Recombinant human collagen-based microspheres mitigate cardiac conduction slowing induced by adipose tissue-derived stromal cells

Abstract

BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5±0.4 and 12.6±0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3±1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3±1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1±1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9±1.0 cm/s, p = NS vs. control).ConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.

Human Cardiomyocyte Progenitor Cells in Co-culture with Rat Cardiomyocytes Form a Pro-arrhythmic Substrate: Evidence for Two Different Arrhythmogenic Mechanisms

“…However, paracrine communication between cells is extremely complex and it is certainly possible that pathways initiated by paracrine factors can be influenced by, e.g., different cellular adhesions. Secondly, the secretion of paracrine factors can also be influenced by the paracrine or autocrine response of different cells in the environment (Smit et al, 2017 ). We argue that by using media conditioned by CMPCs we demonstrate that direct paracrine release, without cellular adhesion to different cells, is not pro-arrhythmic, but does not per se exclude any paracrine signaling depending on the level of adhesion in co-cultures.…”

Current development of biodegradable polymeric materials for biomedical applications

“…In response to these limitations, present investigations have directed focus toward recombinant systems that can produce human-based collagen. 35 , 36 Several potentially useful systems already exist for large-scale production and purification of recombinant collagen, such as yeasts, transgenic animals, and, most recently, Escherichia coli . 37 , 38 Because the amino acid sequence of recombinant collagen can be directly modified, it is possible to make controlled, targeted collagen products for specific applications, thereby diversifying and increasing the potential of collagen-based products.…”

Bioresorbable Polymeric Scaffold in Cardiovascular Applications

“…Polymeric biomaterials used in biomedical applications have to fulfil certain specifications such as being non-toxic, having the appropriate biomechanical properties, suitable biocompatibility and hemocompatibility. In the case of biodegradable polymeric biomaterials, additional considerations would have to be in place, such as the relation of mechanical strength to the degradation rate, and also the toxicity and clearance pathway of by-products produced after degradation in the body [12,13]. Given the detrimental implications that may arise due to poor polymeric choice, several important parameters need to be considered in order to determine the most suitable polymer type for use.…”