Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles

Q: What is the clinical evidence from this study?

Population: Chronic myocardial infarction (rat model) (n=54). Intervention: Cardiosphere-derived extracellular membrane vesicle (CSp-EMV)-primed dermal fibroblasts or CSp-EMV alone vs. Unprimed rat dermal fibroblasts (2M cells) or vehicle (phosphate-buffered saline). Primary outcome: Left ventricular ejection fraction, scar mass, infarct wall thickness, and vessel density at 4 weeks post-injection (p=≤0.05).

Q: What does this research mean for the field?

Priming dermal fibroblasts with cardiosphere-derived extracellular membrane vesicles renders them therapeutically active, improving cardiac function and vessel density while reducing scar mass in chronic myocardial infarction. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Eleni Tseliou; Joseph Fouad; Heidi Reich; Leandro N. Slipczuk; Geoffrey de Couto; Mark A. Aminzadeh; Ryan Middleton; Jackelyn Valle; Eduardo Marbán

doi:10.1016/j.jacc.2015.05.068

August 1, 2015Journal of the American College of CardiologyOpen Access

Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles

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Key result

CSp-EMV-primed fibroblasts improve LVEF and vessel density while reducing post-MI scar mass.

P≤0.05
n=54

Why the study?

Cardiosphere-derived cells mediate therapeutic regeneration after myocardial infarction through exosomes and possibly other extracellular membrane vesicles (EMVs), motivating an investigation into the effects of cardiosphere-derived EMVs on fibroblasts in vitro and whether priming with these vesicles confers salutary properties on fibroblasts in vivo.

Does priming dermal fibroblasts with cardiosphere-derived extracellular membrane vesicles convert them into therapeutically active cells that improve cardiac function and reduce scar mass in a rat model of chronic myocardial infarction?

Key Points

To investigate the functional effects of cardiosphere-derived extracellular membrane vesicles on fibroblasts in vitro and assess whether vesicle priming confers therapeutic regenerative properties on fibroblasts in vivo.
Extracellular membrane vesicles (175 ± 12 nm, expressing CD63, CD9, and CD81) were isolated from serum-free media conditioned by cardiospheres for 3 days.
Dermal fibroblasts were primed with cardiosphere vesicles for 24 hours to analyze phenotypic markers, secretome alterations, and microRNA profiles.
In a chronic rat myocardial infarction model (1 month post-ligation), animals were randomly assigned to intramyocardial injection of PBS, unprimed fibroblasts, cardiosphere vesicles, or vesicle-primed fibroblasts, followed by functional and histological evaluation 1 month later.
Priming with cardiosphere vesicles suppressed smad2/3, smad4, and snai1, attenuated FSP1 and DDR2, and significantly increased secretion of stromal cell-derived factor 1 and vascular endothelial growth factor.
Conditioned media from primed fibroblasts significantly reduced cardiomyocyte apoptosis under oxidative stress and stimulated tube formation in Matrigel angiogenesis assays.
In vivo, intramyocardial injection of primed fibroblasts or cardiosphere vesicles significantly improved left ventricular ejection fraction, reduced scar mass, increased infarct wall thickness, and enhanced capillary density across infarct, border, and remote zones.

Structured PICO

Does priming dermal fibroblasts with cardiosphere-derived extracellular membrane vesicles convert them into therapeutically active cells that improve cardiac function and reduce scar mass in a rat model of chronic myocardial infarction?

P

Population

54 female Wistar Kyoto rats (5-6 weeks old) with chronic myocardial infarction induced by permanent LAD ligation 4 weeks prior, followed for 4 weeks post-injection.

I

Intervention

Intramyocardial border zone injection at 4 weeks post-MI of either: 1) rat dermal fibroblasts (2M cells) incubated overnight with rat cardiosphere-derived extracellular membrane vesicles (rCSp-EMV) and washed (n=16), or 2) rCSp-EMV derived from 2M cells alone (n=16), monitored for 4 weeks. In vitro: priming of human dermal fibroblasts with hCSp-EMV for 24 hours.

C

Comparator

Intramyocardial border zone injection of unprimed rat dermal fibroblasts (2M cells, n=12) or vehicle control (phosphate-buffered saline [PBS], n=10).

