Myocardial Cell Signaling During the Transition to Heart Failure: Cellular Signaling and Therapeutic Approaches.

Cardiovascular disease leading to heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Improved pharmacological and interventional coronary procedures have led to improved outcomes following acute myocardial infarction. This success has translated into an unforeseen increased incidence in HF. This review summarizes the signaling pathways implicated in the transition to HF following cardiac injury. In addition, we provide an update on cell death signaling and discuss recent advances in cardiac fibrosis as an independent event leading to HF. Finally, we discuss cell-based therapies and their possible use to avert the deteriorating nature of HF. © 2019 American Physiological Society. Compr Physiol 9:75-125, 2019.

Modeling the behavior of human induced pluripotent stem cells seeded on melt electrospun scaffolds.

BACKGROUND: Human induced pluripotent stem cells (hiPSCs) can form any tissue found in the body, making them attractive for regenerative medicine applications. Seeding hiPSC aggregates into biomaterial scaffolds can control their differentiation into specific tissue types. Here we develop and analyze a mathematical model of hiPSC aggregate behavior when seeded on melt electrospun scaffolds with defined topography. RESULTS: We used ordinary differential equations to model the different cellular populations (stem, progenitor, differentiated) present in our scaffolds based on experimental results and published literature. Our model successfully captures qualitative features of the cellular dynamics observed experimentally. We determined the optimal parameter sets to maximize specific cellular populations experimentally, showing that a physiologic oxygen level (∼ 5%) increases the number of neural progenitors and differentiated neurons compared to atmospheric oxygen levels (∼ 21%) and a scaffold porosity of ∼ 63% maximizes aggregate size. CONCLUSIONS: Our mathematical model determined the key factors controlling hiPSC behavior on melt electrospun scaffolds, enabling optimization of experimental parameters.

Emerging Biofabrication Strategies for Engineering Complex Tissue Constructs.

The demand for organ transplantation and repair, coupled with a shortage of available donors, poses an urgent clinical need for the development of innovative treatment strategies for long-term repair and regeneration of injured or diseased tissues and organs. Bioengineering organs, by growing patient-derived cells in biomaterial scaffolds in the presence of pertinent physicochemical signals, provides a promising solution to meet this demand. However, recapitulating the structural and cytoarchitectural complexities of native tissues in vitro remains a significant challenge to be addressed. Through tremendous efforts over the past decade, several innovative biofabrication strategies have been developed to overcome these challenges. This review highlights recent work on emerging three-dimensional bioprinting and textile techniques, compares the advantages and shortcomings of these approaches, outlines the use of common biomaterials and advanced hybrid scaffolds, and describes several design considerations including the structural, physical, biological, and economical parameters that are crucial for the fabrication of functional, complex, engineered tissues. Finally, the applications of these biofabrication strategies in neural, skin, connective, and muscle tissue engineering are explored.

Electrospun biomaterial scaffolds with varied topographies for neuronal differentiation of human-induced pluripotent stem cells.

In this study, we investigated the effect of micro and nanoscale scaffold topography on promoting neuronal differentiation of human induced pluripotent stem cells (iPSCs) and directing the resulting neuronal outgrowth in an organized manner. We used melt electrospinning to fabricate poly (ε-caprolactone) (PCL) scaffolds with loop mesh and biaxial aligned microscale topographies. Biaxial aligned microscale scaffolds were further functionalized with retinoic acid releasing PCL nanofibers using solution electrospinning. These scaffolds were then seeded with neural progenitors derived from human iPSCs. We found that smaller diameter loop mesh scaffolds (43.7 ± 3.9 µm) induced higher expression of the neural markers Nestin and Pax6 compared to thicker diameter loop mesh scaffolds (85 ± 4 µm). The loop mesh and biaxial aligned scaffolds guided the neurite outgrowth of human iPSCs along the topographical features with the maximum neurite length of these cells being longer on the biaxial aligned scaffolds. Finally, our novel bimodal scaffolds also supported the neuronal differentiation of human iPSCs as they presented both physical and chemical cues to these cells, encouraging their differentiation. These results give insight into how physical and chemical cues can be used to engineer neural tissue.

Fabrication of poly (ϵ-caprolactone) microfiber scaffolds with varying topography and mechanical properties for stem cell-based tissue engineering applications.

Highly porous poly (ϵ-caprolactone) microfiber scaffolds can be fabricated using electrospinning for tissue engineering applications. Melt electrospinning produces such scaffolds by direct deposition of a polymer melt instead of dissolving the polymer in a solvent as performed during solution electrospinning. The objective of this study was to investigate the significant parameters associated with the melt electrospinning process that influence fiber diameter and scaffold morphology, including processing temperature, collection distance, applied, voltage and nozzle size. The mechanical properties of these microfiber scaffolds varied with microfiber diameter. Additionally, the porosity of scaffolds was determined by combining experimental data with mathematical modeling. To test the cytocompatability of these fibrous scaffolds, we seeded neural progenitors derived from murine R1 embryonic stem cell lines onto these scaffolds, where they could survive, migrate, and differentiate into neurons; demonstrating the potential of these melt electrospun scaffolds for tissue engineering applications.

Controlled release of glial cell line-derived neurotrophic factor from poly(ε-caprolactone) microspheres.

Glial cell line-derived neurotrophic factor (GDNF), a growth factor expressed in the central nervous system, promotes the survival of both dopaminergic and motor neurons, making it a promising candidate for neurodegenerative disease therapy. Although GDNF is currently being evaluated in clinical trials for the treatment of Parkinson's disease (PD), the current delivery method using catheter implantation has certain limitations in terms of delivering GDNF safely and effectively. As a proof of concept, we encapsulated GDNF into poly(ε-caprolactone) (PCL) microspheres to enable controlled drug release for 25 days. First, microspheres were loaded with bovine serum albumin (BSA) to determine the optimal fabrication conditions necessary to achieve the desired release rates of protein. BSA was then used as a carrier protein to preserve GDNF activity during the fabrication process in the presence of organic solvents. GDNF-encapsulated microspheres were created and characterized using scanning electron microscopy. Next, the in vitro release of GDNF along with microsphere morphology was tracked over 25 days. Finally, the bioactivity of the released GDNF was confirmed using PC12 cells. This work demonstrates the potential of such microspheres for the delivery of bioactive GDNF with the end goal of developing a suitable, clinically relevant formulation for injection to appropriate regions of the brain in PD patients.

Biomaterial-based drug delivery systems for the controlled release of neurotrophic factors.

This review highlights recent work on the use of biomaterial-based drug delivery systems to control the release of neurotrophic factors as a potential strategy for the treatment of neurological disorders. Examples of neurotrophic factors include the nerve growth factor, the glial cell line-derived neurotrophic factor, the brain-derived neurotrophic factor and neurotrophin-3. In particular, this review focuses on two methods of drug delivery: affinity-based and reservoir-based systems. We review the advantages and challenges associated with both types of drug delivery system and how these systems can be applied to neurological diseases and disorders. While a limited number of affinity-based delivery systems have been developed for the delivery of neurotrophic factors, we also examine the broad spectrum of reservoir-based delivery systems, including microspheres, electrospun nanofibers, hydrogels and combinations of these systems. Finally, conclusions are drawn about the current state of such drug delivery systems as applied to neural tissue engineering along with some thoughts on the future direction of the field.