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Ischemic heart disease (IHD) causes myocardial infarction (MI), which results in the death and loss of cardiomyocytes (CMs). Apoptosis, necrosis, and autophagy in CMs are the typical hallmarks of cardiac pathology in MI. Recent studies have shown that the combination of cell-based therapy and tissue engineering technology can improve stem cell engraftment and promote the therapeutic effects of the treatment for MI.
- myocardial infarction
- stem cells
1. Types of Progenitor or Stem Cells Used for the Treatment of Myocardial Infarction
Cardiac tissue engineering aims to replace fibrotic scars by creating contractile and functional heart tissues. A wide variety of stem cells, their derivatives, and progenitor cells are currently being tested for these purposes. Stem cells can be divided into two types according to their sources: embryonic stem cells (ESCs) and adult progenitor/stem cells [12]. In terms of their differentiation capabilities, stem cells can be divided into four main types: totipotent stem cells, PSCs, multipotent stem cells, and unipotent stem cells [12]. The major progenitor/stem cells used in the field of cellular cardiomyoplasty are myoblasts [13,14,15], mesenchymal stem cells [16,17,18], ESCs [19,20], and iPSCs [21,22,23]. The advantages and disadvantages of each cell type are summarized in Table 1. Since ESCs and iPSCs can be differentiated into cardiovascular cells, including cardiac progenitor cells (CPCs), CMs, endothelial cells (ECs), and smooth muscle cells (SMCs), these stem cells may be used for cardiac tissue engineering and are being extensively investigated.
Table 1. Advantage and disadvantages of four types of cells used for cellular cardiomyoplasty.
| Cell Types | Advantages | Disadvantages |
|---|---|---|
| Skeletal myoblasts |
|
|
| Mesenchymal stem cells |
|
|
| Embryonic stem cells |
|
|
| Induced pluripotent stem cells |
|
|
Mouse embryonic stem cells (mESCs) were established by two research teams led by Martin Evans and Matthew Kaufman in 1981 [12]. On the other hand, human ESCs (hESCs) were established by James Thomson in 1998 [12]. Mouse iPSCs (miPSCs) were established by Yamanak in 2006 using octamer binding transcription factor 3/4, sex determining region y-box 2, the cellular-myelocytomatosis viral oncogene, and kruppel-like factor 4 transcription factors from mouse fibroblasts [12]. The following year, Yamanak and James Thomson independently and simultaneously reported the establishment of hiPSCs from human dermal fibroblasts [12]. Generally, miPSCs or hiPSCs are almost identical to their counterpart, mESCs or hESCs.
PSCs are classified into two distinct states: naïve and primed pluripotent states. Naïve PSCs include mESCs and miPSCs, while primed PSCs include mouse epiblast stem cells (mEpiSCs), hESCs, and hiPSCs [24]. Although both naïve and primed PSCs are capable of self-renewal and can differentiate into the three germ layers in vitro and in vivo, only naïve PSCs can generate germline-competent chimeras in vivo [25].
Recent studies demonstrate that hiPSCs are a powerful tool for modeling diseases and treating various human diseases, including cardiovascular diseases, degenerative neuronal diseases, and diabetes, due to their unique advantage (Table 1). Like hESCs, hiPSCs have self-renewal capabilities and differentiate into all somatic cells found in the body regardless of their tissue of origin. hiSPCs are therefore being extensively explored to develop functional tissues for the treatment of myocardial injury.
2. Application of Tissue Engineering in PSC Reprogramming, Differentiation, and Treatment of Myocardial Infarction
Biomaterial scaffolds, which mimic the natural extracellular matrix (ECM) environment, have been extensively investigated for the engineering of cardiac tissues for PSC reprogramming, differentiation, and treatment of MI.
2.1. Tissue Engineering for the Regulation of PSC Reprogramming
Some biomaterials have been shown to improve reprogramming efficiency by changing epigenetic barriers. Downing et al. showed that the microgroove substrates increased the reprogramming efficiency of fibroblasts into iPSCs [26]. Notably, micro-grooved surfaces increased histone H3 acetylation and methylation, overcoming epigenetic barriers in reprogramming [26]. A study using tumor-initiating stem-like cells showed that a matrix made of fibrin gel promoted H3K9 demethylation and Sox2 expression [27], both of which are known to be involved in iPSC reprogramming [28,29].
An engineering technique, such as the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is sought as a preferred method for the reprogramming and genetic modification of PSCs [30,31]. CRISPR/Cas9-based gene activator (CRISPRa), which has a high multiplexing capacity and direct targeting of endogenous loci, has also been used for cellular reprogramming [32]. Weltner et al. showed that using CRISPRa reduces the reprogramming efficiency of human dermal fibroblasts [32]. Moreover, Howden et al. developed a protocol that combined the CRISPR/Cas9 system and the enhanced episomal-based reprogramming to simultaneously generate gene-edited and passage-matched unmodified iPSC lines through the electroporation of human fibroblasts [33]. Compared to human fibroblasts, erythroblasts are later found to be a better cell candidate for simultaneous reprogramming and gene-editing using CRISPR/Cas9 [34]. These studies suggest that CRISPR/Cas9 technique may be a better option for iPSC reprogramming and gene editing.
