Dataset Information

Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

ABSTRACT:

Background

The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac human MSCs (hMSCs) remodels and can regulate arrhythmia substrates.

Methods

hMSCs were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or nonfailing hMSCs were cocultured with normal human cardiac myocytes derived from induced pluripotent stem cells. Using fluorescent indicators, action potential duration, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined.

Results

Failing and nonfailing hMSCs from both sources exhibited similar trilineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared with nonfailing hMSCs, failing hMSCs prolonged action potential duration by 24% (P<0.001, n=15), increased Ca2+ alternans by 300% (P<0.001, n=18), and promoted spontaneous calcium release activity (n=14, P<0.013) in human cardiac myocytes derived from induced pluripotent stem cells. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL (interleukin)-1β (98%, P<0.0001) and IL-6 (460%, P<0.02) compared with nonfailing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged action potential duration but only IL-6 increased Ca2+ alternans and promoted spontaneous calcium release activity in human cardiac myocytes derived from induced pluripotent stem cells, replicating the effects of failing hMSCs. In contrast, nonfailing hMSCs prevented Ca2+ alternans in human cardiac myocytes derived from induced pluripotent stem cells during oxidative stress. Finally, nonfailing hMSCs exhibited >25× higher secretion of IGF (insulin-like growth factor)-1 compared with failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs.

Conclusions

We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.

SUBMITTER: Sattayaprasert P

PROVIDER: S-EPMC7578059 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundMesenchymal stem cell (MSC) therapy has emerged as a promising novel therapeutic strategy for managing inflammatory bowel disease (IBD) mainly via dampening inflammation, regulating immune disorders, and promoting mucosal tissue repair. However, in the process, the associated changes in the gut microbiota and the underlying mechanism are not yet clear.MethodsIn the present study, dextran sulfate sodium (DSS) was used to induce colitis in mice. Mice with colitis were treated with intraperitoneal infusions of MSCs from human umbilical cord mesenchymal stem cells (HUMSCs) and evaluated for severity of inflammation including weight reduction, diarrhea, bloody stools, histopathology, and mortality. The proportion of regulatory T cells (Tregs) and immunoglobulin A-positive (IgA+) plasmacytes in gut-associated lymphoid tissue were determined. The intestinal and fecal levels of IgA were tested, and the proportion of IgA-coated bacteria was also determined. Fecal microbiome was analyzed using 16S rRNA gene sequencing analyses.ResultsTreatment with HUMSCs ameliorated the clinical abnormalities and histopathologic severity of acute colitis in mice. Furthermore, the proportion of Tregs in both Peyer's patches and lamina propria of the small intestine was significantly increased. Meanwhile, the proportion of IgA+ plasmacytes was also substantially higher in the MSCs group than that of the DSS group, resulting in elevated intestinal and fecal levels of IgA. The proportion of IgA-coated bacteria was also upregulated in the MSCs group. In addition, the microbiome alterations in mice with colitis were partially restored to resemble those of healthy mice following treatment with HUMSCs.ConclusionsTherapeutically administered HUMSCs ameliorate DSS-induced colitis partially via regulating the Tregs-IgA response, promoting the secretion of IgA, and facilitating further the restoration of intestinal microbiota, which provides a potential therapeutic mechanism for HUMSCs in the treatment of IBD.