Microenvironment Design for Stem Cell Fate Determination - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 228

1 Introduction
Stem cells possess tremendous clinical potential for use in cell-based therapeutic
strategies, due to their capacity for expansion in culture and differentiation to
specific cell lineages. Stem cells derived from bone marrow have been proven to
be safe for use in human patients and have exhibited promising therapeutic effects
in several diseases. Human embryonic stem cells are currently being investigated
in phase I clinical studies for treating patients after spinal cord injury. Considering
the enormous clinical potential of stem cells, extensive research efforts have been
directed to find methods of better controlling cell fate and differentiation. One
attractive approach involves microenvironmental design for stem cell cultivation.
The stem cell microenvironment can be broadly defined as the collection of all
the surrounding external signals to which stem cells are exposed (Fig. 1 ). This
would include the architectural space, physical engagement of the cell membrane
with tethering molecules on neighboring cells or surfaces, signaling interactions at
the interface of stem cells and other microenvironmental cells, paracrine and
endocrine signals from local or distant sources, neural input and metabolic prod-
ucts of tissue activity [ 1 , 2 ]. The interplay between all these components defines
the complex and interactive microenvironment and determines stem cell fate,
toward self-renewal or lineage-specific differentiation.
Effective replication of the stem cell microenvironment has been hypothesized
to allow stem cells to reach their regenerative potential [ 3 ]. However, it is still a
great challenge to engineer the multi-dimensional environment with the right
context of all cues converging to lead the cells into one specific fate. Moreover,
there is much we do not know about the natural cell microenvironment. Never-
theless, recent studies have demonstrated that artificial microenvironments,
designed by implementing some bio-inspired components of the natural stem cell
niche, are capable of controlling stem cell behavior.
Our goal in this review is to provide an overview of the current state and
knowledge of the design of synthetic microenvironments, aimed to control stem
cell fate determination. Specifically, we will describe the research conducted on
three major components of the microenvironment: (1) the soluble factors (growth
factors, cytokines and chemokines), (2) the insoluble matrix (extracellular matrix
[ECM]) and (3) the mechanical stimuli to which the cells are exposed.
1.1 Stem Cell Types and Their Microenvironments
1.1.1 Bone-Marrow-Derived Stem Cells
The bone marrow (BM) environment, also termed ''niche'', has been studied
since the late 1970s and is the best characterized stem cell microenvironment.