O

Outcome

Functional and structural cardiac recovery at 4 weeks post-injection, assessed by transthoracic echocardiography (left ventricular ejection fraction, end-systolic diameter) and histology (scar mass, infarct wall thickness, capillary and microvessel density).surrogate

Main Result

p-value: p=≤0.05

Priming inert dermal fibroblasts with cardiosphere-derived extracellular membrane vesicles converts them into antifibrotic, antiapoptotic, and angiogenic cells that improve cardiac function and attenuate remodeling in chronic myocardial infarction, revealing a positive-feedback mechanism for amplifying exosome bioactivity.

Limitations

Evaluation of the immunological sequelae of allogeneic and xenogeneic EMVs was beyond the scope of the study.
Precipitation by polyethylene glycol pulls down all EMVs and macromolecules including RNA-protein complexes, so some results might be attributable to larger microvesicles, apoptosomes, or non-EMV entities.
It remains unknown if EMVs or an EMV subgroup suffice to durably reprogram dermal fibroblasts to a fully-distinct cell type.
Evaluation of the immunological sequelae of allogeneic and xenogeneic EMVs was beyond the scope of the present study.
The polyethylene glycol precipitation isolation method pulls down all EMVs as well as macromolecules including RNA-protein complexes, meaning some results might be attributable to larger microvesicles, apoptosomes, or non-EMV entities.
It is unknown whether EMVs or an EMV subgroup (e.g., exosomes) suffice to durably reprogram dermal fibroblasts to a fully-distinct cell type.

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Implication

May support further preclinical testing of vesicle-primed fibroblasts; does not yet inform clinical practice.

Abstract

BACKGROUND Cardiosphere-derived cells (CDCs) mediate therapeutic regeneration in patients after myocardial infarction and are undergoing further clinical testing for cardiomyopathy. The beneficial effects of CDCs are mediated by the secretion of exosomes and possibly other extracellular membrane vesicles (EMV). OBJECTIVES We investigated the effect of cardiosphere-derived EMVs (CSp-EMV) on fibroblasts in vitro and tested whether priming with CSp-EMV could confer salutary properties on fibroblasts in vivo. METHODS CSp-EMVs were isolated from serum-free media conditioned for 3 days by cardiospheres. Dermal fibroblasts were primed with CSp-EMV for 24 h followed by exosomal micro-ribonucleic acid (miRNA) profiling. In vivo, we injected CSp-EMV-primed or -unprimed dermal fibroblasts (or CSp-EMV) in a chronic rat model of myocardial infarction and defined the functional and structural consequences. RESULTS CSp-EMV amplified their own biological signals: exposure of “inert” fibroblasts to CSp-EMV rendered the fibroblasts therapeutic. Intramyocardially-injected CSp-EMV-primed (but not unprimed) fibroblasts increased global pump function and vessel density while reducing scar mass. CSp-EMV priming caused fibroblasts to secrete much higher levels of stromal-cell derived factor 1 and vascular endothelial growth factor, and dramatically changed the microRNA profile of fibroblast-secreted EMVs in vitro. The priming was followed by significant angiogenic and cardioprotective effects. CONCLUSIONS CSp-EMVs alter fibroblast phenotype and secretome in a salutary positive-feedback loop. The phenotypic conversion of inert cells to therapeutically-active cells reveals a novel mechanism for amplification of exosome bioactivity.

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Cite This Study

Tseliou et al. (2015) studied Chronic myocardial infarction (rat model) (n=54). Cardiosphere-derived extracellular membrane vesicle (CSp-EMV)-primed dermal fibroblasts or CSp-EMV alone vs. Unprimed rat dermal fibroblasts (2M cells) or vehicle (phosphate-buffered saline) was evaluated on Left ventricular ejection fraction, scar mass, infarct wall thickness, and vessel density at 4 weeks post-injection (p=≤0.05). Intramyocardially-injected CSp-EMV-primed fibroblasts and CSp-EMV significantly improved ejection fraction and vessel density while reducing scar mass compared to unprimed fibroblasts or vehicle.

synapsesocial.com/papers/6ad9d438c375966509584896 https://doi.org/10.1016/j.jacc.2015.05.068

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Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Fibroblasts Rendered Antifibrotic, Antiapoptotic, and Angiogenic by Priming With Cardiosphere-Derived Extracellular Membrane Vesicles

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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