Engineering microenvironments to control stem cell fate and function

Abstract

The two definitive characteristics of stem cells, the capacity for proliferation without loss of potency and the ability to differentiate into specialized cell type(s), endow these cells with great promise for the development of cell replacement therapies for degenerative disease and injury. Furthermore, stem cells are increasingly being recognized as versatile systems for developmental biologists to study lineage specification and tissue organization.Understanding the mechanisms that underlie stem cell self-renewal and differentiation is central to realizing this potential, and efforts have increasingly focused on elucidating the signals that regulate cell function in the tissues where they reside, i.e. the endogenous stem cell niche. The governing principle of this niche, first proposed 30 years ago, is that stem cell fate decisions are influenced by cells’ interactions with components of their microenvironment, and these cell extrinsic factors include soluble and immobilized factors, the extracellular matrix, and signals presented by neighboring cells. Thus, recreating or simulating this microenvironment may be critical for properly expanding and controlling the differentiation of stem cells outside the body, for both basic biological study and therapeutic translation.In this chapter we review the biology of stem cell niches, focusing on the mechanisms and “strategies” by which various niche components support stem cell functions, including immobilization of signals to control activity and dosage, progressive specification of cell behavior by a series of sequential signals, complex signaling feedback from adjacent niche cells, and presentation of mechanical cues. We then illustrate how these mechanisms can be translated into design criteria for stem cell engineers to create biomimetic microenvironments that emulate the ability of native niches to precisely control cell function.