Deterministic Encapsulation of Human Cardiac Stem Cells in Variable Composition Nanoporous Gel Cocoons To Enhance Therapeutic Repair of Injured Myocardium

Abstract

Although cocooning explant-derived cardiac stem cells (EDCs) in protective nanoporous gels (NPGs) prior to intramyocardial injection boosts long-term cell retention, the number of EDCs that finally engraft is trivial and unlikely to account for salutary effects on myocardial function and scar size. As such, we investigated the effect of varying the NPG content within capsules to alter the physical properties of cocoons without influencing cocoon dimensions. Increasing NPG concentration enhanced cell migration and viability while improving cell-mediated repair of injured myocardium. Given that the latter occurred with NPG content having no detectable effect on the long-term engraftment of transplanted cells, we found that changing the physical properties of cocoons prompted explant-derived cardiac stem cells to produce greater amounts of cytokines, nanovesicles, and microRNAs that boosted the generation of new blood vessels and new cardiomyocytes. Thus, by altering the physical properties of cocoons by varying NPG content, the paracrine signature of encapsulated cells can be enhanced to promote greater endogenous repair of injured myocardium.

Strategies for controlling egress of therapeutic cells from hydrogel microcapsules

“…Ultralow gelling temperature (UL‐GT) agarose is particularly useful as it allows for a quick (seconds) sol–gel transition at temperatures withstood by cells. Recently, microcapsules of agarose incorporating fibrinogen and fibronectin have been shown to increase the viability of therapeutically delivered mesenchymal stromal cells (Hakimzadeh, Stewart, & Courtman, ; Karoubi, Ormiston, Stewart, & Courtman, ) and cardiac stem cells (Davis & Stewart, ; Kanda et al, ; Mayfield et al, ) in animal models. Combinations of agarose and gelatin have also been exploited for their different phase transition temperatures in an effort to improve cell viability and egress (Mak et al, ; Mak, Magne, Cheung, Atanasova, & Griffith, ).…”

Advanced Functional Biomaterials for Stem Cell Delivery in Regenerative Engineering and Medicine

“…[47b] Single cell encapsulation represents another major technique for cell protection with advantages of higher encapsulation efficiency and permeability of nutrients compared to conventional hydrogel delivery . Kanda et al encapsulated single explant‐derived cardiac stem cells (EDCs) in nanoporous gel (NPG) cocoons consisting of ECM and low melt agarose with an average diameter around 60 µm ( Figure ) . The ECM component provided adhesive sites that protected cells through integrin‐dependent prosurvival signaling.…”

“…C) Echo analysis showing left ventricle ejection fraction ( n = 10−9 mice/cell and saline (vehicle) treated group); * p < 0.05 versus vehicle, † p < 0.05 for 3.5% versus 2% NPG cocooned or suspended EDCs. Reproduced with permission . Copyright 2018, American Chemical Society.…”

Concise Review: Heart-Derived Cell Therapy 2.0: Paracrine Strategies to Increase Therapeutic Repair of Injured Myocardium

“…The right panel summarizes the effect of cocoon density on hierarchical clustering of differentially expressed miRNA. Adapted with permission from Kanda et al . Abbreviations: ADH, adherent EDC; EDC, explant‐derived cell; LCA, left coronary artery; NPG, nanoporous gel.…”

“…However, the number of transplanted cells that finally engraft even using biomaterials is small (~1–2,000) and unlikely to account for the cell‐mediated benefits seen in myocardial function and scar size. As such, we explored the possibility that cell dose has finite effects on treatment outcomes by broadening the paracrine output of individual cells without altering cell retention . This was accomplished by varying the density of an inert nanoporous gel (NPG) cocoon surrounding transplanted cells (Fig.…”