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13.1 Introduction
The stem cell microenvironment (niche) plays a major role in controlling the cellu-
lar fate and therefore any application of these cells in vitro and in vivo. To date,
increasing knowledge of the in vivo niche has improved the engineering of in vitro
systems for stem cells by integrating critical three-dimensional features, such as
specific cellular and extracellular components, tissue responsiveness to stiffness and
blood flow. While some of these aspects are not fully recapitulated in in vitro mod-
els of the stem cell niche and some of these models better recapitulate some aspects
of the in vivo niche versus others depending on their application, this review aims at
describing briefly the latest technologies based on our knowledge of the stem cell
niche and more in details current approaches for its engineering, with a particular
focus on future applications for human disease modeling, including drug discovery
and toxicity high-throughput assays and regenerative medicine.
13.2 Stem Cell Niche In Vivo and In Vitro
Stem cells and their applications generated a great hope for research and medicine
in the past decades. However, their use in humans has been limited by several fac-
tors, including ethical conundrum on stem cell editing (Lanphier et al. 2015 ). From
the engineering point of view, their use is very costly per se and they present limited
survival following their injection in the host tissue, which further increases costs
associated with their use for therapies in humans. To overcome these limitations, 3D
cultures have been investigated based on our knowledge of a highly-defined spatial
and temporal bioavailability of factors during embryogenesis and organogenesis,
such as oxygen, growth factors, cytokines and extracellular matrix (ECM) mole-
cules (please see Fig. 13.1) (Passier et al. 2016 ; Gunter et al. 2016 ; Gentile 2016 ;
Dennis et al. 2015 ). For instance, survival of dissociated stem cells is less than 5%
within the first days of delivery. On the contrary, 3D cultures of stem cells increased
cell survival over time (Dennis et al. 2015 ). Similarly, incorporation of vascular
cells, growth factors and cytokines improved stem cell survival into the host (Gentile
2016 ). Stem cells and progenitor cells also respond to the same stimuli in different
ways based on their origin and differentiation state (Gentile 2016 ). Based on their
intrinsic cell composition, the 3D in vivo niche of pluripotent stem cells (PSCs)
typical of the blastocyst is characterized by cells of the three germ layers (meso-
derm, endoderm and ectoderm), which is recapitulated in vitro within embryoid
bodies (EBs) (Doetschman et al. 1985 ; Itskovitz-Eldor et al. 2000 ; Vallier and
Pedersen 2005 ; Bratt-Leal et al. 2009 ; Carpenedo et al. 2009 ; Lanphier et al. 2015 ).
Conversely, multipotent mesenchymal stem cells (MSCs) are characterized by a
less-defined niche than PSCs, as MSCs are present within the blood stream until
they reach the host tissue to differentiate. However, 3D in vitro cultures of MSCs in
either mesenspheres or fibrin gels show improved features compared to monolayer
cultures (Potapova et al. 2007 ; Murphy et al. 2014a). 3D cultures of neural and
D. Mawad et al.