Introduction
Stem cells are defined as having the capacity for self-renewal and the potential to generate multiple types of differentiated cells. These two qualities provide a fantastic foundation for stem cells to benefit the field of regenerative medicine. In the early days of stem cell biology, researchers were challenged by ethical issues and also by limited access and the low number of embryonic stem cells (ESCs) available (Volarevic et al., 2018). This difficulty was overcome with the generation of induced pluripotent stem cells (iPSCs) (Takahashi et al., 2007; Takahashi & Yamanaka, 2006). iPSCs possess the ability to be derived from easily accessible cells, allowing their collection in big numbers while avoiding ethical concerns associated with ESCs (Takahashi et al., 2007; Takahashi & Yamanaka, 2006). Other limitations of stem cell efficacy have arisen that must be addressed to tap the full potential of these cells. iPSC differentiation to target cell types can be a laborious process that takes weeks or months depending on the cell type. Once the differentiation process is complete, the produced cells often have a low efficiency of complete differentiation and a limited resemblance to their natural counterparts (Cahan et al., 2014; Tabar & Studer, 2014). Although there are many contributors to the differentiation result of iPSCs, the microenvironment of the cells is an important player in the successful outcome of differentiation. Media-derived factors, primarily cytokines, as well as the specific material on which the cells grow, impact the success of maturation. Biomaterials act as a beneficial growth platform for cells and may help in the differentiation of iPSCs (Dawson, Mapili, Erickson, Taqvi, & Roy, 2008). Biomaterials are compounds that interact with biological systems, thus impacting the growth and health of cells around them. A combination of ideal media and proper growth platform is an exciting prospect to increase the similarity between iPSC derived cells and theirin vivo counterparts.
Biomaterials have been used for targeted differentiation to generate a variety of cell types. For example, human adipose-derived adult stem cells grown on biomaterials like alginate, agarose hydrogels, and porous gelatin scaffolds can effectively be differentiated towards chondrocytes (Awad, Wickham, Leddy, Gimble, & Guilak, 2004). Moreover, it was indicated in 2011 that thiolated-hyaluronic acid (HA) hydrogels crosslinked with polyethylene glycol diacrylate appeared to mimicin vivo tissue stiffness and resulted in the generation of more mature cardiomyocytes than previous matrices used (Young & Engler, 2011). This finding highlights the role of biomaterials as factors to improve the quality of differentiation in generating more mature cells (Young & Engler, 2011). Another example was highlighted in 2009 in which Smith and colleagues indicated that the use of nanofibrous gelatin/apatite can simulate the normal bone extracellular matrix (ECM) and subsequently increase the differentiation efficiency of stem cells towards an osteogenic fate (Smith, Liu, Hu, Wang, & Ma, 2009). Since these initial examples confirmed biomaterials to be important contributors to proper stem cell differentiation, a wide range of biomaterials have been used for a variety of cell types. These include polystyrene, graphene, nano-structured hydroxyapatite (HAp), fibrin, poly-lactic-co-glycolicacid (PLGA), and self-gelling alginate, used to generate neuronal stem cells, astrocytes, adipocytes, osteoblasts, cardiomyocytes, and chondrocytes (Bagheri-Hosseinabadi, Mesbah-Namin, Salehinejad, & Seyedi, 2018; Jakobsen, Ostrup, Zhang, Mikkelsen, & Brinchmann, 2014; Jeon et al., 2016; Leong et al., 2016; N. Li et al., 2013; Tay et al., 2010). Despite extensive studies using biomaterials to direct stem cells towards a specific fate, the most effective biomaterial for each circumstance remains unknown. Additionally, many of the mechanisms of effectiveness remain to be elucidated, making it difficult to logically progress from one biomaterial to another.
Although the specific effect of different biomaterials on cellular development may be unclear, it is evident that particular biomaterials have a significant impact on the proper differentiation of cells. The choice of biomaterial induces complex biological changes in cells, namely at the transcriptomic level, that will ultimately affect cell fate. The advent of high throughput transcriptomic technologies like microarray, bulk RNA-sequencing (RNA-seq), and single cell RNA-seq (scRNA-seq) allows us to understand these complex cellular changes. Several groups have applied high throughput transcriptomic data analysis to assess the effect of biomaterials on stem cells (Jaager, Islam, Zajac, Linnarsson, & Neuman, 2012; Kim et al., 2016; Q. Li et al., 2018; Roson-Burgo, Sanchez-Guijo, Del Canizo, & De Las Rivas, 2014; Yeung et al., 2015). Knight and colleagues found that culturing a human astrocytic cell line on the hydrogel PuraMatrix™ can induce neuronal transformation of cultured cells, as evidenced by a functional shift of these cells towards neurons (Knight & Serrano, 2017). Also, in 2011, the effect of two different long-term degradable materials, PLLA-co-TMC (Resomer® LT706) and poly-ε-caprolactone, on the differentiation of mesenchymal stem cells (MSCs) toward osteogenic fate was assessed (Neuss et al., 2011). The results showed that Resomer® LT706 is the more potent biomaterial in inducing osteogenic fate through increasing the expression of genes involved in bone development, resulting in MSC derived cells that share a greater similarity with endogenous cells (Neuss et al., 2011). Despite the availability of sophisticated transcriptomic technologies, bioinformatics, and systems biology tools, the field of stem cells and biomaterials is not well connected. As detailed above, many groups have used high throughput techniques to analyze stem cell and biomaterial interaction. That being said, these analyses generally skim the surface of stem cell differentiation effectiveness. The use of bioinformatics and systems biology tools to look at interactions of gene regulatory networks, key biological processes, and transcription factors implicated in differentiation processes will provide a deeper understanding of both stem cells and of biomaterials.
In this study, we investigated the interaction between different biomaterials and stem cells, as well as the differentiation potential of stem cells derived from a particular cell of origin. Both questions were addressed using high throughput transcriptomic data analysis and application of systems biology tools. Overall, we showed that the type of the biomaterial used, and the origin of stem cells are both key contributors to the successful differentiation process of stem cells by affecting the transcriptome. We hope that this study emphasizes the importance of biomaterial and cell-of-origin selection to optimize stem cell differentiation. These types of analyses highlight the importance of integrating the fields of biomaterials and stem cells through the use of bioinformatics analysis.