Publications

Cardiac tissues are difficult to regenerate due to the low proliferative capacity of cardiomyocytes. A new therapeutic strategy for cardiac regenerative medicine could include a device capable of ensuring cell grafting, stimulating cardiac tissue regeneration, and serving as an appropriate scaffold for the controlled and sustained release of lactate over time as an inducer of cardiomyocyte proliferation. An effective source of lactate could consist of the lactic acid polymer (PLA) itself, which generates free lactic acid during its degradation. In this work, we have developed a nanocomposite hydrogel for lactate release based on a biocompatible and biodegradable matrix formed by elastin-like recombinamers cross-linked via click chemistry. Polylactic acid particles were encapsulated in the matrix after these particles had been partially degraded to lactic acid through oxygen plasma treatment. In the first 48 h, an early and modulated release of free lactic acid from plasma-treated PLA degradation is observed, and over longer periods, a sustained release of lactic acid produced by the hydrolytic degradation of PLA under physiological conditions occurs. Lactate is available from the very beginning ("early release"), addressing the drawback of the slow degradation (by hydrolysis) of polylactic acid. Therefore, a biomedical device has been designed and implemented, formed by an ELR polymeric matrix as an analogue of cardiac tissue, acting as a device for early, controlled, and sustained lactate release, with dosing at concentrations similar to those previously studied as suitable for promoting cardiomyocyte proliferation, showing promise for its use in the regeneration of infarcted cardiac tissue.

JTD Keywords: Biomaterials, Bone morphogenetic protein-10, Early and sustained releas, Elastin-like polypeptides, Elastin-like recombinamers, Equation, Hydrogel, Nanocomposite, Peptid, Polylactic acid, Solute release

In situ tissue engineering strategies are a promising approach to activate the endogenous regenerative potential of the cardiac tissue helping the heart to heal itself after an injury. However, the current use of complex reprogramming vectors for the activation of reparative pathways challenges the easy translation of these therapies into the clinic. Here, we evaluated the response of mouse neonatal and human induced pluripotent stem cell-derived cardiomyocytes to the presence of exogenous lactate, thus mimicking the metabolic environment of the fetal heart. An increase in cardiomyocyte cell cycle activity was observed in the presence of lactate, as determined through Ki67 and Aurora-B kinase. Gene expression and RNA-sequencing data revealed that cardiomyocytes incubated with lactate showed upregulation of BMP10, LIN28 or TCIM in tandem with downregulation of GRIK1 or DGKK among others. Lactate also demonstrated a capability to modulate the production of inflammatory cytokines on cardiac fibroblasts, reducing the production of Fas, Fraktalkine or IL-12p40, while stimulating IL-13 and SDF1a. In addition, the generation of a lactate-rich environment improved ex vivo neonatal heart culture, by affecting the contractile activity and sarcomeric structures and inhibiting epicardial cell spreading. Our results also suggested a common link between the effect of lactate and the activation of hypoxia signaling pathways. These findings support a novel use of lactate in cardiac tissue engineering, modulating the metabolic environment of the heart and thus paving the way to the development of lactate-releasing platforms for in situ cardiac regeneration.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

JTD Keywords: cardiac regeneration, cardiac tissue engineering, cell cycle, failure, growth, heart regeneration, induced pluripotent stem cells, ischemia, lactate, metabolic environment, metabolism, mouse, proliferation, repair, Bone morphogenetic protein-10, Cardiac tissue engineering, Cardiomyocytes, Cell cycle, Induced pluripotent stem cells, Lactate, Metabolic environment