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.