Developing Thick Cardiac Tissue with a Multilayer Fiber Sheet for Treating Myocardial Infarction

Abstract

Human-induced pluripotent stem cell (hiPSC)-derived cardiac patches have been extensively used for treating myocardial infarction and have shown potential for clinical application. However, the limited patch thickness can hamper its therapeutic effect. We previously developed a fibrous scaffold that allowed the formation of well-organized cardiac tissue constructs. In the present study, based on the above technology, we developed a three-dimensional multilayer fibrous scaffold with dynamic perfusion, on which approximately 20 million hiPSC-derived cardiomyocytes (CMs) could be seeded in a single step and organized into 1 mm thick and viable tissue. The multilayer cardiac tissue demonstrated enhanced contractile properties and upregulated cytokine secretion compared with the control group. Notably, when used on the myocardial infarction model, the multilayer group showed improved functional recovery and less fibrosis. These results indicated that the appropriate hiPSC-CM dose requires careful evaluation in developing clinical therapy. The multilayer cardiac tissue group demonstrated significant improvement than the control group, indicating that higher doses of transplanted cells may have improved therapeutic effects in treating myocardial infarction.

Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction

“…Numerous studies have highlighted the ability of iPSC-CMs to engraft, establish a functional myocardium, and further improve the cardiac function in diverse animal models of MI [ 22 , 32 ]. PLGA is a biodegradable and biocompatible copolymer that has been used in FDA-approved therapeutic devices including several in our previous studies [ 16 , 18 , 19 , 24 , 25 , 33 ]. Our previous studies have demonstrated that constructing and organizing hiPSC-CMs into tissue sheets using PLGA fiber scaffold in vitro could enhance their therapeutic capabilities after transplantation [ 17 , 19 , 34 ].…”

“…Our previous studies have demonstrated that constructing and organizing hiPSC-CMs into tissue sheets using PLGA fiber scaffold in vitro could enhance their therapeutic capabilities after transplantation [ 17 , 19 , 34 ]. Additionally, we attempted to enhance the function of tissue sheets and their therapeutic effects in vivo through several methods, such as physical stimulation [ 20 ], utilization of pharmaceutical agents [ 18 ], and stacking multiple fibers [ 16 ]. However, despite improvements in engraft retention achieved through the above approaches, there are still remaining issues in therapeutic efficacy because of the limited paracrine functions of exogenous hiPSC-CMs [ 16 , 18 , 20 , 35 ].…”

“…The activation map was generated using the local activation time from the single electrodes by calculating the minimum of the raw curve’s first-derivative plot. Linear interpolation between the electrodes was used to calculate the isochronal map using MATLAB (MATLAB, MathWorks, USA) [ 16 ].…”

“…However, the cardiac functional recovery capacity of MSCs is limited owing to severe cell loss, uneven local distribution, and inability to restore the lost contractility necessary for proper electromechanical heart function. Several studies have demonstrated the potential of induced pluripotent stem cell-derived CMs (iPSC-CMs) to engraft and improve the performance of myocardium after MI [ [16] , [17] , [18] , [19] , [20] , [21] ]. Several iPSC-CMs are currently in the clinical trial phase [ 22 ].…”

“…In our previous studies, we have constructed 3D hiPSC-CM tissue sheets and 3D MSC tissue sheets using PLGA fiber scaffold [ 17 , 25 ]. Our tissue sheet technology based on PLGA fiber scaffold exhibits numerous advantages, including well-organized and thick tissue, abundant ECM deposition, enhanced secretion, simple construction methods, excellent operability, and ultimately contributes to MI therapy [ 13 , [16] , [17] , [18] , [19] , [20] , 25 ]. In addition, previous studies have demonstrated that MSCs can reduce the apoptosis, improve the maturation, and inhibit the immune rejection of CM [ [26] , [27] , [28] ].…”