What distinguishes stem cells from other cell types is the capability to self-renew and differentiate into lineage-specific progenies. These characteristics have made stem cells a promising tool in the fields of regenerative medicine99
and cancer biology.18
However, despite their potential, the translation from laboratory to clinic has been slow.22
One reason is the inability to expand adult stem cells in vitro
while preserving their differentiation capacity, and another is the lack of control over the differentiation of stem cells into desired cell types. To overcome these bottlenecks, it is crucial to understand the biology of stem cells and the molecular mechanisms governing stem cell self-renewal and lineage commitment.
Common stem cell types include embryonic,128
adult, and induced-pluripotent stem cells (iPSCs).125
Adult stem cells have a limited differentiation capacity (multipotent), meaning they are able to form several lineages within a tissue and are organ specific. For instance, the bone marrow houses mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), whereas neural stem cells (NSCs) reside in the subventricular zone and hippocampus.89
In contrast, embryonic stem cells (ESCs) and iPSCs are capable of producing all the cell types of an organism (pluripotent). ESCs are derived from the inner cell mass of the blastocyst of an embryo and iPSCs are generated by the genetic reprogramming of somatic cells into pluripotent stem cells.
It is becoming increasingly appreciated that the stem cell microenvironment, or niche, is responsible for regulating stem cell behavior and homeostasis.43, 94, 95, 117, 132
Indeed, in their niche, stem cells are maintained or can undergo proliferation and differentiation in response to injury, disease, or aging to replenish lost cells or tissue. This homeostatic function is governed by intrinsic (genetic and epigenetic) as well as extrinsic (environmental) biological stimuli. The discovery of the niche and the continual uncovering of its constituents have allowed scientists to study the function of each component by deconstructing the niche into its individual parts.11, 133
Recently, bioengineering methods have been instrumental in tackling biological questions that cannot be answered by conventional cell culture techniques.20, 121
In this regard, engineering principles drawn from materials science to microfabrication have emerged to be useful, not only in the simplification but also the construction of an in vitro
stem cell niche.65
The niche is composed of several constituents that work together to modulate stem cell function (). Inside this microenvironment, stem cells are exposed to a milieu of extracellular matrix (ECM), support or hub cells, and soluble factors. ECM is made up of proteins and polysaccharides that form a cross-linked network and impart structural and mechanical integrity to tissues. However, their role extends beyond acting as scaffolds to providing ligands that interact with cell receptors, such as integrins, to mediate cell adhesion, shape, migration, apoptosis, self-renewal, and differentiation.80
Similarly, support cells interact with stem cells via membrane proteins. Soluble factors, such as cytokines, are another element that control stem cell behavior. Particular examples of such cytokines include wingless-related (Wnts)109
and hedgehog proteins,9
fibroblast growth factors (FGFs),25
and bone morphogenetic proteins (BMPs).143
Metabolic products, such as calcium, are another class of biological cues that affect stem cells. The impact of these biophysico-chemical components on the stem cell phenotype are an important design consideration in engineering the stem cell microenvironment, in vitro
Figure 1 The stem cell microenvironment, or niche. In the niche, stem cells are exposed to ECM, soluble and immobilized molecules (cytokines, metabolic products), support cells, and physical cues (topography, structure, stiffness, static and dynamic forces). Stem (more ...)
In this review article, recent progress in stem cell engineering is highlighted. Specifically, we dissect the stem cell niche into its individual elements including scaffold, biophysical and biochemical factors, and describe how engineering approaches are being applied towards studying these elements. Furthermore, recent technologies that have been used or are promising for the fabrication of complex, tissue-like structures using stem cells are described. We conclude by introducing the role of advanced biomaterials in stem cell-based in vivo therapeutics.