Deterministic paracrine repair of injured myocardium using microfluidic-based cocooning of heart explant-derived cells

Kanda, Pushpinder; Benavente‐Babace, Ainara; Parent, Sandrine; Michie, Connor; Soucy, Nicholas; Steeves, Alexander J.; Lu, Aizhu; Cober, Nicholas D; Courtman, David W.; Variola, Fabio; Alarcon, Emilio I.; Liang, Wenbin; Stewart, Duncan J.; Godin, Michel; Davis, Darryl R.

doi:10.1016/j.biomaterials.2020.120010

Cited by 21 publications

(37 citation statements)

References 88 publications

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“…The salutary effects of transplanted adult cells are largely mediated by paracrine transfer of bioactive molecules, such as cytokines or EVs. As such, we explored the cytokines and EVs produced by all 3 cell types in hopes of identifying the most effective therapy for COVID-19 lung injury [ 26 , 31 , 32 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…EVs were isolated from conditioned media using differential ultracentrifugation [ 32 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To generate conditioned media for experimentation and to reflect the hypoxic lung milieu, cells were grown in their respective basal media (BM-MSC/HDCs: Nutristem basal media; UC-MSC: DMEM alone) at 1% oxygen for 48 h. EVs were isolated using ultracentrifugation (10,000×g 30 min and 100,000×g 3 h [ 31 , 32 ]. EV content, size, and surface marker expression were analyzed using nanoparticle tracking analysis (NanoSight LM10) and the Exo-Check Exosome Antibody Array (EXORAY200B, Systems Biosciences), respectively.…”

Section: Methodsmentioning

confidence: 99%

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Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury

Vaka

Khan

et al. 2022

Stem Cell Res Ther

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Background Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy. As such, we assessed the impact of inflammatory cytokines on the viability, and paracrine profile (extracellular vesicles) of bone marrow-derived mesenchymal stromal cells, heart-derived cells, and umbilical cord-derived mesenchymal stromal cells. Methods All cell products were manufactured and characterized to established clinical release standards by an accredited clinical cell manufacturing facility. Cytokines and Extracellular vesicles in the cell conditioned media were profiled using proteomic array and nanoparticle tracking analysis. Using a survey of the clinical literature, 6 cytotoxic cytokines implicated in the progression of COVID-19 ARDS. Flow cytometry was employed to determine receptor expression of these 6 cytokines in three cell products. Based on clinical survey and flow cytometry data, a cytokine cocktail that mimics cytokine storm seen in COVID-19 ARDS patients was designed and the impact on cytokine cocktail on viability and paracrine secretory ability of cell products were assessed using cell viability and nanoparticle tracking analysis. Results Flow cytometry revealed the presence of receptors for all cytokines but IL-6, which was subsequently excluded from further experimentation. Despite this widespread expression, exposure of each cell type to individual cytokines at doses tenfold greater than observed clinically or in combination at doses associated with severe ARDS did not alter cell viability or extracellular vesicle character/production in any of the 3 cell products. Conclusions The paracrine production and viability of the three leading cell products under clinical evaluation for the treatment of severe COVID-19 ARDS are not altered by inflammatory mediators implicated in disease progression.

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Section: Resultsmentioning

confidence: 99%

“…EVs were isolated from conditioned media using differential ultracentrifugation [ 32 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury

Vaka

Khan

et al. 2022

Stem Cell Res Ther

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“…Microfluidic cocooning has several advantages over vortex cocooning, such as limited consumption of biomaterials, precise cocoon size and cell number, extremely limited shear stresses on cells during cocooning, high individual unit throughput, etc. [182]. Another key benefit of the microfluidic system is the ability to pattern cell and extracellular matrix (ECM) at the cell length scale.…”

Section: Application Of Microfluidics In MI Researchmentioning

confidence: 99%

Recent Advances in Cardiac Tissue Engineering for the Management of Myocardium Infarction

Sharma

Dash

Govarthanan

et al. 2021

Cells

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Myocardium Infarction (MI) is one of the foremost cardiovascular diseases (CVDs) causing death worldwide, and its case numbers are expected to continuously increase in the coming years. Pharmacological interventions have not been at the forefront in ameliorating MI-related morbidity and mortality. Stem cell-based tissue engineering approaches have been extensively explored for their regenerative potential in the infarcted myocardium. Recent studies on microfluidic devices employing stem cells under laboratory set-up have revealed meticulous events pertaining to the pathophysiology of MI occurring at the infarcted site. This discovery also underpins the appropriate conditions in the niche for differentiating stem cells into mature cardiomyocyte-like cells and leads to engineering of the scaffold via mimicking of native cardiac physiological conditions. However, the mode of stem cell-loaded engineered scaffolds delivered to the site of infarction is still a challenging mission, and yet to be translated to the clinical setting. In this review, we have elucidated the various strategies developed using a hydrogel-based system both as encapsulated stem cells and as biocompatible patches loaded with cells and applied at the site of infarction.

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“…Increasing the long‐term retention of transplanted cells using biomaterials does not necessarily improve treatment outcomes. Previously, we have shown that encapsulation of heart‐derived cells within protective hydrogel cocoons prior to intramyocardial injection increases acute and long‐term engraftment 91‐93 . Akin to many biomaterial studies, increased cell retention was associated with salutary effects on myocardial function and scar size.…”

Section: Introductionmentioning

confidence: 95%

State-Of-Play for Cellular Therapies in Cardiac Repair and Regeneration

Vaka

Davis

2021

Stem Cells

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Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the “state-of-play” of cellular therapies for cardiac repair and regeneration. We outline the progression of new ideas from the preclinical literature to ongoing clinical trials. Recent data supporting the mechanics and mechanisms of myogenic and paracrine therapies are evaluated in the context of long-term cardiac engraftment. This discussion informs on promising new approaches to indicate future avenues for the field.

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Deterministic paracrine repair of injured myocardium using microfluidic-based cocooning of heart explant-derived cells

Cited by 21 publications

References 88 publications

Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury

Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury

Recent Advances in Cardiac Tissue Engineering for the Management of Myocardium Infarction

State-Of-Play for Cellular Therapies in Cardiac Repair and Regeneration

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