeling ( [44]).…”

Telbivudine in chronic lymphocytic myocarditis and human parvovirus B19 transcriptional activity

“…For the measurement of (DiO+) Annexin V+/7AAD-, α-smooth muscle actin+/VE-cadherin-, sarcomeric myosin heavy chain, and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein diacetate, acety ester (CM-H 2 DCFDA) + cells, cells were stained with the appropriate antibodies and/or dyes and measured as described in detail previously. [29][30][31] Samples were analysed on a MACSQuant Analyser (Miltenyi Biotec, Bergisch Gladbach, Germany). Re-analysis of flow cytometry data was performed using FlowJo software version 8.8.6.…”