Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 232

Gerecht et al. [ 34 ] were the first to demonstrate the generation of human
embryoid bodies (hEBs) directly from hESC suspensions within 3D porous algi-
nate scaffolds. The confining environments of the alginate scaffold pores enabled
efficient formation of hEBs with a relatively high degree of cell proliferation and
differentiation; encouraged round, small-sized hEBs; and induced vasculogenesis
in the forming hEBs to a greater extent than the conventional EB formation
investigated in cell suspensions in static or in rotating cultures [ 33 ]. In another
study, Gerecht et al. [ 34 ] used hydrogels of hyaluronic acid (HA), a constituent of
the ECM present during early stages of embryogenesis, to develop a synthetic
microenvironment that maintained hESCs in their undifferentiated state, preserved
their normal karyotype, and maintained their full differentiation capacity as indi-
cated by embryoid body formation.
Since the pluripotent stem cell microenvironment has no definitive aspect, most
of the research in the field is still focused on the design of adult stem cell microen-
vironments, subsequently applying the principal elements of these microenviron-
ments to pluripotent stem cell research as well.
2 Microenvironmental Soluble Factors
2.1 Natural Factors
Soluble factors and cytokines were the first microenvironmental elements shown
to be essential for the support of stem cell proliferation, differentiation and survival
of distinct cell populations [ 35 ]. Due to their ease of manipulation in culture, most
of the pioneer studies on stem cell expansion and differentiation used secreted
factors as the principal induction factors. Thus, soluble factors are the best-char-
acterized environmental signals impacting stem cell behavior. The factors exert
their effect through activation of specific signaling pathways. In some cases, the
role of the factors is mainly in specifying stem cell self-renewal and mediating cell
survival, as Wnt proteins function in the HSC BM niche [ 5 ]. In other cases, the
secreted factors play an instructive role in cell differentiation [ 19 , 36 - 39 ]. It should
be noticed that one factor may have an effect on a variety of signaling pathways,
and the eventual cellular response is context-dependent. For example, the bone
morphogenetic protein (BMP) signaling pathway as well as Wnt/beta-catenin
signaling were shown to be essential for ESC self-renewal [ 40 , 41 ]. However,
various BMP proteins are also useful for chondrogenic and osteogenic differen-
tiation of MSCs [ 19 , 36 , 37 , 42 , 43 ]. Specifically, the BMPs are known to activate
the osteo-inductive Smad1/5/8 pathway. In our study, BMP 2 and 4 were shown
for the first time to also activate the Janus-activated kinase (JAK)-STAT pathway
in human MSCs (hMSCs). The activated STAT3 pathway in turn was shown to
negatively modulate hMSC osteogenic differentiation (Fig. 3 ).