Human Endomyocardial Biopsy Specimen-Derived Stromal Cells Modulate Angiotensin II-Induced Cardiac Remodeling
Kapka Miteva1, Sophie Van Linthout2,3,4, Kathleen Pappritz1
1Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Berlin, Germany.
Insights
Cardiac-derived adherent proliferating cells (CardAPs) improve heart failure by reducing cardiac fibrosis and hypertrophy. These cells also modulate the immune system, offering a novel therapeutic approach for heart conditions.
Area of Science:
- Regenerative Medicine
- Cardiovascular Biology
- Cell Therapy
Background:
- Heart failure remains a significant clinical challenge despite current treatments.
- Novel therapeutic strategies, including cell therapy, are being explored for cardiac repair.
- Cardiac-derived adherent proliferating cells (CardAPs) share properties with mesenchymal stromal cells.
Purpose of the Study:
- To evaluate if intramyocardial injection of CardAPs can mitigate cardiac fibrosis and hypertrophy in a mouse model of angiotensin II-induced systolic heart failure.
- To investigate the underlying mechanisms by which CardAPs exert their effects.
- To assess the immunomodulatory properties of CardAPs in this model.
Main Methods:
- Intramyocardial injection of CardAPs into angiotensin II-infused mice.
- Assessment of left ventricular function, cardiac fibrosis, and hypertrophy.
- Analysis of molecular mediators of hypertrophy and fibrosis (e.g., Akt, ERK, α-SMA, collagen).
- In vitro co-culture experiments with cardiac fibroblasts and cardiomyocytes.
- Evaluation of systemic immunomodulation through analysis of splenic immune cells and their functions.
Main Results:
- Intramyocardial CardAP administration improved left ventricular function and reduced cardiac remodeling, including fibrosis and hypertrophy.
- CardAPs decreased cardiac myosin expression and phosphorylation of Akt, ERK1, and ERK2.
- In vitro, CardAPs reduced reactive oxygen species production, α-SMA expression, fibroblast proliferation, and collagen production.
- CardAPs induced systemic immunomodulation, increasing regulatory T-cell populations and decreasing splenic mononuclear cell activity.
- CardAP effects were dependent on nitric oxide and interleukin-10.
Conclusions:
- CardAPs demonstrate significant antifibrotic and antihypertrophic effects in a mouse model of heart failure.
- The therapeutic benefits of CardAPs are mediated through paracrine actions and immunomodulatory properties.
- CardAPs hold promise as a potential cell-based therapy for treating heart failure.
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, α-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.
Significance:
Despite 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.