2.2. Tissue Engineering for the Differentiation of PSCs into Cardiovascular Cells
Recent advances in tissue engineering allow for the designing of cellular structures or the incorporation of molecules to control the mechanical force and the release of certain factors that affect the differentiation of PSCs. Poh et al. developed a method to generate germ layers from a single line of mESCs [35]. In this study, an embryoid colony formed from a single mESC in 3D matrix, which was then cultured in 1 kPa collagen-1-coated 2D substrates. This resulted in the self-organization of the ectoderm, mesoderm, and endoderm layers in vitro.
When hiPSC-ECs were cultured in peptide-functionalized poly(ethylene glycol) (PEG) hydrogels, polygonal vascular networks were formed [38]. Vascular networks with lumens were stable for at least 14 days. A microcarrier (MC) suspension agitated platform has been shown to differentiate hESCs and hiPSCs into CMs [39]. Agitation results in homogenous and hydrodynamic shear stress, therefore inducing CM differentiation. The resulting yield is 38.3% and 39.3% higher for Troponin T and myosin heavy chain, respectively, than static culture control. Electrospun polylactide-glycolic acid/collagen (PLGA/Col) scaffolds have been used to differentiate ESCs to CMs [40]. Better interaction and growth of differentiated ESCs were observed on the PLGA/Col scaffolds relative to PLGA-only scaffolds. On the other hand, a cryopreserved amniotic membrane has been shown to direct the differentiation of hiPSC-derived cardiac progenitor cells to CMs in the presence of cytokines [41]. Amniotic membranes increased the expression of cardiac transcription factors and myofibril proteins, accelerated the intracellular calcium transients, and enhanced the mitochondrial complexity formation in CMs. These studies suggest that some biomaterials can be designed to provide PSCs with essential mechanical and chemical cues to direct their differentiation.
2.3. Tissue Engineering Using PSC-Derived Cardiovascular Cells for the Treatment of MI
It has been established that poor cell engraftment rate is one of the primary factors limiting the effectiveness of cell transfer therapy for cardiac repair. The low engraftment rate can be improved by combining the technique with cardiac tissue engineering, in which cells are transplanted within a supporting matrix [8]. Biomaterials can provide mechanical support for the stem cells and supply nutrients and oxygen to encapsulated cells [9,10,41,42].
Cardiac tissue engineering combines cells and biological scaffolds to make heart grafts to replace the damaged heart tissue and restore or improve the heart structure and function. In addition to cellular cardiomyoplasty, heart valve reconstruction, and vessel graft manufacturing are also the main target areas of heart tissue engineering.
Common tissue engineering materials are made of either natural or synthetic biomaterials. Natural biomaterials include Matrigel [42,43,44], hyaluronic acid [45,46], gelatin [47,48,49], chitosan [50,51], alginate [52,53,54], collagen [42,55,56,57,58,59], fibrin [21,22,23,55,60,61,62,63], elastin [64], amniotic membrane [41], and spider silk proteins [65]. Synthetic biomaterials, on the other hand, include poly(ethylene glycol) (PEG) [66,67], polylactide-glycolic acid (PLGA) [68,69], polyacrylamide (PAA) [70], poly(N-isopropylacrylamide) (PNIPAAm) [71], polycaprolactone (PCL) [72], and polyurethane (PU) [73]. More recently, natural/synthetic hybrid hydrogels are being developed as an alternative biomaterial that combines natural and synthetic materials through covalent grafting or crosslinking [74,75].
2.3. 3D Printing in Cardiac Tissue Engineering Using PSC Derived Cardiovascular Cells
In recent years, the rapid development of 3D printing technology enabled the construction of hydrogels and myocardial patches into highly precise and repeatable nanoscale 3D structures using multiple cell types. Biomaterials that are used for the 3D printing of myocardial tissue include alginate [93,94], fibrin [94], collagen [95,96], gelatin [97,98,99], hyaluronic acid [98], hydroxypropyl chitin [100], thixotropic magnesium phosphate [101], gellan gum [99], and decellularized ECM scaffolds [102,103,104]. Maiullari et al. manufactured a vascularized heart tissue using human umbilical vein endothelial cell (HUVEC) and miPSC-CMs using alginate and PEG/fibrin hydrogel extruded through a microfluidic printing head [94]. This study successfully generated a functional patch made of miPSC-CMs that aligned along the fiber printing direction. Furthermore, it was also observed that a pre-formed vasculature in 3D heart tissue has the potential to anastomose with the host’s vessels rapidly to supply blood to the implanted sample [94].
Lee et al. described a 3D printing technique to build complex collagen scaffolds for engineering vessels, contractile cardiac ventricle models, trileaflet heart valves, and even neonatal-scale human hearts [95]. Collagen gelation was controlled by modulating the pH and the printing resolution (up to 10 μm). With this technique, cells were successfully embedded in the collagen scaffolds. This is the first study to demonstrate successful 3D printing of a neonatal-sized heart with validated functions.
This entry is adapted from the peer-reviewed paper 10.3390/jcdd8110153
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